Tmp66e2 TMP

! "#
$
!
%

"%%& !
"
'
( )

%
*

(

)

#

+

)
)
'
"

(

!

" #
$ !% ! & $
' ' ($
' # % % ) % * %
' $ '
+ " % &
' !#
$,
( $

- .

!
"- (
%

.
%
% % % $
$$ -
-

- -
// $$$
0
1"1"#23."

4&)*5/ +)

* !6!& 7!8%779:9& % ) 2
; !
* &

/- <:=9>4&)*5/ +)
"3 " & :=9>
Expertise Pharmacology
Dr. Md Rezaul Karim

MBBS, MD Neurology (Thesis)
Fellow Member of American College of Physicians
Resident Physician, Dapartment of Neurology
Taihe Hospital of Hubei University of Medicine
Hubei Province, P. R. China
Dedicated
To
My Mother
W
Preface
Pharmacology is one of the most difficult and at the same time most important
subject for Medical students as well as in various post-graduate medical
entrance examinations.
In this book, I have tried to make pharmacology as easy and informate as
possible. It covers all the chapters with important and specific informations.
This book is suitable for all students those are studying medical as well as to
doctors who are currently in clinical practice and preparing for post graduate
medical entrance examinations. Acronyms where given within the content
where it is needed within the chapters.
Whereever it was nessasary given the definations before the content, so that
students can easily review in a short period of time. In some chapters diagram
was attached from various sources to make it easy and also some desease
information was given as well, before starting about specific drug, so that
students and health professional will be able to understand the correlation
between the clinical practice and study.
All the chapters in this book have been updated to include recently introduced
drugs and published informations as well as latest therapeutic guidelines from
leading professional bodies. This book has been standerdised by showing step
wise description of drugs.
Thanks are due to my dear one who always inspired me and believed in me. I
would like to express my gratitude to my beloved parents for their support and
encouragement throughout my life.
Hubei Province, P. R. China
February, 2015
Dr. Md Rezaul Karim

dr_mdrezaulkarim@yahoo.com
W
Quick Index
CHAPTER 1: General Principle
i.
ii.
iii.
iv.
v.
Introduction
Routes of Administration and Dosages
Pharmacodynamics and Pharmacokinetics
Adverse Drug Reaction
Drugs during Pregnancy and Lactation
6
9
16
29
32
CHAPTER 2: Anti-Microbial Drugs

i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
Anti-Bacterial drugs
a. Sulfonamides, Quinolones, Co-trimoxazole
b. Beta-Lactam (Penicillin, Cephalosporin & Other drugs)
c. Broad Spectrum (Tetracycline & Chloramphenicol)
d. Amino glycosides
e. Macrolides & Urinary Antiseptics
Anti-Tubular drugs
Anti-Leprotic drugs
Anti-Fungal drugs
Anti-Viral drugs
Anti-Malarial drugs
Anti-Amoebic drugs
Leishmaniasis, Giardiasis, Tripanosomiasis
Anti-Helminthic drugs
34
34
43
58
63
68
73
81
85
94
106
116
120
128
CHAPTER 3: Respiratory Drugs

i.
ii.
Treatment of Cough
Bronchial Asthma
134
138
CHAPTER 4: Circulatory System Drugs

i.
ii.
iii.
Anemia & Erythropoietin

Coagulation, Bleeding & Thrombosis
Hypolipidaemic drugs
145
152
161
CHAPTER 5: Cardiovascular Drugs

i.
ii.
iii.
iv.
Drugs for Heart Failure

Anti-Arrhythmic drugs
Anti-Anginal & Anti-Ischemic drugs
Anti-Hypertensive drugs
166
174
186
192
W
CHAPTER 6: Gastro-Intestinal drugs

i.
ii.
iii.
Peptic Ulcer
Digestive disorders
Constipation & Diarrhea
208
213
216
CHAPTER 7: Urinary System drugs

i.
ii.
Diuretics
Anti-Diuretics
219
229
CHAPTER 8: Anti-Cancer Drugs
230
CHAPTER 9: Nervous System Drugs

Section A: Central Nervous System Drugs
i.
ii.
iii.
iv.
v.
vi.
General Anesthetic Agents

Anti-Epileptic drugs
Anti-3DUNLQVRQVGUXJV
Sedatives, Hypnotics
Anti-Psychotic drugs
Anti-Depressant drugs
236
244
250
255
258
264
Section B: Peripheral Nervous System (Somatic & ANS) Drugs

i.
ii.
iii.
iv.
v.
Local Anesthetic Agents

Cholinergic drugs
Anti-Cholinergic drugs
Sympathomimetic Agents
Sympatholytic Drugs
270
273
275
278
281
CHAPTER 10: Autacoids, Hormones & Miscellaneous Drugs

i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
Histamines & Anti-Histamines

Drug Therapy of Migraine
Prostaglandins
NSAIDS
Anti-Rheumatoid drugs
Anti-Gouts drugs
Insulin
Oral Hypoglycemic drugs
Corticosteroids
Immunosuppressant
284
286
287
288
296
298
301
303
307
308
Abbreviations
311
Bibliography
315
W
&+$37(5*(1(5$/35,1&,3/(
(i)
Introduction
Pharmacology (Greek: Pharmacon-drugs; Logos-discourse in) is the science that deals

with drugs. It consist detailed study of drugs, particularly their actions on living system.
Two main divisions:(a) Pharmacodynamics
(b) Pharmacokinetics
Pharmacodynamics (Greek: Dynamics-power) :KDWWKHGUXJGRHVWRWKHERG\It is

the quantitative study of the biological and therapeutic effects of drugs and their
mechanism of actions at molecular/sub-cellular/organ system levels.
E.g. Cardiac glycosides combine irreversibly with Na-K ATPase pump
Inhibition of Na-K pump activity
Increase Na ions concentrations intra-cellularly
Greater Ca ions infuse into cell
Strong systolic concentration of Myocardium
Pharmacokinetics (Greek; Kinesis-movement) :KDWWKHERG\GRHVWRWKHGUXJ. It is

defined as the movement of the drug in and alteration of the drug by the body. It describes
the study of absorption, distribution, metabolism and excretion of drugs and their
relationship to pharmacological response.
Drug (French-Drogue: a dry herb)

WHO definition of drug: A drug is any substance or product that is used or is intended
to be used to modify or explore physiological system or pathological states for the benefit
of the recipient.
W
Drug nomenclature: A drug has 3 names:(i)

Chemical Name: It is the name which indicates drugs chemical structure.
E.g. 4-aminodophenol
(ii)
Generic/Official/Non-Proprietary Name: It is the name accepted by a competent
scientific body/authority.
E.g. paracetamol (acetaminophen)
(iii)
Trade/Brand/Proprietary Name: Name given to drug by manufacturers, also
known as commercial name.
E.g. panadol, fevadol
Dosage forms of drugs: The forms of the drug by which it is administered:(i)

Liquid
(ii)
Solid
(iii)
Semisolid
Sources of drugs
(i)
Animals:- Hormones, Enzymes E.g. Insulin, Heparin
(ii)
Plants E.g.
R Atropine: Atropa belladona
R Morphine: Papava sominiferum
R Digitalis: Foxglove
R Aspirin
R Quinine
(iii)
(iv)
(v)
Inorganic E.g. Li, Ca, Mg, K, etc.

Chemical synthesis: Most of the drugs are recombinant.
Microorganisms: E.g. penicillin
Some important terminologies

Pharmacotherapeutics
It is the application of pharmacological information together with knowledge of disease
for its prevention, mitigation or cure.
Chemotherapy
It is the treatment of systemic infection or malignancy with the effects of drugs upon
microorganisms, parasites living and multiplying in a living organism without or minimal
effects on the host cells.
W
Clinical pharmacology
It comprises all aspects of scientific study of drugs in man. Clinical pharmacology
provides the scientific basis for:R General aspects of rational, safe and effective drug therapy.
R Drug therapy of individual disease.
R Introduction of new medicines.
Toxicology
It is the study of poisonous effects of drugs and other chemicals with emphasis on
detection, prevention and treatment of poisonings.
Pharmacy
It is the art and science of compounding and dispensing drugs or preparing suitable doses
forms for administration of drugs in man or animals. It includes collection, identification,
purification, isolation, synthesis, standardization and quality control of medical
substances.
Pharmaceuticals
Large scale manufactures of drug is called pharmaceuticals.
Dose
It is an appropriate amount of drug needed to produce a certain degree of response in a
patient.
Poison
It is a substance which endangers life by severely affecting one or more vital functions.
Materia medica
It is a branch of pharmacology concerned with sources, description, and preparation of
drugs.
Pharmacopoeia
It is an official code containing a selected list of the established drugs and medicinal
preparations with description of their physical properties and tests for their identity, purity
and potency.
E.g. British Pharmacopoeia
W
&+$37(5*(1(5$/35,1&,3/(
(ii)
Routes of Drug Administration and Dosages
Routes of Drug Administration

Factors which are governing choice of route:(i)
Physical and Chemical properties of drugs.
- Solid, Liquid, Gas
- Solubility, Stability, P
- Irritancy
(ii)
Site of desired action.

- Localized or Generalized
(iii)
Rate and extent of absorption of drugs from different route.
(iv)
Effect of digestive juice and first pass metabolism on the drug.
(v)
Rapidity with which the response is desired.

- Routine treatment or emergency
(vi)
Accuracy of dosage required.

- IV and Inhalation can provide fine tuning
(vii)
Condition of the patient.

- Unconsciousness
- Repeated vomiting
Classification of routes of drug administration

A. Enteral routes
R Oral
R Sublingual
R Rectal
B. Parenteral routes
R Intravascular (I.V.)
R Intramuscular (I.M.)
R Subcutaneous (S.C.)
W
C. Others routes
R Inhalation
R Intradermal
R Intranasal
R Topical
R Intrathecal
R Intraventricular
R Intraperitoneal
Figure: 1.2.1 - Routes of Drug Administer
Enteral routes
Oral route
Oral ingestion is the oldest and commonest method. Solid dosages form (Powder,
Tublets, Capsules) and Liquid dosages form (Syrups, Mixture). Some drugs are absorbed
in stomach, however duodenum is the major site of the entry to the systemic circulation
because of its large absorptive area.
Advantages
a. Convenient (i.e. easy to administer) and cheaper.
b. Easy to handle, take and store.
c. Easy to treat in case of toxicity - do stomach levage.
d. No need for patient to be hospitalized (Patients can take drug on their own).
Disadvantages
a. Needs a co-operative patient.
b. Not suitable for irritable drugs.
c. Absorption is not complete (stomach juice, 1st - pass effect).
d. Less bioavailability and delayed affect.
e. Not suitable for infants and unconscious patients.
Sublingual route
Placement under the tongue allows the drug to diffuse to the capillary network and enter
the systemic circulation.
Advantages
a. By passing intestine and the liver for the 1st - pass metabolism gets 100%
bioavailability.
b. Rapid onset of the action.
c. In case of desired effect or side effect drug can be spit.
W
Disadvantage
Inconvenient to patients. E.g. Nitroglycerine, Clonidine.
Rectal route
Irritant and the unpleasant drugs are used from this route.
Advantages
a. Used for those patient having recurrent vomiting.
b. Bypass liver.
Disadvantages
a. Inconvenient to patient and lot embarrassing.
b. Delayed and the unpredictable absorption.
c. Rectal inflammation can results from irritable drugs.
Parenteral routes
This refers to the administration by injection which takes the drugs directly into the tissue
fluid or blood without crossing the intestinal mucosa.
Advantages
a. Faster and the onset of the action - valuable in the emergency.
b. Gastric irritation, vomiting is not provoked.
c. Can be administering to unconscious, uncooperative and the vomiting patients.
d. No change or interference with the digestive system and bypassed liver.
Disadvantages
a. The preparation has to be sterilized.
b. Invasive, painful and assistance of another person is needed.
c. Chances of the injury to tissue.
d. Expensive.
Intravascular (I.V.)
Used only in water soluble drugs which will not crystallize. E.g. Gentamycine.
Advantages
a. Fast onset of action and can calculated the accurate dose.
b. Very useful for irritant drugs - dissolves in blood.
c. Large volume can be injected without any 1st - pass effect
W
Disadvantages
a. Difficult to treat toxicity and for self medication.
b. Not appropriate for precipitates and lipid soluble drugs.
c. Needs septic media and may need hospital care.
Intramuscular (I.M.)
Drug which administered by injection into skeletal muscle. E.g. Deltoid, Gluteus
maximus, Rectus femoris etc. The rate of absorption is is uniform and the onset of action
is rapid. Volume should not exceed 10 ml of injection.
Advantages
a. Suitable for oil soluble drugs and can be used a big volume but not as large as
intravascular.
b. Faster then oral and easier then intravascular.
c. Used for drugs that cannot be given orally.
Disadvantages
a. Not useful for irritant drugs.
b. Blood flow rate affects rate of absorption.
Subcutaneous (S.C.)
Drug which administered by injection in the loose subcutaneous tissue which is richly
VXSSOLHGE\WKHQHUYHVEXWOHVVYDVFXODUVRLUULWDQWGUXJVFDQWEHDGPLQLVWHUHG
Advantages
a. Faster than oral and easier than intravascular.
b. No 1st - pass effect.
Disadvantages
a. Not useful for irritant drugs.
b. Blood flow rate affects rate of absorption.
E.g. Insulin
Special form of subcutaneous route
a. Dermojet
b. Pellete implantation
c. Sialistic implants
W
Other routes
Inhalation
Inhalation provides the rapid delivery of the drugs across the large surface area of the
mucous membrane of the respiratory tract and the pulmonary epithelium producing and
effect almost as rapid as by intravenous injection. Used for localized diseases such as
asthma - (bronchodilator), drugs that are gases (anesthetics).
Advantages
a. Controlled administration is possible and action is very rapid.
b. Particularly effective and convenient for the patients with respiratory complain.
c. Systemic side effects are minimized.
Disadvantages
a. Irritation to mucous membrane.
b. Increased secretion in the respiratory tract.
Intra-dermal Injection
Used for vaccination and hypersensitivity tests.
Intranasal
To mucous membrane of the nose can rapidly absorb many drugs; digestive juice and
liver are bypassed.
Topical
These routes are applicable for localized lesions at accessible sites. Systemic absorption
of the drug is minimal or absent.
1. Skin drugs which are applied as ointment, cream, lotion, paste, powder, dressing,
spray.
2. Mucous membrane
a) Mouth and the pharynx lozenges, mouth washes, gargles.
b) Eye, Ear, Noses drops, ointment.
c) Bronchi and the lungs inhalations, aerosols.
d) Vagina pesseries, vaginal tablets, cream.
e) Anal canals ointments, suppository.
Disadvantage and advantage
a. Local irritation.
b. Systemic effect depends on blood flow rate.
W
Intrathecal
Administered into spinal cord in subarachnoid space to treat localized diseases in Central
Nervous System. E.g. Meningitis.
a. For drugs that cannot penetrate the blood brain barrier (BBB).
b. Increased hazard and need specialized staff.
Intra-ventricular
Intra-peritoneal
a. Increased size of absorption.
b. If the drug is not absorbed, it needs to be taken out.
c. Needs hospitalization.
Intra-arterial
a. Can send the drug to the exact site we want.
b. Needs a specialized person to administer it.
c. Increased hazard.
Dosages
Standard dose
Same dose is appropriate for most of patients. E.g. oral contraceptives, penicillins etc.
Regulated dose
The dose is accurately adjusted by repeated measurement of the affected physiological
parameters. E.g. anti-hypertensives, hypoglycemics etc.
Target level dose
An empirical dose aimed at attaining the target is given in the beginning and adjusted are
made later by actual monitoring of plasma concentrations. E.g. anti-depressants, antiepileptics etc.
Titrated dose:
TKHGRVHQHHGHGWRSURGXFHPD[LPXPWKHUDSHXWLFHIIHFWFDQWEHJLYHQEHFDXVHRI
intolerable adverse effects. Optimal dose is arrived at by titrating it with an acceptable
level of adverse effect. E.g. anti-cancer drugs.
W
Dose calculation
Based on body weight
Body weight
Individual dose =
X Average adult dose
70
Based on body surface area
Body surface area (Sq. m)
Individual dose =
X Average adult dose
1.7
Child dose calculation
Age
Child dose =
Age + 12
X adult dose
<RXQJVIRUPXOD
Age
Child dose =
X adult dose
20
'LOLQJVIRUPXOD
Weight of child in lbs
Child dose =
X adult dose
150
W
&+$37(5*(1(5$/35,1&,3/(
(iii)
Pharmacodynamics and Pharmacokinetics
Pharmacodynamics
:KDWWKHGUXJGRHVWRWKHERG\
It is the quantitative study of biological and therapeutic effects of drugs and their
mechanism of action at macro-molecular or sub-cellular or organ system levels.
Basic principles of drug action
1. Stimulation
It is the selective enhancement of the level of activity of specialized cells. E.g.
Adrenaline stimulates heart.
2. Depression
It is selective diminution of activity of specialized cells. E.g. Barbiturates depresses
CNS.
3. Irritation
Non selective often noxious effect and is particularly applied to less specialized cells
such as epithelium, connective tissues.
4. Replacement
It refers to use of natural metabolites, hormones or their congeners in deficiency
states. E.g. Insulin in DM.
5. Cytotoxic action
Selective cytoxic action for invading parasites or cancer cells, attenuating them
without significantly affecting the host cells. E.g. Penicillin, Chloroquine.
Receptors
It is defined as macro-molecular or binding site located on the surface or inside the
effector cell that serves to recognize the signal molecule or drug and initiate the response
to it but it has no other functions to itself. It is macro-molecular; protein substances, part
of a component of cell, endogenous substances and drugs act via binding to receptors.
Receptors are responsible for
a. Selectivity and specificity of drug action.
b. Quantitative relationship between drug and effect.
c. Mediation of actions of agonists and antagonists.
Agonist
Binds to specific receptor and produce a positive effect. It activates receptors to produce
an effect similar to that of physiological signal molecules. It has the affinity and maximal
intrinsic activity. E.g. Salbutamol acts on Beta receptors, Adrenaline acts on Alpha and
Beta receptors.
W
Inverse Agonist
It actives receptors to produce an effect opposite direction to that of the well-recognized
agonist. It has the affinity and maximal intrinsic activity with negative sign.
E.g. Carboline.
Antagonist
Blocks or reverses the action of an agonist. It binds to specific receptor to prevent the
action or the subsequent response but does not have any effects on its own. It has affinity
but no intrinsic activity. E.g. Propanolol
An antagonist can be Pharmacological, Physiological and Chemical. Based on
Pharmacological antagonist can be divided into two types(i)
(ii)
Competitive antagonists
It has weak H-bonds and overcome by increasing the dose of the agonist.
E.g. Atropine blocks acetylcholine at muscarinic receptors.
Non-competitive antagonists
It has strong covalent bonds and does not overcome.
E.g. Phenoxybenzamine blocks adrenaline at Alpha receptors.
Partial Agonist
It actives receptor to produce submaximal effect but antagonizes the effect of the full
agonist. It has the affinity and submaximal intrinsic activity. E.g. Pindolol
Ligand
It has a molecule which attach selectively to particular receptor of sites. It indicates
binding without functional changes.
- Agonist and competitive antagonist are ligands to the same receptor.
Mechanisms of Drug action
a. Physical action
b. Chemical action
c. Through enzymes
d. Through receptors
Drugs acting on the Cell Membrane
On the specific receptors.
E.g. Adrenoceptors, Histamine receptors , Acetylcholine receptors.
Interference with selective passage of the ions across cell membrane.
E.g. Calcium entry blockers.
Inhibition of the membrane bound proteins and the pumps.
- Membrane bound ATPase by cardiac Glycosides.
W
Drugs acting on the metabolic processes with in the cell.

Enzyme inhibition.
E.g. Xanthine oxidase by Allopurinol.
Inhibition of the transport process.
E.g. Blockade of the anion transport in renal tubules by Probenecid.
Altering the metabolic process of the antimicrobial agents.
- Inhibition of the folic acid synthesis of the Sulphonamides.
Drugs acting out side the cell wall.
Direct chemical interaction. E.g. Antacids
Osmosis. E.g. Purgatives
Function of Receptors
a. To propagate regulatory signals from outside to within the effector cell.
b. To amplify the signals.
c. To integrate various extra-cellular and intra-cellular regulatory signals.
d. To adopt short term and long term changes in the melieu and maintain homeostasis.
Drug Potency and Efficacy
Drug Potency
It refers to Amount of drug needed to produce a certain response. If 10 mg of morphine
= 100 mg of pethidine, then morphine is 10 times more potent than pethidine.
Drug efficacy
It refers to maximum response that can be elicited by the drug. E.g. morphine produces
a degree of analgesia not obtained with any dose of aspirin. So, morphine is more
efficacious than aspirin.
R A is more potent than B.

R C is more potent but less
effective than A & B.
R D is less potent but as
effective as A & B.
Figure: 1.3.1 - Potency and

Efficacy
W
Combined Effect of the drugs

When two are more drugs are given simultaneously or in the quick succession, they may
be either indifferent to each other or exhibit synergism or antagonism. The interaction
may take place in Pharmacokinetics or Pharmacodynamic level.
Synergism
When the action of one drug is facilitated or increased by the other drug, they are said to
be synergism. It can be:
a. Additive
The effects of the two drugs are in same directions and simply add up. Effect of drug A
+ Effect of drug B = Effect of drug A +B.
E.g Aspirin + Paracetamol = analgesic + antipyretic
b. Supra Additives
The effect of the combination is greater than individual effect of the compounds. Effect
of drug A + B > Effect of drug A + Effect of drug B.
E.g. Acetylcholine + physostigmine (Inhibition of beak down)
Antagonism
When one drug decreases or inhibits the action of another, they are said to be
antagonistic. Effect of drug A + B < Effect of drug A + Effect of drug B.
(a) Physical
Based on physical property of drugs. E.g. Charcoal adsorbs alkaloids.
(b) Chemical
Two drugs react chemically and form an inactive product. E.g. KMNO4 oxidizes
alkaloids - use in gastric lavage poisoning. Chelating agents (BAL, Cal Disod, Edetate
complex metals (As, Pb), (Thiopentone sodium + succinylcholine) React chemically.
(c) Physiological or Functional
Have opposite action on physiological function.
E.g. Histamine or Adrenaline on bronchial muscle and blood pressure.
(d) Receptor
One drug (Antagonist) blocks the receptor action of the other drug (agonist). The
antagonist interferes with the binding of the agonist with its receptor or inhibits the
generation of the response. Can be two types:
i.
Competitive antagonists. E.g. Ach Morphine
ii.
Non Competitive antagonists. E.g. Diazepam- Biculline.
W
Figure: 1.3.2- Dose - Response curves

1. Dose response curve with an agonist (Ach) alone
produces maximal Response.
2. Dose response curve with same agonist (Ach) in the presence of a competitive antagonist
(atropine)
no maximal response, but can be obtained if we increase the dose or
concentration of the agonist in the presence of the antagonist.
3. Dose response curve with agonist (Ach) in the presence of a non - competitive
antagonist
no maximal response & cannot be re-obtained except after the
formation of a new receptor.
Therapeutic Window Phenomenon
Unusual feature of certain drugs; Optimal therapeutic phenomenon is exerted only over a
narrow range of the plasma drug concentration or drug dose. Both below and the above
this range, beneficial effect is sub optimal. E.g. 0.2-2.0 Kg /ml. Clonidine, Imipramine.
Therapeutic index
The gap between the therapeutic effect of the drug response curve and adverse effects
drug response curve defines the safety margins or therapeutic index.
Median lethal dose
-
Therapeutic index =
Median effective dose
LD50
=
ED 50
W
Pharmacokinetics
:KDWWKHERG\GRHVWRWKHGUXJ
It is defined as the movement of the drug in and alteration of the drug by the body. It
describes the study of absorption, distribution, metabolism and excretion of drugs and
their relationship to pharmacological response.
Absorption of Drugs
It is defined as the movement of drug from site of administration to blood circulation.
Absorption is complete in case of I.V. administration. It may be partial in other routes.
Drugs are absorbed from GIT by :
Passive diffusion - Drugs moves from region of high concentration to region of low
concentration.
Active diffusion - Drugs entry involves specific carrier proteins. It is energy dependent.
Factors Affecting Absorption
I.
The pH
II. Blood flow rate
III.
Surface area
IV.
Concentration gradient
V.
GI motility: increased GI motility
decreased absorption
VI.
Dissolution rate: decreases by increased GI motility
VII. Molecular weight
VIII. Solubility of the drug
IX.
Chemical characters of the drug
Bioavailability
It is the fraction of administered drug that reaches the systemic circulation in an
unchanged form. Drug administered through intravenous route is 100% and is lower if
administered orally because of incomplete absorption through gut mucosa or first pass
metabolism. It is determined by comparing plasma levels of a drug after a particular route
of administration (E.g. oral) with plasma drug levels achieved by injection.
AUC Oral
-
Bioavailability =
100
AUC Injected
W
Figure: 1.3.3 Bioavailability Graph
Factors affecting Bioavailability

i.
First pass hepatic metabolism: drugs absorbed from GI first enter portal circulation
before entering systemic circulation. If drug is rapidly/greatly metabolized by liver,
the amount of unchanged drug reaching systemic circulation is decreased.
ii.
Solubility of drugs: for a drug to be readily absorbed, it must be largely hydrophobic
yet have some solubility in aqueous solution.
iii.
Chemical instability: Penicillin G is unstable in gastric pH; Insulin is destroyed by
degradative enzymes in GI.
iv.
Nature of drug formation: size of particle, salt form, excipients can alter rate of
absorption.
Therapeutic index
Is the ratio of the dose that produces toxicity to the dose that produces clinically desired
or effective response in a population of individual (the more large the ratio, the more safe
the drug is).
-
Therapeutic Index (TI = MTC/MEC)

MTC: Minimum Toxic Concentration
MEC: Minimum Effective Concentration
Drug distribution
It is the process by which a drug reversibly leaves the blood stream and enters the
interstitial and/or cells of the tissues, the rate of extent being dependent on its lipid
solubility, ionization at physiologic pH, and extent of binding to plasma and tissues
protein and differences in regional blood flow.
W
Volume of distribution
It is the hypothetical volume of fluid into which the drug is disseminated.
Vd = dose administered I.V. / plasma concentration
R Pathological states (CHF, uremia, etc.) can alter the volume of distribution of many
drugs.
- If Vd </=5 L
the drug doesn't get out from the central compartment yet.
- If Vd > 5 L
the drug is distributed outside the central compartment.
Factors governing volume of distribution
- Lipid: water partition coefficient
- Degree of plasma protein binding
- Affinity for different tissues
- Fat: lean body mass ratio
- Disease condition
Factors that increase volume of distribution:
i.
Increased tissue binding
ii.
Decreased plasma binding
iii.
Increased lipid-solubility
Factors Affecting Distribution
i.
Binding to tissue proteins
increases distribution
ii.
Binding to plasma proteins
decrease distribution
iii.
Solubility: lipid solubility, increased solubility
increases distribution to adipose
tissue. While water solubility
increases muscle and ECF.
iv.
Increased cardiac output
increases distribution
v.
Blood flow rate: increased blood flow rate
increased distribution
vi.
Drug forms
a) Free forms
b) Bound forms
Binding of drugs to plasma proteins
Drugs bound to plasma protein are trapped and so inactive.
Drugs bound to plasma proteins have:
- Low volume of distribution
- Longer duration of action
Drugs binding to albumin:
- E.g. Barbiturates, penicillin, NSAIDS, Tetracycline.
Loading Dose: high dose given at once to raise the drug level into the steady state in a
very short time.
W
Maintenance dose: is the dose given to maintain the therapeutic window.

Drug metabolism/Bio-transformation
Chemical alteration of drugs in the body is biotransformation which renders lipid soluble
compounds lipid insoluble so that they are not reabsorbed in the renal tubules and are
excreted. It is an important route of elimination. It converts non-excretable drugs into
excretable drugs (from lipid- soluble to water-soluble). Two changes occur:
i.
Reduction in the lipid solubility (make it more polar)
ii.
Alteration in the biological activity
- Primary site: Liver
- Others: Kidney, Intestines, Lungs, Plasma
Classification of biotransformation reactions
1. Phase I/Non-Synthetic reactions: A functional group is generated or exposedmetabolized may active or inactive.
2. Phase II/Synthetic reactions: Metabolite may inactive; except some few drugs.
E.g. Glucuronide conjugate of Morphine.
Phase I reactions
i.
Oxidation
a) Microsomal oxidation
- In the SER
- Done by certain enzymes. E.g. Cytochrom P-450 microsomal system. MFO system
(mixed function oxidase).
- 99% of oxidation is done by cytochrom P-450 system
x Hydroxylation
x Dealkylation
x Deamination
b) Non-microsomal oxidation
- By cytosolic soluble enzymes
minor oxidation.
E.g. by Alcohol dehydrogenase.
*Alcohol
acetaldehyde
ii.
iii.
Reduction
This reduction is the converse of oxidation and involves cytochrome P-450 enzymes
working in the opposite direction. Alcohols, Aldehyds, Quinines are produced. Drugs
primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin.
Hydrolysis
This is cleavage of drug molecule by taking up a molecule of water.
Esterase
- Ester + H2O
Acid + Alcohol
W
iv.
Cyclization
This is formation of ring structure from a straight chain compound. E.g. Proguanil.
v.
Decyclization
This is opening up of ring structure of the cycle drug molecule. E.g. Barbiturates,
Phenytoin.
Phase II reactions
i.
Glucuronidation
Catalyzed by UDP-glucuronyl transferase in the liver, mainly the endoplasmic
reticulum. Transfers glucuronic acid to N, O or S.
E.g. paracetamol, salicylate & chloramphenicol
ii.
Acetylation
Catalyzed by N-acetyl transferase (NAT). E.g. isoniazide, sulphonamides
iii.
Methylation
Catalyzed by N-methyl transferase. E.g. noradrenaline & steroids
iv.
Conjugation to sulfate
E.g. paracetamol & minoxidil
v.
Conjugation to glycin
E.g. salicylate
Factors Affecting Metabolism

a) Age: metabolism decreases in infants & old people
b) Sex: males metabolize drugs more than females
c) Race/Geneticism
d) Nutrition: metabolism increases with alcohol & it decreases in a deficient diet
e) Disease: liver disease, congestive heart failure
f) Radiation decreases metabolism
g) Hormonal: increases with androgen & decreases with estrogen
Induction of microsomal enzymes
- Involved in both phases I & II
- Inducing agents include: phenobarbitone, carbamazepine, alcohol, rifampin, DDT,
phenylbutazone & benzpyrene
Inhibition of microsomal enzymes
- Cimetidine inhibits phenobarbitone
- Erythromycin inhibits theophyllin
W
g)
h)
i)
j)
k)
Body surface area

Free fraction of the blood
Plasma protein binding
Factors affecting passive diffusion & absorption
Organ excretion ratio (kidney, liver)
Important processes in renal clearance

a) Filtration
passive secretion
b) Reabsorption. E.g. aspirin experiment
Ionized
not reabsorbed
excreted
Metabolism of non-ionized
ionized
c) Secretion
active
excreted
Factors that decrease clearance

1) Decreased blood flow rate
2) Renal or hepatic dysfunction
3) Increased binding
Half time (t )
Is the time needed for plasma drug concentration to fall (decrease) by 50%.
R Half time (t ) = (0.693 x Vd) / Cl
R Half life is a function of volume of distribution & clearance
R Half life (t ) also depends on dose:
x Small dose
short half life
x Large dose
large half life
W
&+$37(5*(1(5$/35,1&,3/(
(iv)
Adverse drug reaction (ADR)

An Adverse drug reaction is defined as any response to a drug that is noxious and
unintended and that occurs at doses used in human for prophylaxis, diagnosis or therapy.
ADR may develop promptly or only after prolonged medications or even after stoppage
of the drug. It is estimated that 15-30% of hospitalized patient suffer from ADR.
Causes of ADR
1) Something wrong with the patient (hypersensitivity)
2) The nature of the drug
3) Errors in prescription writing
Importance of knowing ADR
1) They are common: about 30% of all hospital admissions are due to ADR.
2) They may be serious: 0.3% of inpatients suffer of fatal ADR and 4th leading cause
of death in the U.S.
3) Often preventable: often caused by errors in prescription writing. Drugs which are
contraindicated or unnecessary commonly prescribed.
4) Increased health care cost: Admission to hospitals or prolonged stay & cost of
treating symptoms.
5) Complicated existing diseases & hinder their treatment.
Types of ADR
1. Type A
- Augmented/increased pharmacological action
- Correlated with pharmacological action
- Usually dose-related
- Largely predictable
- Mortality is generally low
- Morbidity is high
- Can occur in all patients
- Usually detected during clinical trails
- Examples:
x Insulin: hypoglycemia
x Warfarin: hemorrhage
x blocker: bradycardia & hypotension
W
2. Type B
- Bizarre
- Unpredictable response
- Not dose-related
- Not correlated with pharmacological action
- Lower morbidity
- Higher mortality
- Lower incidence
- Not usually detected during clinical trials
- Infrequent
- Examples:
x Allergic reaction (hypersensitivity)
x Idiosyncratic reactions such as Aplastic anemia with chloramphenicol
x Maybe genetically determined such as G6PD
x Polymorphic drug metabolism
x Slow acetylator status such as Risk of systemic lupus with hydralazine
3. Type C
- Chronic
- Long term effect
- Osteoporosis with steroids
- &XVKLQJVV\QGURPHZLWKVWHURLGV
4. Type D
- Delayed includes:
R Teratogenesis E.g. Phecomelia
induced by thalidomide
R Carcinogenesis E.g. Vaginal carcinoma in daughters
diethylstilbestrol
5. Type E
- End of dose
- Withdrawal effects after long term treatment
- Rebound response E.g. rebound hypertension after ending blockers
Predisposing factors (high-risk groups for ADRs)
I. Age: increased risk in very young & very old > 70 years age
II. Gender: increased incidence in women
III. Genetics: inter-individual & inter-ethnic
IV. End-organ failure E.g. liver & renal impairment
V.
Polypharmacy: taking multiple drugs at the same time
VI. Multiple disease states
VII. Allergy: history of allergy to one drug may predispose to further allergy
W
R Next six weeks or first trimester period Susceptible to the damage.

R Second and the third trimester is comparatively safe
Guidelines for safe prescribing
I.
Use caution while prescribing the drugs for women of the childbearing age. Ask
for the history of the last menstrual period.
II.
If possible all drugs should be avoided specially during the first trimester of the
pregnancy.
III.
Choose the drug, which have been extensively used in the pregnancy and appears
to be usually safe. ***Old is gold.
IV.
Prescribe relatively safe drugs for the diseases (epilepsy) with prolonged therapy.
V.
Advice to avoid even OTC drugs.
VI.
Prescribe only if the expected benefit to the mother is thought to be greater than
the risk to the child.
VII.
The smallest effective dose for the minimal duration should be used.
VIII.
Few drugs have been conclusively shown to be teratogenic in human but no drugs
are safe beyond all doubt in pregnancy.
IX.
Keep inform your self for changing the scenario.
X.
As the pregnancy is evolves, profound changes occurs in physiology, including
fluid and the tissue composition.
- Absorption
- Distribution
- Hepatic metabolism
- Elimination
Lactation
Category A: - Compatible with breast feeding
Category B: - Effect of the drug on nursing mother is unknown, but can be given
Category C: - Significant effect, given in concern
Category X: - Avoided in all nursing mother.
Pregnancy
Category A: Adequate studies in the human have failed to demonstrate a risk to the
feotus. E.g. Inj. magnesium sulphate, Thyroxine
Category B: Adequate human studies are lacking, but the animal studies have failed to
demonstrate a risk to the feotus. E.g. Penicillin V, Paracetamol
Category C: No adequate studies in pregnant women and the animal studies are lacking
or have shown the adverse effect on feotus, but the potential benefit may be warrant
use of the drug in pregnant women despite potential risk. E.g. Morphine, Atropine.
Category D: There is evidence of human feotal risk, but the potential benefits from the
use of the drug may be acceptable despite the potential risk. E.g. Aspirin, Phenytoin.
Category X: Studies in human or the animals have demonstrated feotal abnormality
and potential risk clearly outweighs possible benefit. E.g. Estrogen.
W
Figure: 2.1.1- Antibacterial Spectrum of Sulfonamides

Resistance
Most bacteria are capable of developing resistance to sulfonamides
Bacterial Resistant to sulfa drugs may be due to plasmid transfer or random mutations.
It can result from:
a) Decreases intracellular accumulation of the drugs
b) Increases production of PABA by bacteria
c) Decreases sensitivity of dihydropteroate synthase to the sulfonamides
d) Adopt an alternative pathway in folate metabolism
Pharmacokinectics
Administration
Rapidly and nearly completed absorbed orally, sulfasalazine not absorbed orally;
mafenide acetate, silver sulfadiazine is used in burn patient topically.
Distribution
Distributed throughout body, enters into serous cavities and well penetration in CSF even
in absence of inflammation, crosses placental barrier and also comes into breast milk.
Binds to serum albumin
Metabolism
Acetylation (Liver), metabolites precipitates in neutral or acidic pH causing crystalluria
(stone formation) which can damage kidney. Intestinal flora splits Sulfasalazine into
sulfapyridine and 5-aminosalicylate (antiinflammatory)
W
Excretion
Excretion of intact drug & acetylated metabolites in urine.
Clinical Uses (sulfonamides)
Active against G +ve, G -ve organisms, Chlamydia, & Nocardia.
Usually used in combination with Trimethoprim (TMP) to prevent resistance
development.
a) Urinary Tract Infections: mainly Acute cystitis, as its concentration in urine is
bactericidal effect
b) Streptococcal pharyngitis and gum infections (alternative to penicillin). Prophylaxis
of Rheumatic fever in penicillin allerigic patients.
c) Trachoma: 10-30% sulfacetamide sod. For 4 weeks as eye drops or ointment
(alternative to tetracycline)
d) Nocardiosis
e) Toxoplasmosis: sulfadiazine + pyrimethamine for 4-6 wks. (Drug of choice).
f) Lymphogranuloma venereum (alternative to tetracycline)
g) Burns: Topical silver sulfadiazine or Mafenide
Adverse effects
1. Hypersensitivity
Allergic reactions, including skin rashes, urticaria and fever (common)
Arthritis, serum sickness like syndroome and polyarteritis nodosa (rare)
2. Gastro Intestinal Drugs
Nausea, Vomiting & Diarrhoea (common)
Mild hepatic dysfunction & Hepatitis (rare)
3. Hematotoxicity (rare)
Granulocytopenia, thrombocytopenia, & aplastic anemia
Acute hemolysis occur in G6PD deficiency
4. Nephrotoxicity
Precipitate in urine at acidic pH
Crystalluria and haematuria with older agents.
Newer agents like sulfisoxazole and sulfamethoxazole are more soluble at urinary pH.
5. Kernicterus
Displace bilirubin from plasma proteins
free bilirubin can cross BBB in
neonates and deposits in brain and causes kernictrus.
These drugs are contraindicated in 3rd trimester of pregnancy and child below 2
months of age.
W
6. Drug interactions
Competition with tolbutamide, phenytoin, warfarin and methotrexate for plasma
protein binding
transiently inc. their plasma level.
Contraindication of Sulfas
Newborns and infants of less than 2 months of age
Pregnancy (especially 3rd trimester)
Should be avoided in patients receiving Methenamine as Formaldehyde condenses
with Sulfonamides.
Quinolones
These are broad spectrum antibiotics. Play an increasingly important role in treatment of
multi-drug resistant bacterial infections. They may be used in patients allergic to
penicillins, cephalosporins, sulfonamides, erythromycins, etc.
Quinolones are synthetic antimicrobial agents
The drugs in this groups are:
a) Nalidixic acid
b) Fluoroquinolones
i.
First generation: Norfloxacin, Ciprofloxacin, Ofloxacin, Pefloxacin
ii.
Second generation: Lomefloxacin, Sparfloxacin, Moxifloxacin
Figure: 2.1.2- Mechanism of Action of Quinolones
Mechanism of action (MOA)

The quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV.
For many gram positive bacteria, topoisomerase IV is the primary target.
For many gram-negative bacteria, DNA gyrase is the primary quinolone target
W
Figure: 2.1.3- Antibacterial Spectrum of Quinolones
Antibacterial spectrum
Bactericidal
Extremely active on gram negetive (E.coli, Salmonella, Shigella, Klebsiella, Proteus,
Neisseria, Enterobacter, Pseudomonas , Haemophilus influenzae, Moraxella
catarrhalis, Legionella, Chlamydia and Mycobacteria except for M. avium
intracellulare complex)
Effective for gonorrhea but not syphilis.
Less active on gram positive
No activity on anaerobes
Used prophylactically before transurethral surgery to decrease postsurgical incidence
of urinary tract infections.
Ciprofloxacin
Pseudomonas infection associated with cystic fibrosis, enterobacteraceae and other
gram negative bacilli
Systemic infections which is not due to MRSA, enterococci, pneumococci
Synergestic action with beta lactams
Alternative to aminoglycosides
Norfloxacin
Both gram negative including Pseudomonas and gram positive organisms in treating
complicated and uncomplicated urinary tract infections, prostatitis
Not used for systemic infection treatment
W
Co-Trimoxazole (TMP-SMZ)
It is the fixed dose combination of sulfamithoxazole and trimithoprim in the ratio of 5:1
(400+80 mg; 800+160 mg).
Sulfamethoxazole inhibits incorporation
of PABA in folic acid and Trimithoprim
prevents the reduction of dihydrofolate
to tetrahydrofolate. The combination is
bactericidal and there is less chance of
emergence of resistance.
Figure: 2.1.4- Mechanism of

Action of TMP-SMZ
Figure: 2.1.5- Antibacterial Spectrum of TMP-SMZ
Salmonella, Klebsiella, Enterobacter, Pneumocystis carinii.
W
Clinical uses (TMP-SMZ/Co-trimoxazole)

i.
Uncomplicated urinary tract infections treatment
ii.
Respiratory, ear & sinus infections due to H. influenzae & M. catarrhalis
iii.
Prevention & treatment of Pneumocystis carinii in immunocompromised pts.
(DOC - Pneumonia)
iv.
Typhoid
v.
Chancroid: Cotrimoxazole (800+160mg) for 7 days
vi.
Bacterial diarrhoea and dysentery
vii. Granuloma inguinale (alternative to Doxyccline/Erythromycin)
Adverse effects: (TMP-SMZ//Co-trimoxazole)
Nausea, Vomitting, Rashes, Megaloblastic anemia, Thrombocytopenia, Leucopenia,
Aplastic anemia
Contraindications
i.
Megaloblastic anemia
ii.
Pregnancy
iii.
Kidney
iv.
Liver disease
v. Malnourished patients
W
&+$37(5$17,0,&52%,$/'58*6
Figure: 2.1.7- List of Drugs
Figure: 2.1.6- /DFWDP5LQJ
(i)
Anti Bacterial Drugs
b. Lactum (Penicillin, Cephalosporin & Other Drugs)
W
Penicillins
It is the first antibiotic to be used clinically in 1941 and first isolated by Alexander
Fleming in 1929 from fungus Penicillum notatum. These days it is obtained from P.
chrysogenum. It is a beta lactam group of antibiotics. These penicillins consist of a
thiazolidine ring (A) connected to a beta-lactam ring (B), to which is attached a side chain
(R). Structural integrity of the 6-aminopenicillanic acid nucleus is essential for the
biologic activity of these compounds. If the beta -lactam ring is enzymatically cleaved by
bacterial beta - lactamases, the resulting product, penicilloic acid, lacks antibacterial
activity.
Classification of Penicillins
I. Natural penicillins:
Penicillin G (Benzyl penicillin), Pen G
Procaine penicillin
Benzathine penicillin
II. Semisynthetic penicillins:
Acid resistant alternative to Pen G: Phenoxymethyl penicillin (Pen V)
Extended spectrum penicillins:
R Antipsudomonal penicillins: Azlocillin, Carbenicillin, Mezlocillin,
Piperacillin, Ticarcillin
R Aminopenicillins: ampicillin, amoxycillin, bacampicillin
R Mecillinam: Timocillin
III. Penicillinase resistant penicillins: (anti-staphylococcal)
Methicillin, cloxacillin, oxacillin, nafcillin, dicloxacillin
- lactamase inhibitors: clavulanic acid, sulbactam
Mechanism of Action (MOA)
Penicillins inhibits baterial transpeptidase enzyme and prevent the cross-linking of
peptidoglycan polymer that is essential for bacterial cell wall integrity. This results in loss
of rigidity and susceptibility to rupture.
Penicillins also bind to and inactivate Penicillin binding proteins (PBPs) involved in cell
wall synthesis.
Autolysin inhibition: autolysin is the degradative enzyme produced by gram positive
cocci, which participate in normal remodelling of bacterial cell wall. In the presence of
penicillin the degradative action of penicillin proceeds in the inhibition of cell wall
synthesis.
Inhibit bacterial growth by interfering with a specific step.
Maintain the shape of the cell and prevent cell lysis from high osmotic pressure.
Five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide
terminates in D-alanyl-D-alanine. Penicillin-binding proteins (PBPs) catalyze the
transpeptidase reaction that removes the terminal alanine to form a crosslink with a
nearby peptide, which gives cell wall its structural rigidity and stability.
W
Figure: 2.1.9- Mechanism of Action of Penicillins
Figure: 2.1.8- Gram negative bacteria cell wall
After a beta -lactam antibiotic has attached to the PBPs, the transpeptidation reaction is
inhibited and there is no cross linking in peptidoglycan layer. So, cell wall deficient forms
of bacteria are produced. Inside of bacteria is hyperosmotic so it swells and bursts leading
to bacterial lysis.
Penicillins are bactericidal only if bacteria are actively growing & synthesizing cell wall.
W
Figure: 2.1.10- Mechanism of Action of Penicillins

Resistance
Natural resistance: occurs in organisms without peptidoglycan cell wall
E.g. Mycoplasma
Beta lactamase activity: hydrolyses cyclic amide bond of beta lactam ring of the drug
by penicillanase produced by Staphylococcus, some strains of gonococci, E.coli,
H.influenzae (Due to transfer of plasmid).
Decreased permeability to drug, altered penicillin binding proteins (By mutations).
Gram negetive bacteria have porins channels in outer membrane and ampicillin and
other members active against gram negetive can cross porins much better than Pen G.
Narrow spectrum
Gram positive bacteria are sensitive
Cocci:
R Gram positive: Streptococci, Pneumococci, Staph aureus
R Gram negative: Neisseria gonorrhoea, N. meningitidis
Bacilli:
R Gram positive: B. anthracis, Corynebacterium diphtheriae, Clostridial species,
Listeria, Spirochetes
R Gram negative: E. coli, Proteus, others -resistant
W
Figure: 2.1.11- Antibacterial Spectrum of Penicillins

Figure: 2.1.12- Antibacterial Spectrum
Pharmacokinetics
Administration
Routes depend on stability of drug to gastric acid and severity of infection.
Oral Route: Pen V, Amoxicillin, and Amoxicillin combined with Clavulanic acid.
W
IV/IM Route: Methicillin, Ticarcillin, Carbenicillin, Mezlocillin, Piperacillin,

Azlocillin and the combinations of Ampicillin with Sulbactam, Ticarcillin with
Clavulanic acid and Piperacillin with Tazobactam.
Depot forms (IM): Procaine pen G and benzathine pen G.
Absorption
Most of them incompletely absorbed except: Amoxicillin almost completely absorbed
Food decreases absorption of pen G and all the penicillinase-resistant penicillins
(Gastric acid destroys drugs). It should be taken 30-60 min before meal.
Distribution
Well distribution throughout the body and crosses placental barrier (not teratogenic)
Well penetration into CNS during meningeal inflammation
Metabolism
Insignificant metabolism
Excretion
Through Tubular secretion and glomerular filteration
Dose should be adjusted in renal failure patients
Probenecid inhibits the secretion of penicillins and Nafcillin is primarily eliminated
through the biliary route.
Penicillins combined with Aminoglycosides
The combination has Synergistic action. Penicilllins increases the permeability of
bacterial cells to aminoglycosides due to aminoglycosides concentration is increased
within the cell but both the drugs should not be given in the same infusion fluid because
on prolonged contact, the positively charged aminoglycosides form an inactive complex
with the negatively charged penicillins.
Adverse drug reactions
i.
Hypersensitivity (most common) such as immune reaction, itching, urticaria, fever,
angioedema and anaphylaxis. Also cross allergic reactions occur among beta lactam
antibiotics.
ii.
Diarrhoea (common especially for Ampicillin)
iii.
Nephritis/acute interstitial nephritis (especially for Methicillin)
iv.
Neurotoxicity: seizure if given intrathecally
v.
Platelet dysfunction - antipseudomonas (carbenicillin and ticarcillin), some extent with
Pen G
vi.
Cation toxicity can occur in CVS or renal disease patients.
vii.
Jarisch-Herxheimer reaction: Penicillin injected in a syphilitic patient may produce
shivering, fever, myalgia, exacerbation of the lesion and even the vascular collapse.
W
Note & Nursing alert:

Pseaudomembranous colitis may occur after 4 to 9 days of treatment with penicillin or
as long as 6 weeks after the drug is discontinued. Pseudomembranous colitis is a type
of bacterial superinfection and potentially life threatening problem develops because
of an overgrowth of micro-organism clostridium difficle. This organism produces
toxin effect that affects lining of the colon. S/S. includes severe diarrhea with visible
blood and mucous, fever & abdominal crams.
Uses of Penicillins
Treatment:i.
Streptococcal infection: pharyngitis, otitis media, rheumatic fever, SABE
ii.
Pneumococcal infection
iii.
Meningococcal infection
iv.
Staphylococcal infection
v.
Gonorrhoea
vi.
Syphillis
vii.
Diphtheria
viii.
Tetanus, Gas gangrene
ix.
Anthrax, Listeriosis, Actinomycosis
Prophylaxis:i.
Rheumatic fever
ii.
SABE
iii.
Gonorrhoea & syphilis
iv.
Surgical infection
Semisynthetic penicillins
The disadvantage of Pen G (natural)
Poor oral efficacy
Susceptibility to penicillinase
Narrow spectrum of activity
Hypersensitivity
Benzathine Penicillin and Procaine Penicillin are salts of Pen G
To overcome these disadvantages semisynthetic Penicillin are produced
Phenoxymethyl penicillin
Pen V
Acid stable so given orally
Used as potassium salt (chance of developing Hypercalcaemia when given in large
dose combining with potassium sparing diuretics)
Antibacterial spectrum is same as Pen G
W
Penicillinase resistant penicillins

Contains side chains that protects beta lactam ring from penicillinase produced by
bacteria. Non-penicillinase producing organisms are less sensitive to these drugs,WVQot
resistant to gram negative beta lactamase.
Cloxacillin
It is Penicillinase resistant, Acid resistant, Well Active against penicillinase producing
Staphylococcus, Incomplete absorption, more than 90% plasma protein boind, Eliminated
through kidney, T1/2: 1 hour.
Methicillin
Resistant to penicillinase, not resistant to acid; route: injection
MRSA (methicillin resistant staph. Aureus): resistant to all penicillinase resistant
penicillins, other beta lactams, erythromycin, aminoglycosides, tetracyclines.
In this case (DOC - vancomycin/ciprofloxacin)
ADR: haematuria, albuminuria, reversible interstitial nephritis
Nafcillin
Given through injection for severe staph. Infection
ADR : Hepatitis, Neutropenia
Broad spectrum penicillins
Broad spectrum of activity and effective against gram negative bacilli such as H.
influenza, E. coli, Proteus, Salmonella, Shigella, B. pertussis
Less effectiev against gram positive cocci and bacteroides than Pen G
Ampicillin, Bacampicillin, Amoxicillin (Rapid and complet abrobtion)
Uses of aminopenicillins: Upper respiratory tract infections, Meningitis (due to H.
influenza, S. pneumonia, N. meningitides), Typhoid fever specially the carriage stage,
Gonorrhoea, Cholecystitis, Subacute bacterial endocarditis (along with
aminoglycosides)
Betalactamase inhibitor
Hydrolysis of beta lactam ring by beta-lactamase, produced by various organisms,
reduces the effectiveness of beta lactam antibiotics.
E.g. Clavulanic acid, sulbactam, tazobactam
They are combined with penicillins
R Amoxicillin + clavulanic acid (oral, inj.)
R Ticarcillin + clavulanic acid (inj.)
Clavulanic acid
It is obtained from Streptomyces clavuligerus. It initially binds with beta lactamase is
reversible but later covalent. It gets inhibited after binding with the enzyme.
W
Uses of Amoxicillin + clavulanic acid

Beta lactamase producing resistant Staph. Aureus, H. influenzae, N. gonorrhoea, E.
coli, Proteus, Klebsiella, Shigella, Bact. Fragilis
Skin and soft tissues infections, intrabdominal and gynecological sepsis,
Urinary, biliary and respiratory tract infections
ADR: same as amoxicillin
Dose combination:
R Gonorrhoea: amoxicillin 3g + clavulanic acid 0.5g + probenecid 1g(single dose)
R Amoxicillin 250mg + clavulanic acid 125mg tab; 1-2 tab TDS
R Amoxicillin 1g + clvulanic acid 0.2g vial for inj. 6-8 hrly for severe infection
Figure: 2.1.13- Structure of Cephalosporins
Cephalosporins
They are lactam antibiotics that are closely related both structurally and functionally to
the penicillins. They are produced from 7-aminocephalosporanic acid by the addition of
different side chains. Developing resistance to bacterias as same way as penicillins.
Classification
1. First generation
Parenteral: Cephalothin, Cefazolin , Cefapirine
Oral: Cephalexine, Cephradine, Cefadroxil
W
2. Second generation
Parenteral: Cefuroxime, Cefoxitin, Cefamandole, Cefotetan, Cefmetazole,
Cefonicid
Oral: Cefaclor, Cefuroxime axetil
3. Third generation
Parenteral: Cefotaxime, Ceftizoxime, Ceftazidime , Ceftriaxone, Cefoperazone
Oral: Cefixime, Cefpodoxime, Cefdinir, Ceftibuten
4. Fourth generation
Parenteral: Cefepime, Cefpirome
Mechanisms of action (MOA)
Bactericidal and same MOA as penicillin
Inhibition of bacterial cell wall synthesis
R Resistance: Similar to that of penicillins
They are not effective against methicillin resistant Staphylococcus aureus (MRSA),
Listeria monocytogenes, Clostridium difficile, the enterococci, atypical organism such as
Mycoplasma, Chlamydia.
A. First generation
Active against gram positive but weaker against gram negative Penicillinase producing
Staph. Aureus and most of streptococcus. Gram negative Proteus mirabilis, E. coli and
Klebsiella pneumonia.
B. Second generation
Less active against gram positive organism than first generation. Cephamycins are
effective against Bacteroides fragilis; cefoxitin is the most potent. Gram negative:
Haemophilus influenzae, Enterobacter aerogenes & some Neisseria.
C. Third generation
Less active against gram positive and expanded gram negetive coverage. It has ability to
cross Blood Brain Barrior (BBB). Citrobacter, Serratia marcescens, Meningitis (DOC Ceftriaxone or cefotaxime), Pseudomonas aeruginosa (DOC - Ceftazidime).
D. Fourth generation
Streptococci and Staphylococci (only those that are methidllin susceptible). Treatment of
serious and resistant hospital acquired infection. Gram negative: Enterobacter, E. coli,
Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa.
W
Figure: 2.1.14- Cephalosporins first, second, third & fourth generation

W
Clinical uses
i.
Alternative to pen G
ii.
Respiratory tract infection
iii.
Urinary tract infection
iv.
Skin and soft tissue infections
v.
Pencillinase producing styphallococcus infection.
vi.
Septicemia caused by gram negative organism
vii.
Typhoid
viii.
Gonorrhoea
ix.
Syphilis
x.
Hospital acquired infection
xi.
Surgical prophylaxis
xii.
Meningitis caused by H. Influenza
xiii.
Mixed aerobic or anaerobic infections
xiv.
Prophylaxis and the treatment of the neutropenic patients.
Uses of Cephalosporins (generation determind)
1) 1st generation
i.
Prophylaxis against surgical infections.
ii.
Alternative for skin & soft tissue infections, strept. pharyngitis
iii.
Urinary tract infections caused by susceptible strains of E.coli, klebsiella &
proteus
iv.
Not idicated for empiric treatment of otitis media or sinusitis.
2) 2nd generation
i.
Upper and lower Respiratory tract infections, sinusitis & otitis media
ii.
Alternative for Urinary tract infections caused by E.coli,klebsiella & proteus
iii.
Prophylaxis in GIT surgery - Cefoxitin may be given.
3) 3rd generation
R Parenteral is limited to:
Resistant gonococcal & penicillin-resistant pneumococci infections
Meningitis.
R Oral:
Otitis media and sinusitis (no advantage over amoxicillin)
Pharingotonsillitis (no advantage over penicillin).
4) 4th generation
Their use should be restricted to the setting of nosocomial sepsis.
W
Pharmacokinetics
Cefuroxime is best absorbed when taken with meal.
Cephalosporins inhibited by probenecid.
Decrease dose in renal impairment.
Cefoperazone and ceftriaxone excreted mainly in the bile so, can be used with renal
failure also.
First & second generation cephalosporins (except cefuroxime) do not enter CSF even
when meninges are inflamed but most of third & fourth generation can enter.
Third & fourth generations + cefuroxime together can enter CSF when there is
meningitis.
Adverse drug reaction
1. Allergic reactions: almost like penicillin but less frequent, cross allergenicity between
penicillin and cephalosporins 5-10%.
2. Pain at site of injection
3. Thrombocytopenia, haemolytic anemia, neutropenia, interstitial nephritis or abnormal
liver functions (> 2weeks, high dose, reversible)
4. Increase nephrotoxicity of aminoglycosides when administered together.
5. Disulfiram like reactions: Cefoperazone, cefotetan, cefamandole maycause reactions
with ethanol.
6. Superinfection (third generation)
7. Ceftriaxone may cause biliary pseudolithiasis.
Bleeding: due to hypoprothrombinemia, thrombocytopenia, and/or platelet dysfunction;
cefamandole or cefoperazone.
2WKHU- Lactam Antibiotics

Carbapenems
They DUH- lactams that have a broader spectrum of activity than most other
beta-lactam antibiotics.
E.g. Imipenem, Meropenem, Etrapenem
Imipenem: MOA & Antibacterial Spectrum
,PLSHQHPLVOLNHRWKHU- lactam antibiotics and it is very resistant to hydrolysis by
most beta-lactamases.
Excellent for a wide variety of aerobic and anaerobic microorganisms, Gram positive
cocci, Enterobacteriaceae, Pseudomonas, Listeria and Anaerobes like B. fragilis, Cl.
Difficile
Resistant to penicillinase
W
Imipenem cilastatin
Imipenem is rapidly hydrolyzed by enzyme dehydropeptidase-I found in the
brush border of the proximal tubule of kidney.
To prolong drug activity, imipenem is combined with cilastatin, an inhibitor of
the enzyme.
Route: Parenterally (Imipenem)
Z,/
/
ED
/
Uses
i.
Urinary tract and lower respiratory infections
ii.
Intra-abdominal and gynecological infections
iii.
Skin, soft tissue, bone, and joint infections
iv.
Serious hospital acquired infections
Adverse effects of Imipenem-cilastatin
Gastrointestinal distress such as Nausea & Vomiting (common)
Skin rash (partial cross-allegenicity with penicillins)
At very high plasma level, CNS toxicity such as confusion, encephalopathy and
seizures.
Monobactum (Aztreonam)
It contains only betalactam ring, so it is called monobctam
Antibacterial spectrum is same as that of Aminoglycosides.
Activity only against gram negative bacteria
Bind to PBP3 & synergistic with aminoglycosides
Eliminated through urine and no cross allerginicity
Uses
i.
ii.
Septicaemia
Complicated Urinary tract infections
Adverse effects of Monobactum

GIT upset hepatotoxicity (rare)
Rashes (no cross-allergenicity with penicillins)
Thrombocytopenia, neutropenia
W
Other drugs (Inhibitors of cell wall synthesis ZKLFKDUHQRW Lactams)

Vancomycin
Narrow spectrum - used for drug resistant gram positive such as MRSA, Penicillin
resistant pneumococci, Cl. Difficile.
Not absorbed from GIT (given orally for Cl. difficile enterocolitis).
Parenterally (modification of dosage in renal impairment).
Uses
i.
Pseudomembranous colitis caused by Cl. Difficile.
ii.
Strept. Endocarditis (if penicillin allergy then with aminoglicosides).
iii.
Serious infection with MRSA.
Adverse effects
Fever, chills, phlebitis
Ototoxicity.
Nephrotoxicity.
Rapid I.V infusion (red man syndrome)
Allergic reaction
Cycloserine
Inhibits cell wall synthesis
Effective orally
Used as second line drug for tuberculosis
Bacitracin
Is a mixture of polypeptides but lacks antigenicity as it has very low molecular weight
Inhibit cell wall synthesis
Highly nephrotoxic
Used only topically
W
&+$37(5$17,0,&52%,$/'58*6
(i)
c. Broad Spectrum (Tetracycline & Chloramphenicol)
Tetracycline
Broad spectrum and these drugs have four fused rings with a system of conjugated double
bonds.
Classification
Group A: short acting & T1/2: 6-10 hours.
Chlortetracycline, oxytetracycline, tetracycline
Group B: intermediate acting & T1/2: 16-18 hours
Demeclocycline, methacycline
Group C: long acting & T1/2: 18-24 hrs
Doxycycline, minocycline
Figure: 2.1.15- Mechanism of Action of Tetracycline

Inhibit bacterial protein synthesis by binding to the 30S bacterial ribosome and
preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome
complex.
They enter gram negative bacteria by passive diffusion through channels formed by
porins in the outer cell membrane and by active transport that pumps tetracyclines
across the cytoplasmic membrane.
W
Resistance
Decreased accumulation of tetracycline.
Production of a ribosomal protein that displaces tetracycline from its target, a
SURWHFWLRQWKDWDOVRPD\RFFXUE\PXWDWLRQDQGHQ]\PDWLFLQDFWLYDWLRQRI
tetracyclines.
Figure: 2.1.16- Antibacterial Spectrum of Tetracycline
Broad spectrum & bacteriostatics.
Effective against a wide range of aerobic and anaerobic gram positive and gram
negative bacteria.
Vibrio cholera, H. influenzae, Corynebacterium, Bacillus anthracis, Yersinia pestis,
Mycoplasma, Rickettsia, Chlamydia.
Pharmacokinetics
Absorption
Incompletely absorbed orally & absorption is lowered by ingestion of dairy products and
antacids. This problem is less with Doxycycline and minocycline.
Distribution
Widely distributed throughout the body including urine and prostate, liver, spleen, bone
marrow and in bone, dentine and enamel of unerupted teeth. Minocycline Passage CSF
and all tetracyclines cross the placenta and enter the fetal circulation and amniotic fluid.
High concentrations are found in breast milk.
W
Metabolism and excretion

Partly metabolised in liver and metabolites & excreted in bile. Doxycycline not
reabsorbed through intestine and excreted via bile through feces.
Adverse effects
Gastric discomfort (Nausea, Vomiting, Diarrhoea, Colitis)
Deposition on calcified tissues in children and causes discoloration and hypoplasia of
teeth and stunting of growth.
Fatal hepatoxicity especially in pregnant women
Photoxicity
Vestibular problems (dizziness, nausea, vomitting): especially with minocycline
Superinfections: candida (vagina), resistant staph. (intestine)
Benign intracranial hypertension characterized by headache and blurred vision
Contraindications
In renal failure (except: doxycycline can be given); children <12 years; pregnant and
lactating mother.
Uses
i.
Mycoplasmal, chlamydial, rickettsial infections
ii.
Respiratory tract infection
iii.
Urinary tract infection
iv.
Plague
v.
Cholera
vi.
Gonorrhoea
vii.
Syphillis
viii.
Streptococcal and staphylococcal infection
ix.
Acne
Dosage
Doxycycline
200 mg on first day then 100 mg daily
Severe infection: 100 mg BD
Acne: 50 mg daily for 6-12 weeks
Chloramphenicol (*** Indicated only for life threatening infections)

Active against gram positive and gram negetive organisms. Broad spectrum antibiotics
and because of its toxicity used only for life threatening infections.
Mechanism of Actions (MOA)
Inhibits protein synthesis in bacteria and to a lesser extent in eukaryotic cells.
It binds reversibly to the 50S ribosomal subunit.
W
Figure: 2.1.17- Mechanism of Action of Chloramphenicol
It prevents the binding of the amino acid containing end of the aminoacyl tRNA to the
acceptor site on the 50S ribosomal subunit. The interaction between peptidyltransferase and its amino acid substrate is blocked, inhibiting peptide bond formation.
Chloramphenicol also inhibits protein synthesis in mammalian mitochondria via
a similar mechanism, perhaps because their ribosomes some what resemble bacterial
ribosomes; erythropoietic cells are particularly sensitive.
Antimicrobial spectrum
Broad spectrum & bacteriostatic but cidal for H. influenzae, N. meningitidis, S.
pneumonia.
Rickettsiae, chlamydia, mycoplasma, salmonella, bordetella, klebsiella
Resistance is done via formation of Acetyl CoA transferase which inactivates the drug.
Pharmacokinetics
Given orally or parenterally and crosses BBB even if there isn't meningitis.
Inactivated in liver by glucuronidation.
10% of parent compound excreted through glomerular filteration.
W
&+$37(5$17,0,&52%,$/'58*6
(i)

d. Aminoglycosides
Aminoglycosides
A group of bactericidal antibiotics originally obtained from various streptomyces species
and sharing chemical, antimicrobial, pharmacologic and toxic characteristics.
Used most widely against gram negative enteric bacteria especially in bacteremia and
sepsis in combination with vancomycin or a penicillin.
Variable cross resistance & Synergize with inhibitors of bacterial wall synthesis.
Group includes: streptomycin, neomycin, kanamycin, amikacin, gentamicin,
tobramycin, sisomicin, netilmicin and others.
They are water soluble, stable in solution and more active at alkaline than at acid pH.
Frequently exhibit synergism with beta - lactams or vancomycin in vitro.
In combination they eradicate organisms more rapidly than would be predicted from
the activity of either single agent.
At high concentrations aminoglycosides may complex with beta -lactam drugs,
resulting in loss of activity and they should not be mixed together for administration.
Common properties of aminoglycosides
Used as sulfate salts which are water soluble.
Ionize in solutions: not absorbed orally, distribute extracellularly & do not cross BBB.
Bactericidal & more active in alkaline pH.
Excreted unchanged in urine (glomerular filteration).
Intereferes bacterial protein synthesis.
Active against gram positive aerobic bacilli.
Narrow therapeutic index.
Ototoxicity and nephrotoxicity.
Rapidly bactericidal and they are driven by the membrane electrical potential. It diffuse
through aqueous channels formed by porin proteins in the outer membrane of gram
negative bacteria and enters the periplasmic space. This rate limiting process can be
blocked or inhibited by a reduction in pH or anaerobic conditions as in an abscess.
Once inside the cell, it binds to polysomes and interferes with protein synthesis by
causing misreading and premature termination of mRNA translation. The resulting
aberrant proteins may be inserted into the cell membrane altering permeability and
further stimulating aminoglycoside transport.
W
Figure: 2.1.18- Mechanism of Action

R Aminoglycoside binds to the 30S ribosomal subunit and interferes with initiation of
protein synthesis by fixing the 30S50S ribosomal complex at the start codon (AUG)
of mRNA. As 30S50S complexes downstream complete translation of mRNA and
detach the abnormal initiation complexes, so-called streptomycin monosomes
accumulate & thus blocking further translation of the message.
R Aminoglycoside binding to the 30S subunit also causes misreading of mRNA leading
to premature termination of translation with detachment of the ribosomal complex and
incompletely synthesized protein.
R Incorporation of incorrect amino acids, resulting in the production of abnormal or non
functional proteins.
Resistance
An altered receptor where the 30S ribosomal subunit binding site has a lowered
affinity for aminoglycosides.
Plasmid associated synthesis of enzymes that modify and inactivate aminoglycoside.
Bactericidal & effective against aerobic gram negative bacilli.
R Gram negative bacilli: Pseudomonas aeruginosa, Vibrio cholerae, Yersinia
pestis, Francisella tularensis.
R Gram negative rods: Enterobacter aerogenes, Escherichia coil, Klebsiella
pneumoniae, Proteus, Serratia marcescens.
W
Figure: 2.1.19- Antibacterial Spectrum

Pharmacokinetics
Absorption
Aminoglycosides are highly polar and thus, poorly absorbed from the GIT and for this
reason given parenterally.
Distribution
Distribute mainly to ECF & T1/2: 2-5 hours. Poor transfer to CSF. High concentrations
accumulate in the renal cortex and in the endolymph and perilymph of the inner ear which
may lead to nephrotoxicity and ototoxicicity. It crosses the placental barrier and may
accumulate in fetal plasma and amniotic fluid.
Elimination
No Metabolism and rapidly excreted into urine unchanged. Dosage adujuchment requires
if renal failure patients.
Uses
i.
Serious aerobic gram negative bacilli infections.
E.g. septicaemia, renal, pelvic & abdominal sepsis
(DOC Gentamicin; if resistant then amikacin)
R For pseudomonas infections, gentamicin, tobramycin or amikacin are
combined with ticarcillin or piperacillin for a synergistic effect.
ii.
Bacterial endocarditis (Gentamicin can be given).
iii.
Tuberculosis, tularaemia, plague (Streptomycin).
W
iv.
v.
Brucellosis (Gentamicin + tetracycline).

Topical uses
R Topically used for aminoglycosides are too toxic for systemic use.
E.g. Neomycin and framycetin, Tobramycin.
Contraindication
i.
Pregnancy
ii.
Renal failure
Adverse effects
Factors increase risk of toxicity
i.
High dose
ii.
Long duration uses
iii.
Inefficient renal clearance. E.g. Cause of any disease, age.
iv.
Co-admintration of other potentially nephrotic drugs such as Loop-diuretic,
Amphotericin.
v.
Dehydrated patient
A. Ototoxicity
Hearing loss, vertigo & tinnitus (irreversible) and motion related headache, dizziness or
nausea.
Serious ototoxicity can occur with topical application including eardrops.
Ototoxicity enhanced with loop diuretics
E.g. furosemide, bumetanide, ethacrynic acid.
B. Nephrotoxicity
Retention of the aminoglycosides by the proximal tubular cells disrupts calcium mediated
transport processes and results in kidney damage ranging from mild renal impairment
(reversible) to severe acute tubular necrosis (irreversible).
Risk factors: Low blood pressure, Loop diuretics, advanced age.
C. Neuromuscular paralysis
It is due to intraperitoneal or intrapleural application of large dose.
Risk fator: myasthenia gravis patients.
D. Allergic reactions
Contact dermatitis is a common reaction to topically applied neomycin.
Gentamicin
Active against Pseudomonas, Klebsiella, Enterococci , E. Coli & most taph. Infections.
R Empiric treatment of septicemia: (gentamicin + beta-lactam)
R Serious G -ve septicemia: (DOC gentamicin)
R Abdominal & pelvic sepsis: (gentamicin in combination)
W
R Strept. & enterococcal endocarditis: (gentamicin + benzyl penicillin / Pen G)

R Staph endocarditis: (gentamicin + antistaph. Penicillin)
Incidence of nephrotoxicity is 2-3 times > ototoxicity
Therapy should rarely exceed 7 days
Gentamicin applied to eye: effective corneal & aqueous humor concentrations.
Tobramycin
Identical to gentamicin but more active against pseudomonas
Much less active in treatment of enterococcal endocarditis
Less nephrotoxic
Amikacin
Same activity on gram negative species as gentamicin and tobramycin
More resistant to inactivating enzymes than gentamicin
Reserved for infections with gentamicin resistant organisms (it is costly)
Effective in multiple drug resistance Tuberculosis including resistance to streptomycin.
Netilmicin
The least susceptible to inactivating enzymes.
Active against some gentamicin & tobramycin resistant bacteria
Less ototoxic and nephrotoxic
Neomycin & Framycetin (Used topically; Broad spectrum)
i.
Skin, eye and ear infections.
ii.
Orally to decrease bacterial load in preparation for bowel surgery.
iii.
In hepatic coma it decreases coliform bacteria and hence decreases ammonia
intoxication.
Streptomycin
Superseded as a first line choice for tuberculosis
Most effective in enterococcal infection (if used with pen G)
W
&+$37(5$17,0,&52%,$/'58*6
(i)
e. Macrolides & Urinanary Antiseptics
Macrolides
A group of antibiotics with a macrocyclic lactone structure. They are used as an
alternative to penicillin in individuals who are allergic to beta lactam antibiotics.
Effective against most of gram positive and few gram negative organisms.
Drugs in this group: Erythromycin, Roxithromycin, Clarithromycin, Azithromycin.
Figure: 2.1.20- Mechanism of Action of Macrolides

They are bacteriostatic at low but bactericidal at high concentrations. It inhibits protein
synthesis by binding reversibly to 50S ribosomal subunits of sensitive microorganisms. It
inhibits the translocation step wherein the nascent peptide chain temporarily residing at
the acceptor (A) site of the transferase reaction fails to move to the peptidyl (P) or donor
site. The binding site is either identical to or in close proximity to that for lincomycin,
clindamycin and chloramphenicol.
W
Figure: 2.1.21- Antibacterial Spectrum of Macrolides
Erythromycin: it is same as pen G, gram positive, not MRSA, Nisseria gonorrhea,
Chlamydia, Mycoplasma, Legionella, Campylobacter jejuni, Gardnerella vaginalis,
Ureaplasma.
Azithromycin: H. Influenzae, Moraxella catarrhalis, Chlamydia trachomatis.
Roxithromycin: Branhamella catarrhalis, Gardnerella vaginalis, Legionella.
Clarithromycin: Mycobacterium avium complex, Helicobacter pylori, Mycobacterium
leprae.
Resistance
Inability of the organism to take up the antibiotic. A decreased affinity of the 50S
ribosomal subunit for the antibiotic resulting from the methylation of an adenine of the
23S bacterial ribosomal RNA. Macrolide hydrolysis by esterases produced by
Enterobacteriaceae.
Pharmacokinetics
Administration
Erythromycin base is acid labile, so it is administered as enteric coated tablets or as an
ester. Food may impair absorption.
Esters of erythromycin base (E.g. Stearate, Estolate)
Clarithromycin and azithromycin are stable to stomach acid and are readily absorbed.
Food interferes with the absorption of erythromycin and azithromycin.
Erythromycin given I.V. can cause thrombophlebitis.
W
Distribution
Erythromycin is widely distributed in the body, serous cavities, crosses placenta but
not blood brain barrier. 70-80 % plasma protein bound.
Clarithromycin and azithromycin are widely distributed in tissues. Serum levels of
azithromycin are low.
Drug is concentrated in neutrophils, macrophages and fibroblasts.
Metabolism
Azithromycin- no metabolism.
Erythromycin is extensively metabolized and inhibits oxidation of many drugs.
Clarithromycin is oxidized to the 14-hydroxy derivative.
Elimination
Erythromycin and azithromycin: excreted primarily in bile.
Clarithromycin and its metabolites are eliminated by kidney as well as liver.
Adverse effects
i.
GI disturbances: Nausea, Vomiting, Diarrhoea, Anorexia.
ii.
Cholestatic jaundice: erythromycin estolate
iii.
Ototoxicity: for high dose of erythromycin
iv.
Skin rashes
v.
Minimally prolonged QT interval.
Contraindication
It is contraindicated in liver dysfunction.
Drug interaction
It inhibits hepatic oxidationm of theophylline, carbamazepine, warfarin, terfenadine,
valproate, astemizole, and cyclosporine.
Uses of Macrolides
Erythromycin
i.
Alternative to penicillin in individuals hypersensitive to penicillins:
a) Streptococcal pharyngitis, tonsillitis, respiratory tract infections caused by
pneumococci, H. influenzae
b) Diphtheria
c) Tetanus
d) Syphillis
e) Gonorrhoea
ii.
It is Drug of choice for:
a) Atypical pneumonia (Mycoplasma)
b) /HJLRQQDLUHVSQHXPRQLD
c) Whooping cough
W
Aaverse drug reactions

i.
GI distress
ii.
At high dose - albuminuria, hematuria and rashes.
iii.
Sulfonamide reacts with formaldehyde.
iv.
Contraindication: Renal failure patients (Mandelic acid may precipitate, so
methenemine mendelic acid should not be used in renal failure patients).
Nitrofurantoin
It is a synthetic nitrofuran that is used to prevent and treat urinary tract infections. The
antibacterial activity is higher in acidic urine.
Bacteria reduce nitrofurantoin to toxic products that inhibits various enzymes and damage
DNA.
Antimicrobial spectrum
Urinary tract infections due to E. coli and gram positive bacteria.
Pharmacokinetics
Oral absorption: rapid & complete
Low plasma concentration
Rapid excretion by glomerular filtration
Drug makes urine brown
i.
Nausea, Vomiting, Diarrhoea, when taken with food or milk can decrease symptoms
ii.
Acute pneumonitis
iii.
Neurological problems: headache, nystagmus, polyneuropathies
iv.
Hemolytic anemia
v.
Contraindication: Pregnancy, Neonates, G6PD deficiency patients.
W
&+$37(5$17,0,&52%,$/'58*6
(ii)
Anti Tubercular Drugs
Treatment of Tuberculosis: History & Drugs

Tuberculosis
It is chronic granulomatous disease caused by Mycobacterium tuberculosis. The disease
primarily affects lungs and causes pulmonary Tuberculosis. It can also affect intestine,
meninges, bones, joints, intestine, lymph node, skin. Major health problem in developing
countries. Emergence of the multi drug resistant Tuberculosis is another important issue.
It has a remarkable progress in the last 50 years.
History of Tuberculosis treatment
R Streptomycin: - 1947
R Isoniazid: - 1952
R Ethambutol: - 1961
R Rifampicin: - 1962
Tuberculocidal drugs
i.
Rifampicin
ii.
Isoniazid
iii.
Pyrazinamide
iv.
Amikacin
v.
Capreomycin
vi.
Streptomycin
vii.
Kanamycin
Tuberculostatic drugs
i.
Ethambutol
ii.
Ethionamide
iii.
Thiacetazone
iv.
Para-aminosalicylic acid
Classification (according to their clinical utility)
First line drugs: have high anti tubercular efficacy as well as low toxicity and are used
routinely.
i.
Isoniazid (H)
ii.
Rifampicin (R)
iii.
Pyrazinamide (Z)
iv.
Ethambutol (E)
v.
Streptomycin (S)
W
Second line drugs: have low anti tubercular efficacy or high toxicity or both and used
in special circumstances
i.
Thiacetazone (Tzn)
ii.
Para amino salicylic acid (PAS)
iii.
Ethionamide (ETM)
iv.
Cycloserine (Cys)
v.
Kanamycin (Kmc)
vi.
Amikacin (Am)
vii.
Capreomycin (Cpr)
Newer Drugs
i.
Ciprofloxacin
ii.
Ofloxacin
iii.
Clarithromycin
iv.
Azithromycin
v.
Rifabutin
Isoniazid
It is a hydrazide of isonicotinic acid and a synthetic analog of pyridoxine. It is active
selectively effective against Mycobacterium tuberculosis. It prevents the synthesis of the
component that is unique to Mycobacterial cell walls. It is bactericidal against the actively
multiplying bacteria and bacteriostatic against the non dividing bacilli. It has little or no
effect against other bacteria. Unless the patient is not able to tolerate it or bacilli are
resistant it is primarily tuberculocidal.
Inhibition of enzymes required for the synthesis of the mycolic acid which are unique
fatty acid component of the mycobacterial cell wall.
Pharmacokinetics
Orally well absorbed & penetrates all body tissue, tubercular cavities, placenta, CSF. It
also penetrates cells to act on intracellular mycobacterium. It is extensively metabolized
in the liver by acetylation.
Adverse Effects
It is well tolerated by the most of the patients but peripheral neuritis, Hepatitis, Rashes,
Fever, Athralgia, Hemolysis in G6PD deficiency patients, Acne, Lupus like syndrome,
Restlessness.
R Contraindicated in hepatitis (jaundice).
R Drug interactions: aluminium hydroxide inhibits isoniazid absorption.
Isoniazid Dose
R Adult dose: 3-5 mg/kg/day (if >50kg: 300 mg OD)
R Child dose: 10-20 mg/kg/day
W
Rifampicin
It is a semisynthetic derivative of rifamycin B obtained from Streptomyces mediterranei.
It is bactericidal to Mycobacterium tuberculosis and many other gram positive and
negative like Staph. aurues, N. meningitis, H. Infleunzae, E Coli. It is efficacious as
isoniazid and better than the other drug. It has a good sterilizing and the resistance
preventing action. It works for both extra and the intra cellular organism.
Rifampicin inhibits DNA dependent RNA polymerase and thus inhibits protein synthesis.
Pharmacokinetics
Well absorbed orally and widely distributed in the body, penetrates cavities, casseous
masses, placenta and the meninges. It is metabolized in the liver by enterohepatic cycle &
Excreted mainly in bile and very less with the kidney.
Adverse effects
i.
Hepatitis, jaundice
ii.
Respiratory syndrome (Breathlessness which may be associated with shock and
collapse)
iii.
Cutaneous syndrome such as flushing, pruritus, rash.
iv.
Flu Syndrome such as chills, fever, headache, malaise, bone pain.
v.
Abdominal Syndrome such as nausea, vomiting, abdominal cramps.
vi.
Orange red urine (Harmless)
Uses
i.
Tuberculosis
ii.
Leprosy
iii.
Chemoprophylaxis of the meningococcal and H. Influenza meningitis & carrier state.
iv.
Severe staphylococcal infection
v.
Legionella infection
vi.
Brucellosis (First line: Doxycilline + Rifampicin)
Drug Interaction
R Potent Microsomal enzyme inducer enhances the metabolism of the warfarin, oral
contraceptives (OCP), sulfonylureas, corticosteroids and the digoxin.
R Contraceptive failure may occur
R Contraindicated in Jaundice
Rifampicin Dose
R Adult dose:
Above 50 kg: 600 mg once daily in empty stomach
Below 50 kg: 450 mg once daily in empty stomach
R Child dose: 10 mg/kg/day
W
Pyarazinamide
It is chemically similar to isoniazid and a weak tuberculocidal but active in acid medium.
It is highly lethal to the intra cellular located bacilli as well as to those at the sites
showing on inflammatory response. It is highly effective for the first two months therapy.
Mechanism of action is same as Isoniazid and also inhibits mycolic acid synthesis but by
interacting with the different fatty acid synthetase encoding gene.
Pharmacokinetics
Well absorbed orally and widely distributed in the body, penetrates CSF, metabolized in
the liver and excreted in urine. In hepatic and renal failure condition plasma half life is
increased.
Adverse drug reactions
i.
Gastrointestinal irritation
ii.
Hyperuricemia and gout
iii.
Hepatotoxicity
iv.
Skin rashes, fever, flushing, arthralgia, loss of diabetic control.
v.
Contraindicated in liver disease.
Pyarazinamide Dose
R Adult dose:
Above 50 kg 2000 mg/day
Below 50 kg 1500 mg/day
R Child dose: 20-30 mg/kg/day
Ethambutol
It is bacteriostatic & is used in conjugation with anti tuberculoisis drug to delay or
prevent the emergence of the resistant bacilli.
Mechanism of action is not fully understood. It has been found to inhibit arabinosyl
transferase involved in synthesis of arabinoglactan which is a component of
mycobacterial cell wall and interfere with the mycolic acid incorporation in the
myocobaterial cell wall.
Pharmacokinetics
Orally absorbed about 3/4th & widely distributed in the body and penetrates meninges.
Less than half of the drug gets metabolize and excreted mainly through kidney, so if renal
impairement than dose should be reduced.
W
Adverse effects (Relatively non toxic)

i.
Optic neuritis
ii.
Loss of visual acuity
iii.
Filed defects
iv.
Reversible red green color blindness
v.
Hyperuricaemia
vi.
Others: nausea, rash, fever, neurological changes.
(Note: ophthalmological monitoring is must during the course of treatment).
Contraindication
i.
Optic neuritis
ii.
Visual impairement
iii.
Child below 6 years
Ethambutol Dose: 15 mg/kg/day
Streptomycin
It is the first anti tubercular drug clinically used for Tuberculocidal but less effective
than Isoniazid and Rifampicin. It penetrates tubercular cavities but does not cross CSF. It
acts only on extracellular bacilli and it has popularity declines because of its adverse
effects & I.M. injection.
It binds with ribosomal 30S subunit and inhibits protein synthesis.
Adverse effects
i.
Nephrotoxicity
ii.
Hepatotoxicity
iii.
Contraindicated in pregnancy, patients with vestibular nerve damage.
Uses
i.
Tuberculosis
ii.
Plague
iii.
Tularemia
iv.
Subacute bacterial endocarditis (SABE)
Streptomycin Dose
R Adult dose:
Less than 33 kg: 500 mg OD deep I.M.
33 - 50 kg: 750 mg OD deep I.M.
More than 50 kg: 1g deep I.M.
R Child: 15-20 mg/kg/day deep I.M.
W
Thiacetazone
It is Tuberculostatic & low efficacy drug. It is used along with Isoniazid as a substitute
for Para amino salicylic acid.
It blocks synthesis of mycolic acid.
i.
Hepatitis
ii.
Steven Johnson syndrome
iii.
Exfoliative dermatitis
iv.
Anorexia
v.
Abdominal discomfort
vi.
Loose motion
vii.
Bone marrow suppression (rare).
Para-amino salicylic acid
It is folate synthesis antagonist & it is active exclusively against Tuberculas bacilli.
It prevents synthesis of folic acid in susceptible organism by competitively blocking
conversion of aminobenzoic acid to dihydrofolic acid.
i.
Hepatoxicity
ii.
GIT distress Nausea, Vomiting, Diarrhoea, Anorexia, Epigastric pain
iii.
Hypothyroidism (Goitre)
Ethionamide
It is congener of Isoniazid which blocks synthesis of mycolic acids and works on both
extracellular and intracellular organism.
i.
Severe GIT irritation
ii.
Hepatitis
iii.
Neurotoxicity
iv.
Endocrine disturbance
E.g. Gynecomastia, Impotence.
Rifabutin
It is structurally similar to rifampicin and mechanism of action but less active against M.
Tuberculosis & more active against Mycobacterium avium intracellular complex (MAC).
W

i.
Gastrointestinal intolerance
ii.
Rash
iii.
Granulocytopenia
Treatment of Tuberculosis: Method

Aims
i.
To cure the patient of Tuberculosis
ii.
To prevent death from active Tuberculosis or its late effects
iii.
To prevent Tuberculosis relapse
iv.
To decrease Tuberculosis transmission to others.
First line drugs & their mode of action
i.
Isoniazid Bactericidal high potency dose: 5 mg/kg/day.
ii.
Rifampicin Bactericidal high potency dose: 10 mg/kg/day.
iii.
Pyrazinamide Bactericidal low potency dose: 25 mg/kg/day.
iv.
Ethambutol Bacteriostatic low potency dose: 15 mg/kg/day.
v.
Streptomycin Bactericidal low potency dose: 15 mg/kg/day.
Principle of therapy
Kill dividing bacilli
Kill persisting bacilli
Categoriy of Tuberculosis treatment
Depends on site of the disease (E.g. pulmonary or extra pulmonary and its severity).
Sputum Positive or negative and history of the previous treatment (it has high chances of
the resistance).
Category I: Description
New cases of the positive pulmonary Tuberculosis.
New smear negative Pulmonary Tuberculosis with extensive pulmonary involvement.
New cases of the Severe form of the extra - pulmonary Tuberculosis. Ie. Meningitis,
pericarditis, bilateral and extensive pleural effusion.
Category II: Description
Smear positive failure, relapse and the interrupted cases.
Treatment failure who again become smear positive after 5 months from the
commencing the treatment.
These patients are at the high risk of the developing multi-resistant Tuberculosis.
W
&+$37(5$17,0,&52%,$/'58*6
(iii)
Anti Leprotic Drugs
Leprosy
It is DOVRNQRZQDV+DQVHQVGLVHDVHcaused by Mycobacterium leprae. It affects skin,
mucous membrane and nerves.
Drugs used for treatment are:
i.
Dapsone
ii.
Rifampicin (see page: 71)
iii.
Clofazimine
iv.
Ofloxacin
v.
Minocycline (see page: 54)
vi.
Clarithromycin (see page: 67)
Dapsone (Diamino - diphenyl sulphone)
Oldest, cheapest and most active and most commonly used antileprotic drug
Structurally related to sulfonamides and is bacteriostatic
Highly toxic so, the drug is given increasingly from low dose to high dose
It inhibits folic acid synthesis which is similar to sulfonamides.
Adverse effects
i.
Hemolytic anemia
ii.
Methemoglobinemia
iii.
Anorexia
iv.
Nausea
v.
Headache
vi.
Photoxicity
vii.
Hypermelanosis
viii.
Allergic rashes
ix.
Hepatitis
x.
Agranulocytosis (rare)
Contraindication
i.
Severe anemia Hb <7%
ii.
G6PD deficiency
iii.
Hypersensitivity rxn
W
Indication of Dapsone
i.
Leprosy
ii.
Pneumocystic pneumonia in HIV patients.
iii.
Chloroquine resistant malaria (combined with pyrimethamine)
iv.
Nodular type acne vulgaris
Dose of Dapsone: 100 mg OD orally given.
Clofazimine
It is phenazine derivative dye having leprostatic and anti-inflammatory properties.
Clofazimine binds with DNA templates and interferes protein synthesis.
Adverse effects
i.
Red brown discoloration of skin
ii.
Eosinophilic enteritis
iii.
Discoloration of skin and body secretion
iv.
Dryness of skin and itching
v.
GI disturbances
vi.
Acne form eruption and photoxicity
Contraindication
i.
1st trimester pregnancy
ii.
Liver disease
iii.
Kidney disease
Indication
i.
As a component of multidrug therapy
ii.
As a second line drug for dapsone resistant cases
iii.
In lepra rxn (due to its anti-inflammatory effect)
Dose of Clofazimine:
300 mg once a month supervised
50 mg daily self administered
W
iv.
v.
vi.
vii.
viii.
ix.
Iritis
Orchitis
Myositis
Lymphadenitis
Fever
Oedema
Management
Mild: Aspirin 600 mg 6 hourly
Severe: Prednisolone 20-40 mg reducing over 1-6 months
If eye involment: 1% hydrocortisone drops or ointment
W
&+$37(5$17,0,&52%,$/'58*6
(iv)
Anti Fungul Drugs
Fungul infection/Mycoses
They are chronic in nature and many common mycotic infections are superficial and only
involve the skin (cutaneous mycoses). They may also penetrate the skin, causing sub cutaneous infection, Life threatening infection (systemic). Symptoms vary from cosmetic
to life threatening.
Types of fungal infections - Mycoses
i.
Superficial mycoses: Affect the skin, hair and nails
ii.
Subcutaneous mycoses (tropical): Affect the muscle and connective tissue
immediately below the skin
iii.
Systemic (invasive) mycoses: Involve the internal organs
iv.
Allergic mycoses: Affect lungs or sinuses. Patients may have chronic asthma, cystic
fibrosis or sinusitis.
Causative fungi
Superficial infections by:
a) Dermatophytes
b) Candida
Deep infections are:
a) Candidiasis
b) Aspergillosis
c) Coccidiomycosis
d) Histoplasmosis etc
Anti Fungal drugs in details

Classification of anti fungal drugs (drugs wise)
i.
Antibiotics
a) Polynes: Amphoterecin B, Nystatin, Hamycin, Natamycin (primaricin)
b) Heterocyclic benzofuran: Griseofulvin
ii.
Antimetabolites: Flucytosine (5-FC)
iii.
Azoles:
a) Imidazoles:
Topical: Clotrimazole, Econazole, Miconazole
Systemic: Ketoconazole
b) Triazoles:
Systemic: Fluconazole, Itraconazole
W
iv.
v.
Allylamine: Terbinafine
Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor,
Ciclopirox oalamine, Sod. thiosulfate
Classification of antifungal drugs

Subcutaneous and systemic mycoses
i.
Amphotericin B
ii.
Fluconazole
iii.
Itraconazole
iv.
Ketoconazole
Superficial/topical mycoses
i.
Clotrimazole
ii.
Econazole
iii.
Griseofulvin
iv.
Miconazole
v.
Nystatin
Figure: 2.4.1- Antifungul therapy targets
Antifungal therapy targets

i.
In cell membrane: use principally ergosterol instead of cholesterol.
ii.
In DNA systhesis: some compounds may be selectively activated by fungi, arresting
DNA synthesis.
iii.
In cell wall: unlike mammalian cells, fungi have a cell wall.
W
Amphotericin B (Systemic mycoses)

It is the antifungal agent with the broadest spectrum of activity and remains the drug of
choice for the vast majority of life-threatening systemic fungal infections. It is produced
by Streptomyces nodusus & naturally occurring polyene macrolide antibiotic. It is
amphoteric in nature & nearly insoluble in water and is therefore prepared as a colloidal
suspension.
Mechanism of action
Amphotericin B binds to ergosterol and alters the permeability of the cell by forming
amphotericin B-associated pores in the cell membrane. The pore allows the leakage of
intracellular ions and macromolecules, eventually leading to cell death. Some binding to
human membrane sterols does occur, probably accounting for the drug's prominent
toxicity.
Antifungal spectrum
Fungistatic or fungicidal depending upon organism and drug concentration. It is effective
against wide range of fungi such as Candida albicans
Histoplasma capsulatum
Cryptococcus neoformans
Coccidioides immitis
Aspergillus sps
Blastomyces dermatitidis.
Resistance
The organism may develop resistance due decreased erosterol content of cell
membrane.
Pharmacokinetics
Absorbed poorly from the gastrointestinal tract and it is administered by intravenous route
but sometimes intrathecal route for treatment of meningitis caused by fungi. Highly
bound to plasma protein; T1/2: 15 days. Crosses placenta, distributed widely. Little
amphotericin B penetrates into CSF, vitreous humor or amniotic fluid. Slowly Excreted in
urine & some is also eliminated via bile.
Adverse effects:
Acute reaction (occurs with each infusion acutly)
i.
Fever and chills
ii.
Hypotension
iii.
Nausea, vomiting
iv.
Thrombophlebitis
v.
Dyspnoea
W
Figure: 2.4.2- Mechanism of Action of Flucytosine

Antifungal spectrum
i.
Narrow spectrum
ii.
Chromoblastomycosis
iii.
Cryptococcosis and Candidiasis
iv.
Used in combination with Amphotericin-B to reduce resistance
Resistance
Is arising during therapy is an important cause of therapeutic failure when flucytosine is
used alone for cryptococcosis and candidiasis; it can result from loss of the permease
necessary for flucytosine transport or decreased activity of UPRTase or cytosine
deaminase.
W
Pharmacokinetics
Well absorbed orally & distributed throughout the body water. Good Penetration into
CSF, important in fungal meningitis. T1/2: 3-4 hours & excretion by glomerular filtration.
Serum level should be monitored in kidney dysfunction patients.
Adverse effects
i.
Hematological toxicity: Leucopenia, Anemia, Thrombocytopenia.
ii.
GI disturbances: Nausea, Vomiting, Diarrhoea, Severe enterocolitis.
iii.
Hepatic dysfunction (Reversible).
Uses
i.
Monotherapy: Now limited use.
ii.
Candidiasis (Combined with Amphotericin B/Fluconazole)
iii.
Aspergillosis
iv.
Cryptococcosis (Combined with Amphotericin B/Floconazole)
Ketoconazole (Systemic mycoses)
It was the first oral azole introduced into clinical use. It is broad spectrum antifungal
useful in both dermatophytes and deep mycosis. It also inhibits gonadal and adrenal
steroid synthesis. It suppresses testosterone and cortisol synthesis.
Mechanism of action
It inhibits fungal cytochrome p450 enzyme system thus inhibiting demethylation of
lanosterol to ergosterol which is the main sterol of fungal membrane. Thus increases
permeability. It has synergestic action with flucytosine.
Antifungal spectrum
i.
Fungistatic or fungicidal depending upon dose
ii.
Same as amphotericin B
iii.
Histoplasmosis, candidiasis
iv.
Nonmeningial coccidiomycosis and blastomycosis
v.
Dermatophytic infection
Pharmacokinetics
Administered orally & absorbed through gastric mucosa by dissolving in acidic gastric
contents. Highly bound to plasma proteins >95%. It does not enter to CSF. Metabolism
mainly occurs in liver & excretion mainly through bile.
Adverse effects
i.
GI disturbance: Nausea & Vomiting (most common)
ii.
Hepatic dysfunction: elevation of serum transaminase
iii.
Endocrine effects: gynecomastia, decreased libido, impotence, menstrual
irregularities.
W
Contraindication
It should not be given with Amphotericin B; pregnancy, lactating mother, liver disease.
Drug interaction
i.
Inhibits cytochrome P450 and hence increases the toxicity of cyclosporine, phenytoin,
terfinadine, astemizole, sucralfate, tolbutamide and warfarin.
ii.
Rifampicin is a cytochrome P450 inducer so decreases the level of ketoconazole and
other azoles.
Fluconazole (Systemic mycoses)
It is recently developed water soluble triazoles having a wider range of activity than
Ketokonazole. It has excellent penetration into CSF.
Mechanism of Action
It inhibits synthesis of fungal membrane ergosterol (same as Ketokonazole).
Antifungal spectrum
i.
Good activity against C. albicans and Cryptococcus neoformans.
ii.
Non-albicans Candida species more likely to exhibit primary resistance.
Resistance
i.
Always: Candida krusi, Candida glabreta.
ii.
Sometimes: Candida parapsilosis, Candida tropicalis, Candida kefyr.
Pharmacokinetics
Almost completely absorbed from the GI tract & distributed widely. Low plasma protein
bounded <12% & >90% of drug excreted unchanged through kidney. T 1/2: 25 hours.
Readily diffuses into body fluids, including breast milk, sputum, saliva and CSF.
Adverse effects
i.
Nausea, Vomiting
ii.
Abdominal pain
iii.
Rashes
iv.
Headache
Contraindication
i.
Pregnancy
ii.
Lactating mothers
Drug interaction
i.
Effects hepatic drug metabolism to a lesser extent than Ketoconazole.
ii.
May increase phenytoin, cyclosporin, rifabutin, warfarin, sulfonylureas and
zidovudine concentrations. Rifampin reduces fluconazole levels.
W
Uses
i.
Cryptococcal meningitis
ii.
Coccidiodal meningitis
iii.
Histoplasmosis
iv.
Sporotrichosis
v.
Systemic and mucosal candidiasis
Dose of fluconazole
i.
Vaginal candidiasis: 150 mg single dose orally.
ii.
Tinea infections and cutaneous candidiasis: 150 mg once a week for 4 weeks.
iii.
Cryptococcal meningitis and other systemic fungal infections: 200 - 400 mg/day for
4-12 weeks.
iv.
Fungal keratitis: 0.3 % eyedrops.
Itraconazole (Systemic mycoses)
It is a synthetic triazole. Lacks endrocrinologic side effects of ketoconazole. MOA is
same as other azoles.
Pharmacokinetics
Well absorbed orally, food increases absorption & good distribution in body tissues. High
plasma protein binding and highly metabolised in liver. Poor CSF penetration and dRHVQW
inhibit Androgen synthesis.
i.
Nausea, Vomiting
ii.
Rashes (imunocomprised patients)
iii.
Hypokalemia
iv.
Hypertension
v.
Edema and headache.
Drug interaction
i.
Itraconzole inhibits CYP3A4: Increases level of terfinadine, astemizole, cisapride,
phenytoin, digoxin, sulfonylureas and cyclosporine.
ii.
Rifampin and carbamazepine induces itraconazole metabolism.
Uses
i.
Blastomycosis (DOC).
ii.
Effective in AIDS associated Histoplasmosis.
iii.
Broad spectrum antifungal: Aspergillosis, Candidemia, coccidioidomycosis,
Cryptococcosis.
W
&+$37(5$17,0,&52%,$/'58*6
(v)
Anti Viral Drugs
Viruses
Consist of a core genome in a protein shell and some are surrounded by a lipoprotein.
Obligate intracellular parasites. They have lack of cell wall and cell membrane. They do not
carry out metabolic processes. The replication depends on the host cell machinery.
Figure: 2.5.1- Viruses
W
Steps for Viral Replication

i.
Adsorption and penetration into cell
ii.
Uncoating of viral nucleic acid
iii.
Synthesis of regulatory proteins
iv.
Synthesis of RNA or DNA
v.
Synthesis of structural proteins
vi.
Assembly of viral particles
vii.
Release from host cell
Antiviral drugs
i.
Anti-herpes virus
Idoxuridine, Vidarabine, Acyclovir, Gancyclovir, Foscarnet, Valacyclovir,
Famcyclovir, Trifluridine, Cidofovir.
ii.
Anti-Retro virus
a) Reverse transcriptase inhibitors
Zidovudine, Lamivudine, Didanosine, Stavudine, Zalcitabine, Abacacir, Nevirapine,
Efavirez, Delavidadine.
b) Protease inhibitors
Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir.
iii.
Anti-influenza virus
Amantadine, Rimantadine.
iv.
Non selective
Ribavirin, Interferon alpha, Pegylated interferon alpha.
v.
Anti-Hepatitis agents
Anti Herpes Viruses

Idoxuridine
It is 5-iodo-2 deoxyuridine, acts as a thymidine analogue. It is the first pyrimidine
antimetabolite used as antiviral drug.
Mechanism of Action
It competes with thymidine & gets incorporated in DNA so that abnormal DNA is formed
which breaks down easily. Abnormal viral proteins formed and infective virus cannot
form.
W

i.
Ocular irritation
ii.
Edema of lids
iii.
Photophobia
Uses
It is effective only against DNA virus and clinically mainly used in Herpes simplex
keraoconjunctivitis.
Dose of Idoxuridine
One drop of 0.1 % solution is put hourly during day and 2 hourly during night. After
acute stage is over 0.5% eye ointment may be applied 4 hourly for 3 weeks.
Vidarabine
It is one of the most effective of nucleoside analogs and is also least toxic; however it has
been supplemented clinically by acyclovir.
Mechanism of Action
It is an adenosine analogue and inside cell converted into it 5-triphosphate analog which
inhibit DNA synthesis.
i.
CNS disturbances
ii.
Fluid overload
Uses
Immunocompramised paients with herpes simplex keratitis or encephalitis.
Acyclovir
It has become one of the most prescribed drugs because of its effectiveness against herpes
viruses.
Mechanism of Action
Acyclovir is deoxyguanosine analogue antiviral drug. Its viral specific enzymes convert it
to active metabolites that inhibit DNA synthesis and viral replication.
Resistance
i.
Alteration in viral thymidine kinase
ii.
Alteration in viral DNA polymerase
iii.
Cross-resistance with valacyclovir, famciclovir and ganciclovir.
i.
Topical:
Stinging or burning sensation after each application.
W
Gancyclovir
It is an acyclic guanosine analog and it requires triphosphorylation for activation.
Monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine
kinase in HSV cells. MOA is same as acyclovir.
Adverse effects
i.
Dose dependent neutropenia
ii.
Bone marrow depression
iii.
Rash, fever, vomiting
iv.
Neuropsychiatric disturbances
v.
Teratogenic effect, carcinogenic
Uses
i.
CMV
ii.
HSV
iii.
VZV
iv.
EBV
Foscarnet
It is an inorganic pyrophosphate.
Mechanism of Action
It inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase. It
does not have to be phosphorylated.
Adverse effects
i.
Nephrotoxicity
ii.
Anemia, nausea, fever
iii.
Hypokalemia and hypomagnesemia
iv.
Seizure, arrhythmia
v.
Resistance: is due to mutations in DNA polymerase gene.
Uses
i.
HSV
ii.
VZV
iii.
CMV
iv.
EBV
v.
HHV-6
vi.
HBV
vii.
HIV
W
Valacyclovir
It is L-valyl ester of acyclovir. It is converted to acyclovir when ingested. MOA is same
as acyclovir.
Adverse effects
Nausea, diarrhea and headache.
Uses:
i.
Recurrent genital herpes
ii.
Herpes zoster infections
Famcyclovir
It is prodrug of pencyclovir. MOA is same as acyclovir. It does not cause chain
termination.
Adverse effects
Nausea, diarrhea and headache.
Uses
i.
HSV-1
ii.
HSV-2
iii.
VZV
iv.
EBV
v.
HBV
Trifluridine
It is fluorinated pyrimidine. It inhibits viral DNA synthesis same as acyclovir. It
incorporates into viral and cellular DNA.
Uses
HSV-1 and HSV-2 (topically)
Cidofovir
It is a cytosine analog & phosphorylation not dependent on viral enzymes.
Adverse effects
Nephrotoxicity (which is prevented by administration of probenecid)
Resistance: mutation in DNA polymerase gene
Uses
i.
CMV
ii.
HSV-1
iii.
HSV-2
iv.
VZV
W
v.
vi.
vii.
viii.
EBV
HHV-6
Adenovirus
Human papillomavirus
Anti Retro Viruses

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Zidovudine
It is a deoxythymidine analoge which enters the cell via passive diffusion. It must be
converted to the triphosphate form by mammalian thymidine kinase. It competitively
inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme, causes chain
termination.
Adverse effects
i.
Myelosuppression, including anemia and neutropenia
ii.
GI intolerance
iii.
Headaches and insomnia
Resistance
Due to mutations in the reverse transcriptase gene
More frequent after prolong therapy and in persons with HIV
Uses
It is available in IV and oral formulations.
i.
Activity against HIV-1, HIV-2 and human T cell lymphotropic viruses
ii.
Mainly used for treatment of HIV, decreases rate of progression and prolongs survival
iii.
Prevents mother to newborn transmission of HIV
Didanosine
It is synthetic deoxy-adenosine analog; causes pancreatitis, GI intolerance, Peripheral
neuropathy as adverse drug reaction.
Lamivudine
It is cytosine analog.
Stavudine
It is thymidine analog; causes peripheral neuropathy, Pancreatitis as adverse drug
reaction.
Abacavir
It is guanosine analog; more effective than the other agents; fatal hypersensitivity
reactions can occur as adverse effects.
W
Zalcitabine
It is cytosine analog; causes peripheral neuropathy as adverse drug reaction.
Non - Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
It binds to site on viral reverse transcriptase. It is different from NRTIs. It results in
blockade of RNA and DNA dependent DNA polymerase activity. They do not compete
with nucleoside triphosphates & do not require phosphorylation. These drugs can not be
given alone. They are substrates and inhibitors of CYP3A4.
Nevirapine
It prevents transmission of HIV from mother to newborn when given at onset of labor and
to the neonate at delivery.
i.
Hepatotoxicity (severe)
ii.
Rash in cluding (Steven Jonsen Syndromes)
Efavirenz
It is teratogenic, therefore can not be given during pregnancy.
Delavirdine
It is teratogenic, therefore can not be given during pregnancy.
Protease Inhibitors
Protease enzyme cleaves precursor molecules to produce mature, infectious virions.
These agents inhibit protease and prevent the spread of infection. These agents cause a
syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia.
Indinavir & Ritonavir
They are the specific inhibitors of the HIV-1 protease enzyme.
Adverse effects: Hyperbilirubinemia
Contraindications: inhibitor/substrate for CPY3A4, do not give with antifungal azoles.
Nelfinavir & Amprenavir
They are the specific inhibitors of the HIV-1 protease enzyme. They have less crossresistance with Amprenavir.
Adverse effects
i.
Diarrhea and flatulence (common in both Nelfinavir & Amprenavir)
i.
Can cause Stevens-Johnson syndrome (Amprenavir)
Contraindications: inhibitor/substrate for CPY3A4
W
Saquinavir
It is a synthetic peptide-like substrate analog which inhibits HIV-1 protease and prevents
cleavage of viral polyproteins.
*Fusion Inhibitors
Enfuvirtide
It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the
conformational changes required for fusion of the viral and cellular membranes. By
blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 cells.
Adverse Effects
ii.
Injection-site reactions
iii.
Hypersensitivity reaction
iv.
Increased risk of bacterial pneumonia
*Neucleotide Inhibitors
Tenofovir
It is an acyclic neucleoside phosphate analog of adenosine. It is used in combination with
other anti retrovirals for HIV-1 suppression.
Adefovir
It is an analog of adenosine monophosphate which is phosphorylated by cellular kinases.
Nephrotoxicity is the side effects and it is used in Hepatitis B.
*Treatment for Pregnant Women
Antiretroviral therapy recommended in all pregnant women to reduce risk of perinatal
transmission.
Drug used in Pregnancy: Neucleoside (NRTIs)
Zidovudine
Efficacy studies and extensive experience.
Should include in the regimen unless significant toxicity or other contraindication.
Lamivudine
Zidovudine + lamivudine is the recommended dual NRTIs backbone.
Drug used in Pregnancy: Non Neocleoside (NNRTIs)
Nevirapine
No evidence of teratogenicity
Increased risk of liver toxicity
W
Drug used in Pregnancy: Protease Inhibitors

PK and clinical trial data available for nelfinavir, saquinavir/ritonavir. Lopinavir/ritonavir
is underway but protease inhibitors are not yet studied.
Conflicting data: preterm delivery in women receiving protease inhibitors.
Drug used in Pregnancy: Fusion Inhibitors
Enfuvirtide
No studies in human pregnancy.
Insufficient data to recommend.
Figure: 2.5.3- Mechanism of Action
Anti Influenza Viruses

Amantadine & Rimantadine
Mechanism of Action
It blocks the viral membrane matrix protein, M2 which is needed for penetration. Hence
blocks penetration of influenza a virus and also Inhibits uncoating of viral nucleic acid.

i.
Insomnia, Nightmares
ii.
Dizziness, Ataxia
iii.
Lack of mental concentration, Hallucinations
iv.
Postural hypotension, Ankle edema
v.
Teratogenic effect in experimental animals
W
Uses
i.
Prophylaxis of influenza A
ii.
Treatment of influenza A
iii.
Parkinsonism
Dose of Amantadine & Rimantadin
Adult: 100 mg BD orally.
Child 5 mg/kg/day.
Non Selective Viruses

Ribavirin
It is a synthetic guanosine analog. It is effective against broad spectrum RNA and DNA
viruses.
Mechanism of Action
Ribavirn is converted to ribavirin triphosphate which inhibits viral mRNA synthesis.
Rinovrus and enterovirus contains preformed mRNA so they are resistant.
i.
Dose dependent transient anemia during oral or IV use. Aerosol is safer
ii.
Elevated bilirubin
iii.
Teratogenic effect in experimental animals.
iv.
Contraindication: Pregnancy
Uses
i.
Severe Respiratory syncitial virus (RSV) in young adults and children
ii.
Influenza A and B
iii.
Acute hepatitis A virus
Interferon D (Alfa)
It is an endogenous protein has low molecular weight glycoprotein cytokines produced by
host cell. It induces host cell enzymes that inhibit viral RNA translation and cause
degradation of viral mRNA and tRNA. It binds to membrane receptors on cell surface &
may also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion
assembly and release. It inhibits many RNA and DNA virus.
i.
Flu Like symptoms
ii.
Malaise, Fever, pain, Visual disturbance
iii.
Neurotoxicity, Mylosupression
W
Uses
i.
Chronic Hepatitis B and C
ii.
AIDS related kaposis sarcoma
iii.
Hairy cell leukemia.
iv.
H. simplex, H zoster and CMV infections
v.
Rhino viral cold
Pegylated interferon Alfa
It is a linear or branced polyethylene gylcol (PEG) moiety is attached covalently to
interferon. It increased half-life and steady drug concentrations & less frequent dosing.
Uses
Chronic hepatitis C in combination with ribavirin
Anti Hepatitis Agents

Lamivudine (it is an NRTI); given orally.
Adefovir (it is a neucleotide inhibitor); given orally.
Interferon Alfa; S/C or I.M. administration.
Pegylated Interferon Alfa; S/C administration.
Ribavirin
W
Figure: 2.6.2- Life cycle of Plasmodium
W
Figure: 2.6.1- Life cycle of Plasmodium
Classification of Antimalarial drugs (Based on stages of treatment)

Tissue schizonticides (kills schizonts in liver)
Primaquine
RBCs schizonticide
Chloroquine
Quinine
Mefloquine
Pyrimethamine
Proguanil
Halofantrine
Gametocides (kills gamets in blood)
Primaquine
Sporonticide (prevent sporogony and multiplication in the mosquito)
Proguanil
Pyrimethamine
Stages to determind which drug to administer
Erythrocyte schizogony: erythrocytic schizontocides
Pre-erythrocytic & exo-erythrocytic: tissue schizontocides
Kill gametocytes in blood: gametocides
Anti - Malarial therapy forms
Causal prophylaxis: pre-erythrocytic phase (Liver)
Proguanil
For P. falciparum
It is not given routinely because it has to be given daily and not reliable.
Primaquine
Causal prophylactic for all species of malaria
Not given in mass program (toxicity)
Suppressive Prophylaxis
The schizontocides which suppresses the erythrocytic phase & exoerythrocytic phase may
continue but clinical diseases do not appear.
Chloroquine 300 mg (base) weekly
Proguanil 200 mg daily + Chloroquine 300 mg weekly
Mefloquine 250 mg weekly or 500 mg fortnightly (for chloroquine resistant)
Clinical cure: erythrocytic schizontocytes
Fast acting high efficacy drugs: Chloroquine, mepacrine, quinine, mefloquine,
halofntrine.
Slow acting low efficacy drugs: Proguanil, Pyrimethamine, sulfonamides,
tetracyclines.
Drugs:
W
Mechanism of action
It is unclear and controversial. Plasmodium parasite enters RBCs, brakes down
hemoglobin and uses amino acids and iron from it. During the process large amount of
soluble heme is released which is toxic to the parasites. But the parasite polymerizes
heme to non toxic hemozoin (pigment) through polymerase enzyme. Chloroquine inhibits
the polymerase enzyme, thus increasing the intracellular accumulation of toxic heme in
the parasites. Heme damages plasmodial membrane thus kills the parasites.
Pharmacokinetics
Excellent orally absorption & widely distributed. Plasma protein bound 50% &
Concentrated in liver, spleen, kidney and lungs, skin, leucocytes. It partly metabolised by
liver & excreted in urine slowly. T1/2: 3-10 days. It has selective accumulation in retina ocular toxicity.
Adverse effects
i.
Nausea, Vomiting, Anorexia
ii.
Uncontrollable itching
iii.
Epigastric pain
iv.
Difficulty in accomodation and headache
v.
Retinal damage leading to loss of vision: (prolong high dose use as in RA, DLE)
vi.
Loss of hearing, photoallergy, myopathy, skin rashes, mental disturbances
vii.
Parenteral administration: Hypotension, cardiac depression, arrhythmias, CNS
toxicity including convulsion.
Resistance
P. Falciperum is resistant is chloroquine.
Uses
i.
Malaria
ii.
Extraintestinal amoebiasis
iii.
Rheumatoid arthritis (RA)
iv.
Discoid lupus erythemartosus (DLE)
v.
Lepra reaction
vi.
Photogenic allergy
vii.
Infectious mononucleosis
Note on Chloroquine
Safe to use in pregnancy
No teratogenecity is seen
Be careful in using in following conditions: Liver diseases, neurological and
hematological diseases, severe GI diseases.
W
Uses
i.
Treatment of acute attack of severe falciparum malaria
ii.
Multidrug resistant malaria, cerebral malaria
iii.
Prophylaxsis: irrational not allowed
Anti - Malarial drugs in pregnancy
Women living in endemic areas in which plasmodium falciparum is sensitive to
chloroquine should take chloroquine prophylactically throughout pregnancy.
Proguanil may be taken for prophylaxis provided it is accompanied by folic acid 5
mg/day.
Chloroquine may be used in full dose to treat chloroquine sensitive infections.
Quinine can be used for treating chloroquine resistant infections during pregnancy.
Pyrimethamine + dapsone should not be given in the first trimester but may be given
in second and third with a folate supplement.
W
&+$37(5$17,0,&52%,$/'58*6
(vii)
Anti Amoebic Drugs
Anti Amoebic Drugs

Amebiac dysentery is an infection of intestinal tract caused by Entamoeba histolytica.
The disease can be acute or chronic with patients showing varying degree of illness, from
asymptomatic to wild diarrhoea to fulminating dysentery. Therapy is aimed not only at
acute ill patient but also at those who are asymptomatic carriers since dormant E.
histolytica may cause future infection in carrier and maybe potential source of infection to
others.
Pathophysiology
Causative agents Entameba histolytica; Intestinal infection (amoebic dysentery); Amoebic
hepatitis & liver abscess; other extra-intestinal infections; Asymptomatic carriers (E.
histolytica cysts in stool).
Classification anti - amoebiac drugs
1. Tissue amoebicides
a) For both intestinal and extraintestinal amoebiasis:
Nitroimidazole: Metronidazole, Tinidazole, Secnidazole,
Alkaloids: Emetine, Dehydroemetine
b) For extraintestinal amoebiasis:
Chloroquine
2.
a)
b)
c)
Luminal amoebicides:
Amide: Diloxanide furoate
8-hydroxyquinolines: Quiniodochlor, Diiodohydroxyquin
Antibiotics: Tetracyclines
Metronidazole
It is prototype of nitroimidazole, Broad spectrum cidal activity against protozoal
including Trichomonas, Giardia lamblia, Entamoeba histolytica. Also active against many
anaerobic bacteria such as Bact. Frgailis, Fusobacterium, Clostridium perfringens,
Helicobacter pylori.
Mechanism of Action
Pyruvate-Ferrodoxin oxireductase system (present in ameoba, trichomonas, giardia and
anaerobic bacteria) reduces metronidazole to its active forms intracellularly. The reduced
metronidazole then disrupts the helical structure of DNA thereby inhibiting bacterial
nucleic acid synthesis and eventually results in cell death.
W
Pharmacokinetics
It is administered orally, intravenously, intravaginally and topically. Almost completely
absorbed after oral administration & well distribution throughout body tissues and fluids.
Metabolized in liver primarily by oxidation and glucoronide conjugation & excreted
through urine. T1/2: 8 hours.
i.
Headache
ii.
Dry mouth, metallic taste, nausea
iii.
Abdominal cramps
iv.
Dark urine
v.
Peripheral neuropathy: numbness and parasthesia
vi.
Thrombophlebitis: injected in vein
Contraindication
i.
Neurological disease
ii.
Blood dyscrasias
iii.
1st trimester of pregnancy
iv.
Chronic alcoholism
Drug Interactions
i.
It decreases renal elimination of Lithium
ii.
It cause Dilsulfiram like reaction to alcohol
iii.
Enzyme inducer may reduce its therapeutic effect. E.g. phenobarbitone, rifampicin
iv.
Cimetidine can decrease metronidazole metabolism
Uses
i.
Amoebiasis (E. histolytica)
ii.
Giardiasis (G. lamblia)
iii.
Trichomoniasis (T. vaginalis)
iv.
Anaerobic bacterial infection
v.
Ulcerative gingivitis
vi.
Helicobacter pylori
vii.
Peritonitis (usually due to anaerobes)
viii.
Guniea worm infestation
Amoebiasis treatment (DOC)
For invasive dysentery and liver disease
Adult: Metronidazole 800 mg TDS for 5-10 days
Child: 30-50 mg/kg/day for 5-10 days
In serious case of liver abscess
Metronidazole 1gm slow infusion IV followed by 0.5 gm every 12 hourly till
oral therapy given.
W
For mild intestinal disease

Metronidazole 400 mg TDS for 5-7 days.
Giardiasis treatment
Adult: Metranidazole 200 mg TDS for 7 days
Child: 15 mg/kg/day in divided dose for 7 days
Trichomoniasis treatment (DOC)
Adult: Metronidazole 200-400 mg TDS for 7 days
Child: 15 mg/kg/day in divided dose for 7 days
Pseudomembraneous colitis
Metronidazole 800 mg TDS
H. pylori (peptic ulcer): triple therapy
Metronidazole 400 mg TDS along with amoxicillin/clarithromycin and a proton pump
inhibitor (omeprazole, pantoprazole) for 2 weeks.
Tinidazole
It is similar to metronidazole but differs in having longer duration of action, better
affective than metronidazole & lesser adverse effects. It is given orally/IV.
i.
Metallic taste
ii.
Nausea
iii.
Skin rashes
Uses
i.
Amoebiasis
Adult: 2 gm OD for 3 days or, 0.6 gm BD for 5-10 days
Child: 30-50 mg/kg/day for 3 days
ii.
Trichomoniasis and giardiasis
2 gm single dose or 0.6 gm OD for 7 days
iii.
Anaerobic infections
Prophylactic: 2 gm single dose before colorectal surgery
Therapeutic: 2 gm followed by 0.5 gm BD for 5 days
iv.
H. pylori
500 mg BD for 1-2 weeks in triple therapy
Secnidazole
It has the same spectrum of activity and potency like metronidaole but having longer
duration of action than metronidazole and tinidazole.
W
Uses
i.
Intestinal amoebiasis
ii.
Giardiasis
iii.
Trichomonas vaginalis
Dose of Secnidazole
Intestinal amoebiasis, giardiasis, T. vaginalis: 2 gm single dose
Hepatic amoebiasis: 1.5 gm/day for 5 days
Chloroquine
For amoebiac liver abscess: 600 mg (base) for 2 days followed by 300 mg base daily for
2-3 weeks.
Diloxanide furoate
It is highly effective luminal amoebicide directly kills trophozoites responsible for
productioon of cysts.
Uses
i.
Asymptomatic cyst passers
ii.
Extraintestinal amoebiasis
i.
Flatulance
ii.
Nausea
iii.
Itching
iv.
Urticaria
v.
Dry mouth
Dose: 500 mg every 8 hours for 10 days.
W
&+$37(5$17,0,&52%,$/'58*6
(viii) Leishmaniasis, Giardiasis, Tripanosomiasis
Leishmaniasis
There are 3 types of leishmaniasis.
i.
Visceral leishmaniasis (Kala-azar) - caused by Leishmania donovani
ii.
Mucocutaneous leishmaniasis - caused by L. braziliensis
iii.
Cutaneous/Dermal leishmaniasis - caused by L. tropica
Figure: 2.8.1- Life cycle of Leishmania sps
Leishmaniasis transmitted by bite of female sandfly (phleobotomus). In the fly, the

parasite exists in flagellate extracellular/promastigote form, while in man it is found only
intracellularly within macrophages in nonflagellate/amastigote form.
Kala Azar - Visceral Leishmaniasis

It is caused by the L. donovani. General infection of macrophages in the entire RES. It
takes wHHNVWRPRQWKVLQFXEDWLRQSHULRG. The lead symptom is abdominal swelling due
to hepatomegally and splenomegaly. High fever, fever often oscillates with a peak every
second day & progressive drastic weight loss (kachexia). Darkening of the skin and
mortality of untreated disease 75-95%.
W
Figure: 2.8.2- Kala Azar

Figure: 2.8.3- Espundia
Espundia or Mucocutaenous leishmaniasis

It is caused by L. braziliensis & ~20% of infected patients develop ulcers of the oral and
nasal mucosa. The progression of the ulceration is slow but steady, ultimately destroying
all soft parts of the nose, the lips and the soft palate. Death can occur through secondary
bacterial infection.
Cutaneous Leishmaniasis
It is usually self-limiting. Old world oriental sore is caused by parasites of the L. tropica
(similar disease in the new world is caused by L. mexicana). A chronic but self-limiting
dry ulceration at the site of the bite. Ulceration starts months after infection. Parasites are
not found outside the lesion. A granuloma is formed which finally leads to healing
leaving a depressed scar. Inoculation to vaccinate has long been practiced in the Middle
East.
W
Figure: 2.8.4- Cutaneous Leishmaniasis

Drugs for leishmaniasis treatment
i.
Sodium stibogluconate
ii.
Pentamidine
iii.
Amphotericin B
iv.
Allopurinol
v.
Miltefosine (under evaluation)
Sodium stibogluconate
It is the drug of choice for kala-azar. It is water soluble pentavalent antimonial. MOA is
unclear. It inhibits glycolysis in the parasite at the phosphofructokinase (PFK) reaction.
Also inhibits fatty acid oxidation pathway.
Pharmacokinetics
It is not orally absorbed so, given I.M./I.V. & it is distributed in extravascular
compartment. Metabolism is minimum & excreted in urine.
i.
Pain at the injection site
ii.
GI upsets: Nausea, Vomiting, abdominal pain, metallic taste
iii.
Cardiac arrhythmia
iv.
Pancreatitis
v.
Liver and kidney damage
Dose: 20 mg/kg/day (max 850 mg) for 30 days I.M./I.V.
W
Need Medical Attention***

Incidence more frequent:
R Cardiotoxicity, Hepatotoxicity, Pancreatitis.
R Anorexia, Arthralgia, Fever and chills, Gastrointestinal disturbances headache,
Lethargy, Malaise, Myalgia, Muscle pain, Spasmodic cough.
Incidence rare:
R Anaphylactoid reaction, Blood dyscrasias, Leukopenia, Dyspnea, Facial edema,
Nephrotoxicity.
Pentamidine
It is a diamidine administered parenterally because it is not well absorbed from GI tract. It
is used in sodium stibogluconate resistant visceral leshmaniasis.
Mechanism of Action
It may interfere with incorporation of nucleotides into RNA and DNA; inhibit oxidative
phosphorylation and biosynthesis of DNA, RNA, Protein and phospholipid. It may also
interfere with folate transformation.
Pharmacokinetics
It is absorbed rapidly from the site of injection. Highest concentration is found in liver,
kidney, adrenal gland and spleen. It stored in liver and kidney for months. It slowly
excreted in urine mostly unchanged form.
i.
Hypoglycemia
ii.
Hypotension
iii.
Rashes
iv.
Kidney and liver damage
v.
Cardiac arrhythmias (rare)
vi.
Mental confusion
vii.
Hepatitis
viii.
Pancreatitis
Uses
i.
Kala-azar
ii.
Pneumocystic carinii pneumonia in AIDS patient (along with cotrimoxazole)
iii.
Trypanosomiasis
Dose:
For Kala-azar: I.V. infusion 2-4 mg/kg over 1-2 hours once a day for 15 days.
W
Need Medical Attention***

Incidence more frequent:
R Diabetes mellitus or hyperglycemia; elevated liver function tests; hypoglycemia,
leukopenia or neutropenia, nephrotoxicity, thrombocytopenia.
R Gastrointestinal disturbances (nausea and vomiting; loss of appetite; diarrhea).
Incidence rare:
R Anemia, cardiac arrhythmias, pancreatitis, phlebitis with intravenous injection, sterile
abscess with intramuscular injection.
R Unpleasant metallic taste.
Giardiasis
Giardia lamblia is a flagellate protozoan which mostly lives as a commensal in the
intestine. It sometimes invades mucosa and causes diarrhea.
Drugs for giardiasis
i.
Metronidazole
ii.
Quiniodochlor
iii.
Tinidazole
iv.
Mepacrine
v.
Furazolidone
Furazolidone
It is a notrofuran compound. It is active against gram negative bacilli including
salmonella, shigella, giardia and trichomonas.
i.
Nausea
ii.
Headache
iii.
Dizziness
iv.
Orange color urine
Dose: 100 mg TDS for 5-7 days.
Trypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused
by parasitic protozoan trypanosomiasis of the genus Trypanosma. More than 66 million
women, men, and children in 36 countries of sub-Saharan Africa suffer from human
Africa trypanosomiasis which is caused by either Trypanosoma brucei gambiense or
Trypanosoma brucei rhodesiense. It is transmitted by tsetse fly. The other human form of
W
Figure: 2.8.5- Trypanosomiasis
trypanosomiasis is called Chagas disease, causes deaths mainly in Latin America. It is

due to T. cruzi and transmitted by blood sucking bugs (Triatomine bugs).
African Trypanosomiasis features

Symptoms begin with fever, headaches and joint pains. As the parasites enter through
both blood and lymph systems, lymph nodes often swell up to tremendous sizes. If
untreated, the disease slowly overcomes the defenses of the infected person & symptoms
spread to include anemia, endocrine, cardiac and kidney diseases and disorders.
Chagas disease
The symptoms are fever, fatigue, body aches, headache and rash, loss of appetite, diarrhea
and vomiting. The signs on physical examination can include mild enlargement of the
liver or spleen, swollen glands and local swelling where the parasite entered the body.
Chemotherapy for Trypanosomiasis
i.
Melarsoprol
ii.
Nifurtimox
iii.
Pentamidine
iv.
Suramin
W
Suramin
It is used primarily for treatment of African trypanosomiasis. Suramin is drug of choice
for treating human Onchocerca volvulus. MOA is inhibition of many enzymes those
involved in energy metabolism.
Pharmacokinetics
It is given I/V. The drug is highly protein bound and T1/2: ~90 days. Renal clearance
accounts for elimination of ~80% of the compound. Very little suramin normally
penetrates the CSF.
i.
Nausea and vomiting
ii.
Shock and loss of consciousness
iii.
Acute urticaria
iv.
Neurological problems that include paresthesia, photophobia, palpebral edema and
hyperesthesia of the hands and feet.
v.
Albuminuria tends to be common, but when cylindruria and hematuria occur,
treatment should stop.
W
&+$37(5$17,0,&52%,$/'58*6
(ix)
Anti Helminthic Drugs
Heliminthic Infections
a) Nematods: (round worm)
Ascaris, Ancylostoma, Entrobius, Strongylaoids, Wuchreria Bancrofti
b) Trematods: (flat worms)
Schistosoma hematobium, Sch. mansoni, Fashiola hepatica
c) Cystodes: (flat worms)
Tenia saginata & solium, cysticercosis, hydatid disease
Antihelmintics
A drug that kills or expels infesting helminths from the body is called Antihelmintics.
They are
i.
Mebendazole
ii.
Pyrantel pamoate
iii.
Thiabendazole
iv.
Albendazole
v.
Piperazine citrate
vi.
Niclosamide
vii.
Diethyl carbamazine
viii.
Praziquantel
ix.
Ivermectin
Mebendazole
It is a synthetic benzimidazole compound & broad spectrum antihelmintic drug but less
effective against tape worms.
Mechanism of Action
It binds to and interferes with the synthesis of parasites microtubules. It decreases glucose
uptake and depletes glycogen stores. It inhibits hatching of parasite larvae and kills
ascaris ova.
Pharmacokinetics
It absorp from GI tract is less. 70-90% passes in feces. It metabolised and excreted
through urine.
i.
Abdominal pain, Diarrhea, Nausea
ii.
Allergic rxn & loss of hair
iii.
Granulocytopenia
W
Thiabendazole
It is the first benzimidazole polyhelmintic drug. MOA is same as mebendazole.
Pharmacokinetics
Rapidly absorped orally & metabolized in liver by hydroxylation and conjugation and
excretion through urine.
i.
Nausea, Vomiting, Diarrhoea
ii.
Headache
iii.
Giddiness
iv.
Neurological symptoms
v.
Bradycardia, hypotension
Dose: 25 mg/kg in 2 divided dose after meal (Chewable tablet).
Pyrantel pamoate
Mechanism of Action
It acts as depolarizing neuromuscular blocking agent, causing persistent activation of
SDUDVLWHVQLFRWLQLFUHFHSWRUV7KHSDUDO\]HGZRUPWKHQ H[SHOOHGIURPKRVWVLQWHVWLQDO
tract.
Pharmacokinetics
It is less absorbed (10-20%) & partly metabolized and excreted though urine.
i.
Nausea, Vomiting, Diarrhoea
ii.
Dizziness
iii.
Headache
Dose: 10-15 mg/kg single dose at bed time (HS).
Piperazine
Salts: Piperazine adipate, Piperazine citrate, Piperazine hydrate
Mechanism of Action
It blocks the neuromuscular transmission in round worm by anatgonizing Acetylcholine
action causing hyperpolarization leading to flaccid paralysis of worms and worms are
expelled out.
Pharmacokinetics
It is partly absorbed orally & partly metabolized in liver and excreted in urine.
W

i.
Nausea, Vomiting, Abdominal discomfort
ii.
Urticaria
iii.
Dizziness
iv.
Convulsion (toxic dose)
Contraindication
i.
Renal efficiency
ii.
Epilepsy
Uses
i.
Round worm
ii.
Pin worm (Enterobius)
Dose
Adult: 75 mg/kg OD for 2 days
Child: 75 mg/year of age
Enterobius: 75 mg/kg single dose and repeated after 3 weeks.
Levamisole
Mechanism of Action
It stimulates ganglia in worms, causes tonic paralysis, which results in expulsion of live
worms. Intereference with carbohydrate metabolism may also be contributing. It is an
immunomodulator restores depressed T cell function.
i.
Nausea, abdominal pain
ii.
Giddiness, drowsiness
iii.
Insomnia, fatugue
Uses
i.
Ascariasis, ancyclostomiasis
ii.
In RA as disease modifying agent
iii.
As an adjunct in malagnancies
Dose
Adult: 150 mg as a single dose orally
Child: 2.5 mg/kg single dose
Diethyl carbamazine (DEC)
It is a selective drug for filariasis.
W
Mechanism of Action
It causes alteration of microfilarial membrane so that they are readily phagocytosed by
tissue fixed monocytes, but not by circulating phagocytes. It also intereferes the muscular
activity of microfilaria and adult worms so that they are dislodged.
Pharmacokinetics
It is absorbed after oral administration and distributed all over body. It is metabolized in
liver and excreted in urine.
i.
Nausea
ii.
Headache
iii.
Dizziness
iv.
Loss of appetite
v.
Weakness
Uses
i.
Filariasis (elephantiasis)
ii.
Tropical eosniophilia
Dose: Orally given
Filariasis: 100 mg TDS for 21 days
Tropical eosinophilia: 2-4 mg/kg TDS for 2-3 weeks
Niclosamide
It is the drug of choice for most cestodes (tape worm) infections. MOA is inhibition of
oxidative phosphorylation in mitochondria and interfering with anaerobic generation of
ATP by tapeworm.
i.
Nausea, Vomiting, Diarrhoea, Anorexia
ii.
Abdominal discomfort
Uses
i.
Taenia saginata (Beef tapeworm)
ii.
Taenia solium (pork tapeworm)
iii.
Diphyllobothrium latum (fish tapeworm)
iv.
Hymenolepis nana (Dwarf tapeworm)
v.
Threadworm
Dose: Orally given 2 gm single dose after light meal.
H. nana: 2 gm OD for 5 days.
Child: 2-6 year: 1 gm; Child <2 years: 500 mg.
W
Figure: 3.2.2- Pathogenesis of BA

Atopic (allergic) asthma
Most common type and it is triggered by environmental antigens (dust, pollen, food)
often with a positive family history of atopy. It is type I hypersensitivity reaction (IgE
mediated).
R An acute phase with binding of antigen by IgE coated mast cells causing release of
primary mediators (leukotrienes) and secondary mediators (cytokines). These
mediators results in bronchospasm, edema, mucus secretion and recruitment of
leukocytes.
R A late phase reaction mediated by recruited leukocytes (eosinophils, neutrophils,
monocytes). Late phase is characterized by persistent bronchospasm and edema,
leukocytic infiltration and loss of damaged epithelial cells.
Non atopic asthma
It is triggered by respiratory tract infections, chemical irritants and drugs. No family
history. No or little evidence of IgE mediated hypersensitivity reaction. Primary cause of
airway reactivity is unknown.
Approaches to treatment
Prevention of Exposure to the allergens
Reduction of the bronchial inflammation and hyperactivity
Dilatations of the narrowed bronchi
W
phosphodiesterase (PDE) that metabolises cAMP. cAMP level rises and causes
bronchpdilatation, cardiac stimulation, vasodilatation.
Pharmacological actions of methylxanthines:
Action on CNS
Stimulant effect on CNS causing increased alertness, a snese of well being, beats
boredom, thinking becomes clearer, improves performances, and increases motor activity.
Higher dose can Causes tremors, nervousness, insomnia, excitement, and even
convulsions. It can also cause vomiting due to stimulation of CTZ and gastric irritation.
Action on CVS
Directly Stimulate heart and increases force of myocardial contraction. By vagal
stimulation decreases heart rate. Tachycardia common with theophyline, high dose can
cause cardiac arrhythmia. Vasodilatation on most of the blood vessels, but caffeine causes
cranial vessels constriction.
Actions on smooth muscles
Smooth muscles relaxed, biliary spasm relieved, negligible effect on intestine and urinary
bladder.
Kidney
Mild diuresis by inhibiting tubular reabsorption of Na ions. Increased renal blood flow
and increases GFR.
Skeletal muscles
Increases sk. muscle contraction by releasing Ca ion from sarcoplasmic reticulum.
Mast cells
Inhibits release of histamine and other mediators from mast cells.
Adverse effects of theophylline
R Small therapeutic window: 5-15mcg/ml
R GI Symptoms: Anorexia, nausea, vomiting
R CNS: Nervousness, Tremors
R Serious CVS, CNS effects seen in the higher dose.
R Rapid IV injection can cause precordial pain, syncope and even death (fall in BP,
arrhythmia, asystole).
Uses:
R Pain at site of I/M injection
R Gastric pain with oral
R Rectal inflammation with suppositories
W
Clinical uses of Theophylline

R Second line drug in addition to steroids in patient whose asthma does not respond
adequately to E2 adrenoceptor agonist.
R V in acute severe asthma
R To reduce the symptoms of the COPD.
R Muscuranic receptors antagonist
R Apnea in premature in infant
Drugs interaction of theophylline
R Agents which induce theophylline: smoking, phenytoin, rifampicin, phenobarbitone
R Agents which inhibit theophylline metabolism: erythromycin, ciprofloxacin,
cimetidine, OCP, allopurinol
R Theophylline enhances the effect of: Frusemide, sympathomimetics, digitalis, oral
anticoagulant, hypoglycaemics.
R Theophylline decreases effect of: phenytoin, lithium
Anticholinergic bronchodilators
Ipratropium bromide
It is competitively inhibit the post synaptic receptor action of acetylcholine at vagal nerve
endings that constrict bronchial smooth muscle.
R Uses: COPD, Asthmatic bronchitis, Psychogenic asthma.
Montelukast and Zafirlukast
It competitively antagonise cystenyl leukotrienes (cys LT1). Increases vascular
permeability and recruitment of eosinophils.
R Adverse effects: Headache, Eosinophilia, rashes, Neuropathy, Churg-struss syndrome
(Vascuilitis with eosinophilia)
R Uses: mild to moderate asthma
R Dose: Orally absorbed
Monteleukast: adult: 10mg OD
Zafirlukast: adult: 20mg OD
Mast cell Inhibitors
Sodium Chromoglycate
It inhibits degranulation of mast cells and release of mediators and inhibiting late allergic
response and bronchial hyperreactivity. Route by inhalation.
R Adverse effects:
Bronchospasm, cough, throat irritation
Dizziness, headache
Arthralgia, rashes
Dysuria
R Uses:
Extrinsic asthma
W
Asthma in children
Exercise induced asthma
Allergic rhinitis
Allergic conjunctivitis
R Dose:
1mg metered dose aerosol: 2 puffs 4 times a day.
Ketotifen
Mast cell stabilizer with Antihistaminic (H1 blockade) action and stimulation of
Immunogenic and inflammatory cells are inhibited.
R Uses:
Rhinitis, conjunctivitis
Urticaria
Food allergy
Atopic dermatitis
R Adverse effects:
Sedation and dry mouth
Dizziness, nausea, weight gain
R Dose:
Adult: syrup/tab 1-2 mg BD
Child: 0.5 mg BD
Corticosteroids
It inhibits influx of inflammatory cells into the air passage following an exposure to an
allergen and inhibition of release of mediators from macrophages and eosinophils. It reduces
leakage of micro vascular leakage.
R Uses:
Severe chronic asthma
Status asthmaticus
W
&+$37(5&,5&8/$725<6<67(0'58*6
(ii)
Figure: 4.2.1- Drugs affecting Coagulation, Bleeding & Thrombosis
Normal response to vascular trauma

Physical trauma to vascular system
Formation of the platelet-fibrin plug
Fibrinolysis
Formation of the clot

Clot formation requires platelets activation, aggregation, followed by the formation of the
thrombin.
1. Role of platelets: Platelets responds to the vascular trauma by activation process
involves the 3 steps:a. Adhesions to the site of the injury
b. Release of the intracellular granules
c. Aggregation of the platelets forming primary haemostatic plug (unstable)
2. Role of the fibrin
a. Local stimulation of the coagulation cascade by factors released from injured tissue
and the platelets result in the formation of the thrombin (factor II)
b. Cross- linking of the fibrin strands stabilizes the clot and forms the secondary
haemostatic plug (stable).
W
Figure: 4.2.5- Factors dec. effect of Warfarin

Other oral anticoagulants
Acenocoumarol
Dicumarol (bishydroxycoumarin)
Ethyl biscoumacetate
Phenindione
Uses of anticoagulants
Heparin is utilized for rapid and the short lived action, where as oral anticoagulant are
used for the maintenance therapy. Generally both are started together and heparin is
discontinued after 4-7 days when warfarin has taken its effect.
(i)
MI
(ii)
Cerebrovascular disease
(iii)
haemodialysis, vascular surgery
(iv)
Prosthetic heart valve
(v)
Deep vein thrombosis and the pulmonary embolism
(vi)
DIC
(vii) Rheumatic heart diseases, Atrial fibrillation
Difference between heparin and the warfarin
Route of administration
Onset of action
Duration of action
Antagonist
Teratogenicity
Actions
Heparin
Parentral
Fast
4-6 hours
Protamine sulfate
Not seen
In vivo and In vitro
Warfarin
Oral
Slow
4-7 days
Vitamin K
Seen
In vivo
W
&+$37(5&$5',29$6&8/$5'58*6
(i)
Drugs for Heart Failure
Heart Failure
Heart failure is a state in which the heart cannot provide sufficient cardiac output to meet
the metabolic needs of the body. It is commonly termed congestive heart failure (CHF)
since symptoms of increase venous pressure are often prominent.
Etiology
It is a common end point for many diseases of cardiovascular system. It can be caused by:
Inappropriate work load (volume or pressure overload)
Restricted filling
Myocyte loss
Forms of Heart Failure
- Systolic & Diastolic dysfunction
- High Output Failure
- Low Output Failure
- Acute heart failure
- Chronic heart failure
- Right & Left sided heart failure
Causes of left ventricular failure
- Volume over load: Regurgitate valve, High output status
- Pressure overload: Systemic hypertension, Outflow obstruction
- Loss of muscles: Post MI, Chronic ischemia, Connective tissue diseases, Infection,
Poisons
- Restricted Filling: Pericardial diseases, Restrictive cardiomyopathy,
tachyarrhythmia
Causes of right sided heart failure
- Most common cause is left sided failure
- Other causes included such as pulmonary embolisms, Pulmonary hypertension,
right ventricular infarction, Mitral Stenosis.
Symptoms of Congestive heart failure
- Shortness of breath, Orthopnea
- Paroxysmal nocturnal dyspnea
- Low cardiac output symptoms
- Abdominal symptoms: Anorexia, Nausea, Abdominal fullness, Right
hypochondrial pain
W
Physical Signs of Congestive heart failure

- High diastolic BP & occasional decrease in systolic BP (decapitated BP)
- JVD
- Rales (Inspiratory)
- Displaced and sustained apical impulses
- 3rd heart sound low pitched sound that is heard during rapid filling of ventricle
- Pale, cold sweaty skin
Framingham Diagnostic Criteria of Heart Failure
Minor Criteria
Major Criteria
-
PND
JVD
Rales
Cardiomegaly
Acute Pulmonary Edema
S3 Gallop
Positive hepatic Jugular reflex
YHQRXVSUHVVXUH!FP+2O
Lower Limb edema

Night cough
Dyspnea on exertion
Hepatomegaly
Pleural effusion
YLWDOFDSDFLW\E\RIQRUPDO
Tachycardia 120 bpm
Weight loss 4.5 kg over 5 days Mx.
Steps in the treatment of chronic heart failure

1. Reduce workload of the heart.
a. Limit activity level
b. Reduce weight.
c. Control hypertension.
2. Restrict sodium.
3. Restrict water (rarely required).
4. Give diuretics.
5. Give digitalis.
6. Give vasodilators.
7. Give newer inotropic drugs.
Drugs for Congestive heart failure
Vasodilators
Ace inhibitors
Hydralazine
Isosorbide
Minoxidil
Sodium niroprusside
Diuretics
Hydrochlorothiazide
Furosemide
Inotropic agents
Cardiac glycosides: Digitoxin, Digoxin
W
Cardiac stimulants: Dobutamine

Phosphodiesterase inhibitors: Amrinone, Milrinone
Diuretics
Diuretic therapy and constriction of sodium play important roles in reducing extracellular
fluid volume.
-Adrenergic blocking agents: It may be used in CHF to improve cardiac function by
inducing vasodilation through both direct and reflex actions.
Angiotensin conventing enzyme inhibitors: These drugs reduced Angiotensin
levels, which reduce peripheral resistance and thereby reduce afterload; they also
reduce salt and water retention by reducing aldosterone secretion and in that way
reduce preload.
Vasodilators
Arteriolar dilators (Decrease after load)
Hydralazine
Minoxidil
Calcium channel blocker (Nefedipine)
Pot. Channel openers (Nicorandil)
Venodilators (Decrease preload)
Nitrates: Glyceral trinitrate, Isosorbide dinitrate
Mixed dilators (Decrease Pre and after load):
ACE inhibitors
Losartan (A-II antagonist)
Prazosin
Phentolamine
Nitroprusside
Inotropic Agents
Cardiac glycosides
They are positive inotropic agents. Enhances cardiac muscle contractility and output in
hypodynamic heart without a proportionate increase in oxygen consumption.
- Cardiac glycosides include digitoxin and Digoxin.
- Cardiac glycosides also called digitalis as most of this drug is obtained from
digitalis (foxglove) plant.
Pharmacological Effects
Cardiac effects:
Positive inotropic effect: dose dependent increase in force of contraction of heart
Negative chronotropic effect
Electrical activity
Extracardiac Effects:
Effects on peripheral vessels
W
Diuretic effect
Effects on CNS
Figure: 5.1.1- Mechanism of Action of Positive inotropic effects
Figure: 5.1.2- Mechanism of Action of Cardiac Glycosides

W
Pharmacokinetics
Terms
-
Oral absorption
Bioavailability
Plasma protein binding
Onset
Peak
Duration
Plasma T1/2
Therapeutic level in plasma
Route of administration
Route of elimination
Generally used for
Digitoxin
-
Very good
90-100%
95%
- 2 hrs
6-12 hrs
2-3 wks
5-7 days
15-30 ng/ml
Oral
Hepatic
Maintenance
Digoxin
-
Good
60-80%
25%
15-30 min
2-5 hrs
2-6 days
33-44 hrs
0.8-2 ng/ml
Oral, I/V
Renal
Routine treatment

GI symptoms
Anorexia, Nausea, Vomiting, Diarrhea
Abdominal pain
Neurological symptoms
Headache, Malaise, Fatigue
Delirium, Disorientation, Confusion
Convulsion
Visual changes
It includes abnormal color perception. Visual changes results from the distribution on
retina of digitalis. Patients cannot distinguish one color from another one. They often
see anything in a yellow or green color. We call it abnormal color perception.
Cardiac symptoms
Bradycardia
Multiple ventricular premature contractions (VPCS)
Ventricular bigemini (hall mark of digitalis toxicity)
All types of arrhythmia except sinus tachycardia
BBB (bundle branch block)
Therapeutic uses
1. Congestive cardiac failure
2. Cardiac arrhythmias
- Atrial fibrillation
- Atrial flutter
- Paroxysmal supraventricular tachycardia
W
Cardiac Stimulants
They are those agents (Adrenaline, Theophyline) which increase oxygen consumption
and decrease myocardial efficiency (increase in oxygen consumption is more than
increase in contractility).
-adrenergic receptor stimulator: Dobutamine
- The search for positive inotropic drugs with less arrhythmogenic potential than
digitalis and less tendency to increase heart rate than isoproterenal has led to the
development of 1 selective agents.
- At the same time, the successful use of vasodilators in congestive heart failure has
resulted in an interest in selective 2 agents for this condition. The selective 1
agonist, dobutamine has been most wildly used in patients with heart failure.
- Dobutamine produces a positive inotropic effect and increases cardiac index (CI)
and cardiac output (CO) through stimulating on 1 receptor located in the heart.
- It reduces peripheral vascular resistance (PVR), cardiac afterload and left
ventricular end diastolic pressure, increases CO by stimulating on 2 receptor
located in the blood vessel.
- Heart Rate changed not significantly.
Therapeutic Uses
- Dobutamine has been used for the treatment of cardiac insufficiency with low CO
and high left ventricular filling pressure.
- It should be contraindicated to the patient with hypotension.
- Some tachycardia and an increase in blood pressure and myocardial oxygen
consumption have been reported.
- It may induce or worsen angina pectoris by increasing cardiac O2 consumption.
Phosphodiesterase Inhibitors: Amrinone and Milrinone
Pharmacological effects
- Increases myocardial contractility
- Increases cardiac output, decrease LVEDP
- Weak vasodilative effect
Clinical uses
Amrinone is used especially when cardiac glycosides and drugs decreasing preload
and afterload are ineffective.
W

- The toxicity of amrinone includes a relatively high incidence of nausea and
vomiting.
- Thrombocytopenia and liver enzyme changes have been reported in a smaller but
significant number of patients.
- This agent is used only for short-term parenteral treatment.
- It may be less likely to cause cardiac arrhythmias than is digitalis.
- Milrinone appears less likely to cause bone marrow and liver toxicity than
amrinone, but it does cause arrhythmias.
- In patients with severe congestive heart failure, oral milrinone increased mortality.
- Therefore, like amrinone, it is now used only intravenously and only for acute heart
failure.
W
&+$37(5&$5',29$6&8/$5'58*6
(ii)
Anti-Arrhythmic Drugs
Anti-Arrhythmic Drugs
Figure: 5.2.1- Electrical System of the Heart
Electrophysiology
Resting potential
A transmembrane electrical gradient (potential) is maintained, with the interior of the
cell negative with respect to outside the cell.
Caused by unequal distribution of ions inside vs. outside cell
Na+ higher outside than inside cell
Ca+ much higher
K+ higher inside cell than outside
Maintenance by ion selective channels, active pumps and exchangers
W
Figure: 5.2.2- Electrocardiogram (EKG) showing wave segments
Cardiac Action Potential

Divided into five phases (0,1,2,3,4)
Phase 0 opening of fast Na channels and rapid depolarization
- Drives Na+ into cell (inward current), changing membrane potential
Transient outward current due to movement of Cl- and K+
Phase 1 initial rapid repolarization
- Closure of the fast Na+ channels
- Phase 0 and 1 together correspond to the R and S waves of the ECG
Phase 2 - plateau phase
- Sustained by the balance between the inward movement of Ca+ and outward
movement of K +
- Has a long duration compared to other nerve and muscle tissue
- Normally blocks any premature stimulator signals
- Corresponds to ST segment of the ECG.
Phase 3 repolarization
- K+ channels remain open,
- Allows K+ to build up outside the cell, causing the cell to repolarize
- K + channels finally close when membrane potential reaches certain level
- Corresponds to T wave on the ECG
Phase 4 - resting phase (resting membrane potential)
- Phase cardiac cells remain in until stimulated
- Associated with diastole portion of heart cycle
W
Mechanisms of Cardiac Arrhythmias

Result from disorders of impulse formation, conduction, or both
Causes of arrhythmias
- Ischemia
- Electrolyte and PH imbalance
- Mechanical injury
- Stretching
- Neurogenic influence
- Drug influence
Disorders of impulse formation
No signal from the pacemaker site
Development of an ectopic pacemaker
May arise from conduction cells
Usually under control of SA node if it slows down too much conduction cells
could become dominant
Often a result of other injury (ischemia, hypoxia)
Development of oscillatory afterdepolariztions
Can initiate spontaneous activity in nonpacemaker tissue
These are secondary depolarization accompanying normal or premature AP
May be result of drugs such as digitalis or, norepinephrine used to treat other
cardiopathologies.
Disorders of impulse conduction
May result in
Bradycardia (if have AV block): conduction block
Tachycardia (if re-entrant circuit occurs)
A-V block
First degree A-V block: Slowed A-V conduction resulting in prolonged P-R interval
Second degree A-V block: Some supraventricular complexes are not conducted;
missed beats
Third degree A-V block: No supraventricular complexes are conducted; ventricle
generates own impulses
Ventricular Re-entry
Re-entry is a self-perpetuating pattern of depolarization involving any cardiac tissues and
does not depend on altered automaticity. It just depends on differences in the areas of the
heart that allows for conduction in one area and block in another. This can exist in the
form of functional or anatomic. Basically, anatomic re-entry is a block in conduction that
is caused by a fixed structure in the tissue. This re-entry causes ventricular arrhythmias
such as ventricular tachycardia. These re-entry circuits are all made up of these cells
whose activity is based on the cardiac action potential.
W
Vaughan Williams Classification of Antiarrythmic drugs

Class I : Na - Channel Blocker
IA. Quinidine, Procainamide, Disopyramide, Moricizine (IA also has III property)
IIB. Lidocaine, Mexiltelene, Phenytoin, Tocainide
IIIC. Propafenone, Flecainide
Class II: Beta Blockers
Propranolol (also class I), Esmolol, Sotalol (also class III)
Class III: K - Channel Blocker
Amiodarone, Bretylium (also class II)
Class IV: Calcium Channel Blockers
Verapamil, Diltiazem
Others: Atropine, Adenosine, Digoxin
Mechanism of Action
Class of Drug
I-Sodium Channel Blocker
IA
IB
IC
II-Beta Blocker
III-Potassium Channel
Blocker
IV-Calcium Channel Blocker
Basic Mechanism
Reduce phase 0 slope and peak of action potential
Moderate reduction in phase 0 slope; increase APD; increase
ERP
Small reduction in phase 0 slope; reduce APD; decrease
ERP
Pronounced reduction in phase 0 slope; no effect on APD or
ERP
Delay repolarization (phase 3) and thereby increase action
potential duration and effective refractory period.
Prolongation of APD and increase ERP; no effect on phase 0
Block L-type calcium-channels; most effective at SA and
AV nodes; reduce rate and conduction.
Class I
The primary action of this drug is to limit the conductance of Na+ across the cell
membrane - A local anesthetic action
Reduces the rate of phase -4 depolarization in automatic cells
Quinidine
Sub class IA
Open state Na+ channel blockers
Supresses A-V conduction and prolongs P- R, QRS, Q-T and APD.
Also used in Malaria
It blunts the upstroke and prolongs phase 2
Moderate reduction in phase 0 slope
Increases APD and ERP
W
1. Heart
Class IA + Class III + Antivagal actions
Decreases automaticity, inhibit extrasystoles, little effect on after-depolarization
Increase threshold for excitation, prolongs ERP more than APD
Reduces rate of 0 phase depolarization and overshoot.
ECG: Increase P-R and Q-T interval
Quinidine MOA in Heart
Quinidine blocks Myocarial Na+ Channels in open state.
Blocks K+ Channel
Moderately inhibits the recovery of Na+ and K+ Channels
At high concentration inhibits L-types Ca++ Channels
2. Blood Pressure
Blocks alpha adrenergic system
Dilates blood vessels- at higher dose can cause marked fall in BP.
3. Skeletal muscles
Decreases contraction of skeletal muscle
4. GIT
Vomiting
Diarrhoea (bitter and irritant)
5. CNS
Neurological manifestation
6. Uterus
Increase Uterine contraction
7. Anti-Malarial action
Pharmacokinetics
Oral absorbed
Peak: 1-2 hour
Plasma protein binding: 80-90%
T1/2: 6 hours
Metabolism: liver
Excretion: urine
Use
Atrial and ventricular Arrhythmias
To maintain sinus rhythm after AF has been terminated by DC shock or other
measures and to prevent reoccurrences of VT
Routes and dose
Given Orally or slow I/V. Injection
But not I/M. because it causes pain and necrosis
Prophylaxis and maintenance: Quinidine Sulphate 200 - 400Mg TDS
W

Risk of sudden death due to Cardiac arrest or VF
Gastrointestinal intolerance: - Nausea, Vomiting, Diarrhea.
Cinchonism: At high dose- ringing ears, deafness, vertigo, headache, visual
disturbances, mental changes, delirium
Idiosyncrasy and hypersensitivity: fever, angioedema, asthma, vascular collapse
Arrhythmias: At high dose it can cause torsades de pointes which may lead to VF
Torsades de pointes
Long Q-T syndrome: prolonged phase 3
Polymorhic ventricular tachycardia
IA drugs can cause early after-depolarization
Blocking of potassium channels and prolonging repolarization
Started by triggered activity and probably is continued by functional re-entry
Contraindication
Intolerance / Idiosyncracy
Heart block- as it can cause asystole
CHF and hypotensive state
History of Embolism
Drug Interaction
Quinidine increases Plasma conc. of digitalis
Diuretics can increase incidence of torsades de pointes and VF due to quinidine
Vasodilators and quinidine simultaneous use can cause orthostatic hypotension
Procainamide
Uses: Alternative drug to quinidine
Adverse effects:
GIT: Nausea, vomiting
CNS: Weakness, confusion
Flushing, hypotension: in rapid I/V injection
Cardiac toxicity: torsades de pointes
SLE: Chronic High dose in slow acetylators.
W
Lignocaine
Subclass IB
Most commonly used local anesthetics
Popular antiarrhythmic drugs in ICU
Suppresses automaticity in ectopic foci
Inhibit increased Phase 4 depolarization in PF
SA node automaticity not reduced
Mechanism of Action (Class IB)
The IB drugs blunt the upstroke slightly because it is a weak sodium channel blocker,
but it also has action at potassium channels which is why it shortens the action
potential duration (APD).
Blocks both open and inactivated cardiac Na+ channels
Exerts greater effects in ischemic tissues
Decreases automaticity by reducing the slope of phase 4 and altering the threshold for
excitability.
No class III property of increase APD.
Pharmacokinetics
Good oral absorption but Very high 1st pass metabolism
PPB: 75%
Rapid redistribution: so I/V bolus dose last only 10-20 minute.
Metabolized in liver and excreted through urine
Adverse effects
Drowsiness
Nausea
Paresthesia
Blurred vision
Disorientation
Nystagmus
Twitching and fits
Uses and Dosage
Used in ventricular tachyarrhythmias (Following MI / cardiac surgery)
Digitalis toxicity (It does not worsen AV block)
Dose: 50 -100mg I/V bolus followed by 20 - 40mg every 10 - 20min (or 1 - 3mg/min
infusion).
W
Mexiletin
Is a local Anaesthetic
Antiarrhythmic given orally. Resistant to 1st pass metabolism
Chemically and pharmacologically similar to Lidocaine
Bradycardia, hypotension, accentuation of A-V block
Neurological: tremor, nausea, vomiting, dizziness, confusion, blurred vision, ataxia
Flecainide (Subclass IC)
Most potent Na + channel blocker
Markedly delay conduction, prolong P- R, broaden QRS complex
Profound effects on His- purkinje fiber and accessory pathway
Uses
AV reentrant tachycardia
Tachycardia associated with WPW syndrome
Patients with paroxysmal AF
Contraindication
Sick sinus syndrome
Cardiac failure
History of MI with asymptomatic ventricular tachycardia
Blurred vision , abdominal discomfort, nausea, dizziness
Abnormal taste sensation and paraesthesia
Propafenone
It has Beta blocking action (class II) + class I action
Class II Beta Blockers
Suppresses adrenergically mediated ectopic foci
Propranolol, Esmolol, Sotalol
Propranolol
Anti-arrhythmic exerted by adrenergic blockade
Decreases slope of phase 4 depolarization and automaticity in SA node
Prolongs ERP of A-V node
Useful in treating inappropriate sinus tachycardia, Atrial and Nodal ES provoked by
emotion or exercise
W
Sotalol
Beta blocker, blocks cardiac K channels
Prolongs ERP
Uses: VT, AF, AFl
Chance of torsades de pointes: as it prolongs APD and QT
Esmolol
Quick and short acting beta-1 blocker
I/V very useful in emergency in AF/AFl, SVT
Class III - Amiodarone
Prolongs APD and ERP, slows conduction and depresses ectopic
Prolongs APD: Block myocardial K + channels
Blocks inactivated Na + channel (Lidocaine)
Inhibits myocardial ca +2 channels
Noncompetitive beta blocker
Uses
Ventricular and Supraventricular arrhythmias
Resistant VT / VF
Fall in BP, Myocardial depression
Less chance of torsades de pointes.
Nausea and GI upset
Photosensitization and skin pigmentation
Pulmonary alveolitis and fibrosis
Pheripheral neuritis
Liver damage
Interfere thyroid function
Drug interaction
Increases warfarin and digoxin level by decreasing their renal clearance
Class IV Ca++ Channel Blocker)
Calcium is involved in the contraction of cardiac and vascular smooth muscle cells,
and in the automaticity of cardiac pacemaker cells.
Cardiac muscle cells are normally depolarized by the fast inward flow of sodium ions,
following which there is a slow inward flow of calcium ions through the L-type
calcium channels.
Pacemaker cells in the SA and AV nodes rely heavily on the slow inward flow of
calcium ions (phase 4) for their capacity to discharge spontaneously.
W
Calcium channel blockers inhibit the passage of calcium through the membrane
channels; the result in myocardial cells is to depress contractility, and in pacemaker
cells to suppress their automatic activity.
Members of the group therefore may have negative cardiac inotropic and
chronoscopic actions.
Verapamil
Blocks L type of calcium channels
Depresses Ca + mediated depolarization
Phase 4 depolarization in SA node and PF
Prolongation of AV nodal ERP
reduced.
Pharmacokinetics
Good oral absorption
Metabolized in liver
Uses
PSVT
To control rate in AF / AFI
Drugs for PSVT
Verapamil
Diltiazem
Propranolol
Digoxin
Adenosine (most commonly used)
Adenosine
Activates Ach sensitive K+ channels and causes the membrane hyperpolarization on
SA node and on A-V node and atrium
Indirectly reduces the Ca2+ current in A-V node and depression of re-entrant circuit
through A-V node
Within 30 sec it can terminate PSVT involving A-V node.
Administered by rapid IV injection (over 1-3 sec)
T1/2: 10 seconds
Dipyridamole potentiates its action by inhibiting uptake
Theophyline/caffeine antagonize its action by blocking adenosine receptors
Advantage of Adenosine for termination of PSVT
Efficacy equivalent to or better than Verapamil
Action lasts < 1 min, So ADR (cardiac arrest) is transient
W
No hemodynamic deterioration. So it can be given in hypotension, CHF, those

receiving beta blockers. Verapamil is C/I in these conditions.
Safe in wide QRS tachycardia (Verapamil unsafe)
Effective in patients not responding to Verapamil
Transient dyspnoea, chest pain, flushing
VF, cardiac arrest for few seconds
Brinchospasm in Asthma
Drugs for AV block
Atropine
AV block due to digitalis toxicity
Decreases AV node ERP and increases the conduction velocity
Sympathomimetics
Adrenaline, Isoprenaline
Facilitates AV conduction and shortening ERP
W
&+$37(5&$5',29$6&8/$5'58*6
(iii)
Anti-Anginal & Anti-Ischemic Drugs
Anti-Anginal drugs
Drugs that prevent, abort or terminate attack of angina pectoris
MOA of antianginal drugs:
1. Decrease myocardial oxygen consumption
2. Increase myocardial blood and oxygen supply
3. antiplatelet, antithrombosis
Classification
1) Nitrates
a. Short acting: Glyceryl trinitrate ( GTN)
b. Long acting: Isosorbide dinitrate, Isosorbide mononitrate.
2) Beta - Blockers
Propranolol, Metoprolol, Atenolol
3) Calcium channel Blockers
Phenyl alkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines: Nefidipine, Felodipine, Nicardipine, Amlodipine, Nimodipine,
Lacidipine, Nitrendipine
4) Pottassium channel opener
Nicorandil, pinacidil, cromakalim
5) Others
Dipyridamole, Oxyphedrine
Nitrates (GTN as Prototype)
Major action is direct non specific smooth muscle relaxation.
Preload reduction
After load reduction
Redistribution of coronary flow
Mechanism of relief of Angina
- Counteracting coronary spasm
- Primary action is to reduce cardiac work by action on peripheral vasculature
Pharmacokinetics
- Well absorbed across skin, mucous membrane of mouth and gut
- Extensive first-pass hepatic metabolism
- Oral dose > S/L dose
W
GTN
- T = 3 min.
- Oily non inflammable liquid
- Tab. fairly stable
- Discard tab. 8 weeks old or exposed to heat or air due to loss of potency
- Nitrogycerin spray as aerosol is available
Uses
- Angina pectoris
- CHF and acute LVF
- Myocardial infraction
- Interventional cardiac procedure
- Biliary colic
- Esophageal spasm
- Cyanide poisoning
- Fullness in head, Throbbing headache
- Flushing , weakness, sweating, palpitation, dizziness and fainting
- Methaemoglobinaemia
E- Blockers
Do not dilate coronaries or other blood vessels
They act by reducing cardiac work and O 2 consumption
Myocardial O 2 consumption
- by p HR and p force contraction
- by p after-load, p pre-load
Reduce myocardial contractility and slow heart rate
May increase spasm in variant angina
Clinical Uses
- Stable and unstable angina
- Myocardia infarction
Contraindications
- Variant angina
- Bronchial asthma
- Bradycardia
Calcium channel blockers
CCBs reduce cardiac contractility, dilate coronary arteries, reduce afterload
CCBs are- Verapamil
- Diltiazem
W
Nifedipine
Amlodipine
Felodipine
Nicardipine
Nisoldipine
Mechanism of Action of CCBs

1. Dilate coronary arteries
2. Reduction in peripheral vascular resistance
3. Negative chronotropic and inotropic, decrease myocardial c oxygen consumpation
Uses of CCBs
- HTN
- Angina (Stable, Unstable, Variant)
- Cardiac arrhythmia
- 5D\QDXGVGLVHDVH
Potassium channel Openers
- Nicorandil, Pinacidil, Cromakalin
- Coronary flow is increased,dilatation of both epicardial conducting vessel and deeper
resistance vessel.
Uses of K+ channel openers
- Angina pectoris
- HTN
- CHF
- MI
- Alopecia
- Bronchial asthma
- 3HULSKHUDO9DVFXODU'LVHDVHV5D\QDXGVGLVHDVH
- Premature labour
- Urinary urge incontinence
Adverse Drug Reaction of Nicorandil
- Flushing
- Palpitation
- Weakness
- Headache, dizziness
- Mouth ulcers
- Nausea and vomiting
W
Other Anti anginal drugs

- Dipyridamole
- Trimetazidine
- Oxyphedrine
Management of Angina Pectoris
- Treatment of contributory cause. E.g. anaemia, arrhythmia
- Changes in life style. E.g. weight reduction, stop smoking
- Immediate pre-exertional prophylaxis: GTN sublingual or nifedipine
- Acute attack: GTN or Nifedipine
Management of acute attack of angina
- GTN is the drug of choice
- 0.5 mg tab. should be chewed and dissolved under tongue or place in buccal sulcus
for rapid and reliable absorption.
- Repeated every 5 minutes for three doses till relief of pain. Spit out the tablet on pain
relief or
- Nitrolingual spray one metered dose every 5 min. for 3 doses
Long term prophylaxis
Beta-blocker : Bisoprolol, Propranolol
- Or, CCBs: Nifedipine or Amlodipine
- Or, Long acting Nitrate: ISDN or ISMO
- Or, Potassium channel opener- Nicorandil
Nocturnal angina prophylaxis
- Transdermal GTN, Oral ISMO
Anti-platelet therapy
- Low dose Aspirin / Clopidogrel
Surgical re-vascularisation
- PTCA, CABG
Drugs therapy in MI
Pain anxiety and apprehension
- Opioid analgesic ( Morphine, Pethidine)
Oxygenation
- By O2 inhalation and assisted respiration if needed
Maintenance of blood volume
- Slow I/V infusion normal saline
Correction of acidosis
- Due to production of lactic acid, sod bicarbonate by iv infusion
Prevention and treatment of arrhythmia
- Prophylactic administration of E- Blockers infusion
- Tachyarrhythmias may be treated with lignocaine
W
Pump failure
- Furosemide
- Vasodilator
- Inotropic agents (Dopamine, Dobutamine)
Prevention of thrombus extension
- Heparin
Thrombolysis
- Streptokinase, Urokinase, Alteplase
Prevention of remodeling and subsequent CHF
- ACE inhibitors
Prevention of further attacks
- Platelets function inhibitors: Aspirin
- E- Blockers
- Control of hyperlipidaemia (Lovastatin, Simvastatin)
Medical Intervention
Coronary Angioplasty
- Percutaneous transluminal coronary angioplasty (PCTA)
- Use of a balloon to breakup the plaque deposit
Surgical Intervention
- Coronary Artery Bypass Surgery (CABG)
- Vein from the leg or artery from the chest is used to bypass the occluded vessel in the
heart
Anti-Ischemic Drugs
Coronary Heart Disease (CHD) also known as coronary artery disease (CAD) or,
ischemic heart disease (IHD)
Ischemia lack of blood flow to an organ
Myocardial Infarction Death of cardiac tissue due to lack of blood flow
Mortality
- CHD is the leading cause of death in men and women in the US; 480,000 people died
in 1992 from CHD
- 1960: 286 per 100,000 died of CHD
- 1990: 152 per 100,000 died of CHD
Etiology of CHD
- Lack of blood flow to the blood vessels surrounding the heart and serving the
myocardium
- Major cause is arteriosclerosis
W
Risk Factors of CHD

- Modifiable
- Hypertension
- Diabetes
- Hypercholesterolaemia
- Smoking
- Non-modifiable
- Age
- Sex
- Family history
Symptoms
- Chest pain:
Causes
- Exercise, stress, emotion especially if cold, after a meal
Description (watch how patient describes pain)
- Crushing, pressure, tight, heavy, ache
Location
- Left chest, shoulder
Radiation
- Arm, neck, jaw, back
Relieved by rest and/or GTN
Breathlessness
Syncope
Management
- Risk factor reduction
- Smoking
- Exercise
- Diet
- Hypertension
- Diabetes
- Drug therapy
- Coronary intervention and surgery
- Angioplasty r stent (PTCA)
- Coronary Artery Bypass Grafts (CABG)
W
&+$37(5&$5',29$6&8/$5'58*6
(iv)
Anti-Hypertensive Drugs
Anti-Hypertensive drugs
Hypertension (HTN)
It is defined as Elevation of arterial blood pressure above 140/90 mm Hg. Types of
Hypertension Primary or essential hypertension: 90%
Secondary hypertension: An underlying disease process: 10%
Renal artery stenosis
Hyperaldosteronism
Pheochromocytoma
JNC VI Stages of Hypertension
It is Joint National Committee on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure.
Stage
High Normal
Stage 1
Stage 2
Stage 3
Diastolic Range (mm Hg)

85-89
90-99
100-109
> 109
Systolic Range (mm Hg)

130-139
140-159
160-179
>179
Treatment Rationale
Short-term goal of antihypertensive therapy to reduce blood pressure.
Primary (essential) hypertension
Secondary hypertension
Long-term goal of antihypertensive therapy to reduce mortality due to Hypertension
induced disease.
Stroke
Congestive heart failure
Coronary artery disease
Nephropathy
Peripheral artery disease
Retinopathy
W
Figure: 5.4.1- Ways of Lowering Blood Pressure
Drug can lower the pressure by Dilatation of the arteriolar resistance vessel.
Dilatation of the venous capacitance vessel.
Reduction in the cardiac contractility and the heart rate.
Depletion of the body sodium, this reduces plasma volume and reduces arteriolar
response to adrenaline.
Inhibition of the formation of the angiotensin II.
Major Risk Factors That Increase Mortality in Hypertension
Smoking
Dyslipidemias
Diabetes Mellitus
Age >60
Gender: men, postmenopausal women
Family history
Principles of the Anti-hypertensive therapy
General measures
Obesity: Reduce it
Alcohol: Stay with in limit
Smoking: Stop it
Diet: of proven value have short term reduction in BP
Relaxation therapy: Worth considering for highly motivated borderline patients.
Drugs therapy
W
Figure: 5.4.2- Treatment Thresholds for Essential Hypertension
Classification of the Antihypertensive Drugs

1. ACE Inhibitors: Captopril, Enalapril, Lisinopril , Ramipril
2. Angiotensin (AT-1) Antagonist: Losartan, Candesartan, Irbesartan
3. Calcium channel blockers: Verapamil, Diltiazem, Nifedipine, Felodipine,
Amlodipine, Nitrendipine, Lacidipine
4. Diuretics
Thiazides: hydrochlorothiazide, chlorthalidone
Loop diuretics: Furosemide
K sparing diuretics: Spironolactone, Triamterene, Amiloride
5. - adrenergic blockers: Propanolol, Metoprolol, Atenolol
6. DGUHQHUJLFEORFNHUV: Labetalol, Carvedilol
7. - adrenergic blockers: Prazosin, Terazosin, Doxazosin, Phentolamine,
Phenoxybenzamine
8. Central sympatholytics: Clonidine, Methyldopa
9. Vasodialators: Hydrazaline, Minoxidil, Diazoxide, Sodium Nitroprusside, Pinacidil,
Cromakalim
W
Monotherapy for Hypertension

ACE inhibitors and ATII antagonists
Diuretics
-adrenoceptor blockers
1-adrenoceptor blockers
Ca2+ channel blockers
Angiotensin Converting Enzyme (ACE inhibitors)
The ACE inhibitors are first choice of drug in all grades of essential as well as
renovascular disease.
Started with lower dose (2.5 10 mg).
Use alone control 50% patients and addition diuretic / beta blocker.
Mechanism of Action
Inhibition of angiotensin-II formation
Competitive inhibition of angiotensin converting enzyme reduces circulating
angiotensin- II, reducing vascular tone.
Figure: 5.4.3- Mechanism of Action of Angiotensin Converting Enzyme
Systemic Effects of ACE Inhibitors

Dec. in systemic arteriolar resistance, systolic, diastolic and mean arterial pressure.
Regional hemodynamic effects:
Increased regional blood flow in proportion to ang II sensitivity of the vascular bed
Increased large artery compliance
Cardiac output and heart rate unchanged
Aldosterone secretion reduced .
Increase plasma kinin levels and kinin further enhances the synthesis of PGs.
W
Pharmacokinetics

Dry cough
Reversible Dysguesia
Hypotension
Skin rash, urticaria
Angioedema : swelling lips, mouth, nose, larynx
Hyperkalemia
Neutropenia
Proteinuria
Headache, dizziness, nausea, bowel upset
Teratogenicity
Therapeutic Uses
1. Hypertension
One of the initial choices for monotherapy of mild to moderate hypertension
Well tolerated as monotherapy.
Drugs of choice in diabetes mellitus with hypertension
Most effective in high renin hypertension
More effective in white Vs. black patients
2. Hypertension with LVH, cardiac arrhythmias or diabetes mellitus
1. Consider ACE inhibitor to treat HTN in asthma instead of -blockers
2. CHF
3. Myocardial infarction
4. Diabetic nephropathy
W
Contraindication
Bilateral renal artery stenosis
Hyperkalemia
Pregnancy
Angiotensin antagonist - Losartan
Competitive antagonist of Ang-II
More selective for AT1 than AT2 receptors
Does not inhibit ACE and hence does not increase level of kinins
Causes fall in Blood pressure in hypertensive patient which can lasts for 24 hours and
HR not altered
ADR: hypotension, hyperkalemia, teratogenic
Does not provoke cough or dysgeusia
Use: Hypertension
AT-II receptor Antagonists
Losartan: 25-50mg/day
Valsartan: 80 mg/day
Candesartan: 8-16 mg/day
Irbesartan: 150-300 mg/day
Calcium Channel Blockers
CCBs are indicated when preferred first line drugs ineffective or C/I
Blocks the cellular entry of the calcium through calcium channel.
Decreases peripheral resistance without compromising cardiac out-put
Despite venodilatation fluid retention is insignificant
Onset of the action is quick
Monotherapy effective in 50% cases.
Classification of CCBs
Diphenalkylamines: Verapamil
Act on both heart and vascular smooth muscles
Benzothiazepines: Diltiazem
Act on both heart and vascular smooth muscles
Dihydropyridines: Nefidipine, amlodipine, felodipine, isradipine, nicardipine,
nisoldipine
Vascular Smooth muscle selective , less cardiac actions so commonly preferred
W
Figure: 5.4.4- Therapeutic Uses of Calcium Channel Blockers
Advantages of CCBs
Do not compromise for heamodynamics: No Impairment in the Physical work
capacity.
No sedation/ CNS effect.
Not contraindicated in the asthma, angina and PVD (peripheral vascular disease)
patients; may benefit these conditions.
Do not impair renal functions
No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance.
No effect on quality of the life
No fetal abnormality noted.
Constipation
Vertigo
Headache
Fatigue
Hypotension
W
Diuretics
Figure: 5.4.5- Effects of Thiazide Diuretics on Blood Pressure

Thiazides
Directics of choice in uncomplicated hypertension
The fall in BP develops gradually over 2-4 weeks.
Heart rate and the cardiac output are unaffected.
TPR is reduced despite compensatory increased in the plasma renin activity.
No effect on the capacitance vessel.
Sympathetic reflex not impaired so Postural Hypotension rare.
Thiazide diuretics: Considerations
Long-term hypokalemia appears to increase mortality.
K+ sparing diuretics are superior to K+ supplementation when diuretics used.
0RVWHIILFDFLRXVLQORZUHQLQRUYROXPH-expanded forms of hypertension
Loop diuretics: Furosemide
Fall in BP is due to reduced plasma volume and C.O.
TPR and vascular responsiveness are not reduced.
Can cause fluid and electrolyte imbalance
Indications of furosemide as antihypertensive:
Chronic renal failure
Coexisting refractory CHF
Resistance to combination regimens containing a thiazide
Marked fluid retention.
W
Potassium sparing diuretics

Aldosterone antagonist or directly inhibit the sodium channel in DT and CD cells
Spironolactones lowers the BP slightly but are used only in conjunction with the
thaizide diuretic to prevent the K+ loss and to augment the antihypertensive action.
adrenergic blockers
Mild antihypertensive, do not significantly reduces BP in the normotensive
Effective in 30%- 40% patients
Majority of the cases used in combination
Antihypertensive action develops over 1-3 weeks.
Types of -blockers
Non selective
Prototype: Propranolol (others: nadolol, timolol, pindolol, labetolol)
Cardioselective
Prototype: Metoprolol (others: atenolol, esmolol, betaxolol)
Non selective and cardio selective -blockers are equally effective in reducing blood
pressure.
Figure: 5.4.6- Effects of Beta Blockers on Blood Pressure
8VHVRI adrenergic blockers

1. Cardiovascular Use
$QJLQDSHFWRULV blockade reduces cardiac work)
Hypertension (Reduces renin secretion and the cardiac output)
Cardiac dysarrthymias
W
Myocardial infraction
2. Endocrine Use
Hyperthyroidism
Phaeochromocytoma
3. Central Nervous System Use
Anxiety
Migraine prophylaxis
Alcohol withdrawal
4. Eye Use
Glaucoma
Bronchospasm (Contraindication: Asthma)
Bradycardia, Cardiac failure, Hypotension
Reduced peripheral blood flow.
Hypoglycemia
Rebound hypertension.
Nonselective beta blocker can cause rise in LDL/HDL ratio
Fatigues, loss of libido and subtle cognitive effects, nightmares
Contraindication of Beta blockers
Cardiac diseases
Asthma
Diabetes
DGUHQHUJLFEORFNHUV
Labetalol
%ORFNLQJERWKDQGUHFHSWRUV
,WUHGXFHVWKH735DQGDFWVIDVWHUWKDQEORFNHUV
On chronic therapy, its antihypertensive efficacy is similar to methyldopa.
Postural hypotension
Failure of the ejaculation
Rashes and the liver damage
-Adrenoceptor Blockers
0HFKDQLVPRIDFWLRQEORFNDGHRIYDVFXODU-adrenoceptors
1RQVHOHFWLYH 1 and 2) blockers: Phentolamine, phenoxybenzamine and dibenamine
6HOHFWLYH 1) prototype:Pprazosin (others: terazosin, doxazosin, trimazosin)
W
Adverse Drug Reaction RI 1-adrenoceptor blockers

First dose phenomenon: postural hypotension and fainting in the beginning. So it
should be given at bed time and start with low dose
Tachycardia
GI effects
Prazosin
)LUVWKLJKO\VHOHFWLYHKDYLQJD1: D2 selectivity ratio 1000:1
Dilates both resistance and capacitance vessels.
Reduces TPR and mean BP
Blocks sympathetically mediated vasoconstriction and produces fall in BP which is
attended by the only mild tachycardia.
Uses
Hypertension
LVF not controlled by the diuretics and the digitalis
Prostatic hypertrophy
Well tolerated in the low dose
Headache, drowsiness, blurred vision, dries mouth, weakness, palpitation, nasal
blockade and rashes.
Postural hypotension ( First dose effect )
Not used as a first choice because of fluid retention and tolerance gradually develops
with the monotherapy.
Ejaculation may be impaired in male with high dose
Central Sympatholytics
Clonidine
Partial agonist with higher affinity and intrinsic activity at D2 receptors
Decreases the sympathetic outflow from medulla fall in BP / bradycardia
Sedation mental depression, disturbed sleep, dryness of the mouth, nose and eyes ;
constipation
Impotence, salt water retention, bradycardia
Alarming rise in BP: Rebound hypertension when 1-2 doses of clonidine missed:
tachycardia, restlessness, anxiety, sweating, headache, nausea, vomiting.
W
Uses
Moderate hypertension
Opiate withdrawal
Analgesic activity / substitute to morphine
Control loose motion due to diabetic nephropathy
Methyldopa
Precursor of dopamine (DA) and NA
D- methyl-NA (selective D2 agonist) formed in brain from methyldopa acts on central
D2 receptor to decrease efferent sympathetic activity
Decreases t.p.r more than HR and CO
Moderately efficacious antihypertensive
Antihypertensive effects develop over 4-6 hours and lasts 12-24 hours.
Dose: 0.25-0.5 g BD-QID oral
Sedation, lethargy, reduced mental capacity
Dryness of mouth, headache, fluid retention, weight gain, impotence
Postural hypotension: in elderly pt. and in those receiving diuretics
Hypersensitivity
Uses
Mild to moderate HTN
It is used in combination with diuretics
Vasodialators
Hydralazine
Direct acting vasodilator: liberates NO from vascular endothelium which stimulates
the production of cGMP in vascular smooth muscle, resulting in relaxation.
Can not be used for monotherapy. Tachycardia with palpitations, hypotension often.
Facial flushing, throbbing headache, dizziness, palpitation, nasal stuffiness
Angina and MI may be precipitated
Parasthesias, tremors, muscle cramps, edema
Lupus-like syndrome may occur with chronic use that is reversible upon continuation
Uses
Moderate to severe HTN not controlled by first line drugs.
Never use as first choice
Not used alone. Low dose added to diuretics and beta blockers
Preferred hypertensive during pregnancy
W
Minoxidil
Prodrug of minoxidil N-O sulfate, which is a direct acting vasodilator
Mechanism: K+ channel opener causes membrane hyperpolarization, reducing ability
of smooth muscle to contract.
Other K channel openers: pinacidil, diazoxide
Refractory hypertension
Long duration of action (>24 hours)
Fluid and water retention: can lead to pulmonary hypertension
Tachycardia and increased cardiac output: can progress to congestive heart failure
Hypertrichosis: Occurs in all patients who take therapeutic doses of minoxidil for a
prolonged time
Uses
Malignant hypertension
Male pattern baldness
Soduim Nitroprusside
Rapidly and consistently acting vasodilators. Endothelial cells generate no from
nitroprusside which relaxes vascular smooth muscles.
Relaxes both resistance (arterioles) and the capacitance (veins) vessel, reduces t.p.r as
well as cardiac output.
Can cause reflex tachycardia
Rapidly metabolized: T1/2 in minutes
Given I/V not orally.
Uses
Management of the hypertensive emergency.
Palpitation, nervousness, vomiting, pain in the abdomen, weakness, disorientation.
Hypotension when given overdose.
Hypertension in the pregnancy

A woman with preexisting essential hypertension becomes the pregnant.
Pregnancy induced hypertension.
W
Antihypertensive safer in pregnancy

Methyldopa still drug of choice
CCBs second line: discontinue before labor as it weaken uterine contraction
Parenteral hydrazaline used in the hypertensive emergency in late pregnancy, in
combination with blocker to prevent tachycardia.
Cardioselective beta blocker in late pregnancy: atenolol, pindolol, acebutolol
Antihypertensive to be avoided during pregnancy
ACE inhibitors
AT1 receptor antagonist
Diuretics
Non-selective beta blocker: propranolol
Sodium nitroprusside: C/I in eclampsia
Severe Hypertension
Systolic blood pressure >220 and diastolic >120mmHg.
Patients with severe hypertension can be classified into 3 categories based upon their
symptoms and the organ systems that are affected at the time of presentation.
1. Hypertensive emergency - also called hypertensive crisis, is severe hypertension with
acute impairment of an organ system. In these conditions, the blood pressure should be
lowered aggressively over minutes to hours. Presence of papilledema indicates
malignant hypertension.
2. Hypertensive urgency - the BP is a potential risk but has not yet caused acute end-organ
damage. These patients require bp control over several days to weeks.
3. Accelerated hypertension - recent significant increase over baseline blood pressure that
is associated with target organ damage. This is usually vascular damage on fundoscopic
examination, such as flame-shaped hemorrhages or soft but without papilledema.
Indications of emergency reduction of BP
CVA (Cerebrovascular Accident) or head injury with high BP
Hypertensive encephalopathy
Hypertensive acute LVF
Unstable angina or MI with raised BP
Dissecting aortic aneurysm
Eclampsia
Hypertensive episodes in pheochromocytoma, cheese reaction, clonidine withdrawl.
Drugs for severe HTN
Once the diagnosis of hypertension is made and end-organ damage confirmed, the BP
should be lowered by about 25% of the mean arterial pressure.
There are 2 main classes of drugs: Vasodilators and Adrenergic inhibitors.
W
Management of severe HTN

Unless contraindicated best drug of the choice is BB - Atenolol 25 or 50 mg orally
In emergencies, vasodilators should be given IV in addition
Labetolol is also choice of drug (Except asthma)
Oral maintenance of the severe hypertension should be started at once if possible;
parental therapy is seldom required for more than 48 hours.
Figure: 5.4.7- Drugs which are commonly used in treating hypertension
Figure: 5.4.8- Hypertension Classified (JNC 7 Classes)

W
Figure: 5.4.9- Antihypertensive Drugs Vasodilators
Figure: 5.4.10- Antihypertensive drugs Adrenergic inhibitors
Figure: 5.4.11- Oral Antihypertensive Drugs
W
&+$37(5*$6752,17(67,1$/'58*6
(i)
Peptic Ulcer
Peptic Ulcer
Peptic ulcer occurs in that part of the gastrointestinal tract which is exposed to gastric
acid and pepsin, i.e. the stomach and duodenum. The etiology of peptic ulcer is not
clearly known. It results probably due to an imbalance between the aggressive (acid,
pepsin, bile and H. pylori) and the defensive (gastric mucus and bicarbonate secretion,
prostaglandins, nitric oxide, innate resistance of the mucosal cells) factors.
Approaches for the treatment of peptic ulcer
1. Reduction of gastric acid secretion
a. H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Roxatidine
b. Proton pump inhibitors: O meprazoie, Lansoprazole, Pantoprazole,
Rabeprazole, Esomeprazole.
c. Anticholinergics:Pirenzepine, Propantheline, Oxvphenonium.
d. Prostaglandin analogue: Misoprostol
2. Neutralization of gastric acid (Antacids)
a. Systemic: Sodium bicarbonate, Citrate
b. Non Systemic: Magnesium hydroxide, Magnesium trisilicate, Aluminum
hydroxide, Magaldrate, Calcium carbonate.
3. Ulcer protective: Sucralfate, Colloidal bismuth subcitrate (CBS)
4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin, Metronidazole, Tinidazole,
Ietraconazole
H2 antagonists
These are the first class of highly effective drugs for acid-peptic disease. Four H2
antagonists cimetidine, ranitidine, famotidine and roxatidine.
Pharmacological Actions
H2 blockade
Gastric secretion
Headaches, dizziness, bowel upset, dry mouth, rashes.
CNS effects like confessional state, restlessness, Convulsions and coma.
I/V. injection can release histamine-has caused bradycardia, arrhythmias and cardiac
arrest: it should always be given by slow Infusion.
Drug Interactions
Cimetidine inhibits cytochrome P-450 isoenzymes and decrease hepatic blood flow.
It inhibits the metabolism of many drugs so that they can accumulate to toxic levels.
Antacids reduce absorption of all H2 blockers.
W
Cimetidine Dose
For ulcer healing 400 mg BD or 800 mg at bed time orally given
Maintenance 400 mg at bed time
for stress ulcer 50 mg/hour I/V. infusion
Ranitidine dose
For ulcer healing 300 mg at bed time or 150 mg BD
For maintenance 150 mg at bed time.
Parenteral dose-.50 mg I/M. or slow I/V. Inj every 6-8 hour (rapid I/V. injection can
cause hypotension), 0.1-0 25 mg/kg/hour by I/V. Infusion has been used for
prophylaxis of stress ulcers
For gastrinoma 300 mg 3-4 times a day
Famotidine Dose
40 mg at bed time or 20 mg BD (for healing)
20 mg at bed time for maintenance
Up to 480 mg/day in Zollinger Ellison Syndrome
Parenteral dose 20 mg I/V. 12 hourly
Roxatidine Dose
150 mg at bed time or 75 mg BD
Maintenance 75 mg at bed time
Uses
Duodenal ulcer
Gastric ulcer
Stress ulcers and gastritis
Zollinger ellison syndrome
Gastroesophageal reflux disease (GERD)
Prophylaxis of aspiration pneumonia
Proton Pump Inhibitors (PPIs)
Omeprazole
It is a prototype member of substituted benzidiazoles which inhibit the final common step
in gastric acid secretion and have overtaken H2 blockers for acid-peptic disorders. The
only significant pharmacological action of omeprazole is dose dependent suppression of
gastric acid secretion.
Uses
Peptic ulcer
Bleeding peptic ulcer
Stress ulcers and Gastritis
Gastro esophngeal reflux disease (GERD)
Zollinger-Ellison syndrome
Aspiration Pneumonia
Nausea
Loose stools
W
Headache
Abdominal pain
Muscle and joint pain
Dizziness
Rashes (1.5% incidence)
Leucopenia and Hepatic dysfunction are infrequent.
Drug Interactions
It inhibits oxidation diazepam, phenytoin and Warfarin levels may be increased.
Clarithromycin inhibits omeprazole metabolism and inc. its plasma concentration.
Dose: 20-40 mg OD.
Esomeprazole
It is the S-enantiomer of Omeprazole; claimed to have higher oral bioavailability and to
produce better control of intra-gastric pH than omeprazole in CERD patients because of
longer t1/2. Higher healing rates of erosive esophagitis and better GERD symptom relief
have been reported in comparative trials with omeprazole.
Dose: 20-40 mg OD.
Lansoprazole
It is more potent than Omeprazole but similar in properties. It has higher oral
bioavailabilify, faster onset of action and slightly longer T1/2 than Omeprazole. Dose
should be reduced in liver disease.
Dose: 15-30 mg OD for ulcer healing.
Pantoprazole
It is a newer drug, similar in potency and clinical efficacy to omeprazole but is more acid
stable and has higher oral bioavailability.
Dose: 20-40 mg OD.
Rabeprazole
This newer PPI is claimed to cause fastest acid suppression and to aid gastric mucin
synthesis. However, potency and efficacy are similar to omeprazore.
Dose: 20 mg OD.
Prostaglandin Analogue
PGE2 and PGI2 are produced in the gastrrc mucosa and appear to serve a protective role
by inhibiting acid secretion and promoting mucus + HCQ secretion. Prostaglandin
Analogue such as: Misoprostol; dose: 200 mcg. Major problems of misoprostol arediarrhoea, abdominal cramp, uterine bleeding, abortion, and need for multiple daily doses.
Antacids
These are basic substances which neutralize gastric acid and raise pH of gastric contents.
Peptic activity is indirectly reduced if the pH rises above 4, because pepsin is secreted as
W
a complex with an inhibitory terminal moiety that dissociates below pH 5: optimum

peptic activity is exerted between pH 2 to 4. It works faster in empty stomach.
Systemic Antacids
Sodium bicarbonate
It is water soluble, acts instantaneously but the duration of action is short. It is a potent
neutralizer. However, it has several demerits:
Absorbed systemically: Large doses will induce alkalosis.
distention, discomfort, belching and risk of ulcer
Produces CO2 in stomach
perforation.
Acid rebound occurs but is usually short lasting.
Increases Na+ load: may worsen edema and CHF.
Sodium citrate
Properties are similar to Sodium bicarbonate.
Non-Systemic Antacids
These are insoluble and poorly absorbed basic compounds; react in stomach to form
corresponding chloride salt. The chloride salt again reacts with intestinal bicarbonate so
that HCO-3 is not spared for absorption so, no acid-base disturbance occurs.
Magnesium Hydroxide
Magnesium trisilicate
Aluminium hydroxide gel
Magaldrate
Calcium carbonate
Antacid combinations: A combination of two or more antacids is frequently used.
Fast and slow acting components yield prompt as well as sustained effect.
Mag. salts are laxative, while alum.
Gastric emptying is least affected; while alum.
Dose of individual components is reduced; systemic toxicity is minimized.
Drug interactions
By raising gastric pH and by forming complexes, the non-absorbable antacids decrease
the absorption of many drugs, especially tetracyclines, iron salts, fluoroquinolones,
ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacin, phenytoin,
isoniazid, ethambutol and nitrofurantoin.
Uses
Antacids are no longer used for healing peptic ulcer because they are needed in large and
frequent doses, are inconvenient. Antacids are now used only for inter-current pain relief
and acidity, mostly self-prescribed by the patients as over the counter preparations.
Ulcer Protective
Sucralfate
It is a basic aluminium salt of sulfated sucrose. It has no acid neutralizing action, but
delays gastric emptying. Sucralfate is minimally absorbed after oral administration; action
is entirely local. It promotes healing of both duodenal and gastric ulcers; efficacy has
been found similar to cimetidine at 4 weeks.
W
Dose: The ulcer healing dose is 1 gm taken 1 hour before the 3 major meals and at bed
time for 4-8 weeks.
Anti-Helicobacter Pylori Drugs
H. pylori is a gram negative bacillus uniquely adapted to survival in the hostile
environment of stomach. It attaches to the surface epithelium beneath the mucus, has high
urease activity produces ammonia which maintains a neutral micro-environment around
the bacteria and promotes back diffusion of H+ ions.
A number of 2-drug and 3-drug regimens of 1 or 2 weeks duration have been tested
reporting 60-96% eradication rates, but the optimum regimen is difficult to proclaim.
Some of the 2 week regimens are:
1.
2.
3.
4.
5.
6.
Amoxicillin 750 + Tinidazole 500 + Omeprazole 20 all BD

Amoxicillin 750 + Tinidazole 500 + Lansoprazole 30 all BD
Clarithromycin 250 + Tinidazole 500 + Lansoprazole 30 ali BD
Clarithromycin 500 + Amoxicillin 1000 + Lansoprazole 30 all BD
Clarithromycin 500 BD + Amoxicillin 750 BD + Omeprazole 20 BD
Amoxicillin 500 TDS/Tetracydine 500 QID + Metronidazole 400 QID
/Tinidazole 500 BD + Bismuth 120 QID
7. Amoxicillin 750 TDS + Metronidazole 500 TDS + Ranitidine 300 OD
8. Amoxicillin 750 BD + Clarithromycin 250 BD + Lansoprazole 30 BD
The US-FDA approved regimen is: lansoprazole 30 mg + amoxicillin 1000 mg +
clarithromycin 500 mg all given twice daily for 2 weeks.
W
&+$37(5*$6752,17(67,1$/'58*6
(ii)
Digestive Disorders
Digestive Disorders
Emesis
Vomiting occurs due to stimulation of the emetic (Vomiting) centre situated in the
medulla oblongata. Multiple pathways can elicit vomiting. The chemoreceptor trigger
zone (CTZ) is located in the area postrema and the nucleus tractus solitarius (NTS) are
the most important relay areas for afferent impulses arising in the GIT, throat and other
viscera. The CTZ is also accessible to blood-borne drugs, mediators, hormones, toxins,
etc. because it unprotected by the blood-brain barrier.
Nausea is accompanied by reduced gastric tone and peristalsis. Rhythmic contractions of
diaphragm and abdominal muscles then compress the stomach and evacuate its contents
via mouth. Conditions that inhibit gastric emptying predispose to vomiting.
Emetics: These drugs are used to evoke vomiting.
Apomorphine: act on CTZ
It is a semi-synthetic derivative of morphine; acts as a dopaminergic agonist on the CTZ.
Injected IM/SC in a dose of 6 mg, it promptly induces vomiting. It should not be used if
respiration is depressed, because it has inherent respiratory and CNS depressant actions.
Ipecacuanha: act reflexly and on CTZ
The dried root of Caphaelis ipecacuanha contains emetine and is used as syrup ipecac
(15-30 ml in adults, 10-15 ml in children, 5 ml in infants) for inducing vomiting. It should
be available in every household for emergency use. It is less dependable than parenteral
apomorphine and takes 15 minutes for the effect but is safer.
Contraindication of Emetics
Corrosive poisoning: risk of perforation and more injury to esophageal mucosa.
CNS stimulant drug poisoning: convulsions may be precipitated.
Kerosine poisoning: chances of aspiration of the liquid.
Unconscious patient may aspirate the vomitus, because laryngeal reflex is likely to be
impaired.
Morphine or phenothiazine poisoning: emetics are ineffective.
Antiemetics: used to prevent or suppress vomiting.
Classification
1. Anticholinergics
Hyoscine; most effective for motion sickness. (0.2-0.4 mg Oral/IM)
Dicvclomine; used for prophylaxis for motion sickness (10-20 mg Oral)
2. H1 antihistaminics
W
3.
4.
5.
6.
Promethazine; used for motion sickness but has sedative action.

Diphenhydramine; same as promethazine.
Dimenhvdrinate; same as promethazine.
Doxvlamine; sedative with prominent anticholinergic activity.
Cyclizine, Meclozine; less sedative and less anticholinergic activity.
Cinnarizine; it is anti-Vertigo drug also protective for motion sickness.
Neuroleptics (D2 blockers)
Chlorpromazine
Prochiorperazine; It has selective anti-Virtigo and antiemetic actions.
Haloperidol
Prokinetic drugs
Metoclopramide
Domperidone
Cisapride, Mosapride
Tegaserod
5-HT3 antagonists
Ondansetron
Granisetron
Adjuvant antiemetic
Corticosteroids (Dose: Dexamethasone 8-20 mg IV)
Benzodiazepines
Cannabinoids
Metoclopramide
Metoclopramide is chemically related to procainamide but has no pharmacological
similarity. It has more prominent effect on upper GIT. Increases gastric peristalsis while
relaxing the pylorus and the first part of duodenum inc. speeds gastric emptying,
especially if it was slow. As in mechanism of action, Metoclopramide acts through both
dopaminergic and serotonergic receptors. It is rapidly absorbed orally, enters brain,
crosses placenta and is secreted in milk. It is partly conjugated in liver and excreted in
urine within 24 hours; t1/2 is 3-6 hours.
Metoclopramide is generally well tolerated. Sedation, dizziness, loose stools, muscle
dystoniasa re the main side effects. Long-term use can cause parkinsonism, galactorrhoea
and gynaecomastia. It should not be used to augment lactation.
Dose: 1.0 mg (children 0 2-0.5 mg/kg) TDS oral or IM. for chemotherapy induced
vomiting 0.3-1.0 mg/kg slow IV./IM.
Uses
i.
Antiemetic use
ii.
Gastrokinetic use
iii.
Dyspepsia
iv.
Gastro esophageal reflux disease (GERD)
Domperidone
It is a D2 antagonist, chemically related to haloperidol but pharmacologically related to
metoclopramide. It has lower ceiling antiemetic and prokinetic actions. It is absorbed
orally.
Dose: 10-40 mg (Children 0.3-0.6 mg/kg) TDS.
W
Ondansetron
It is the prototype of a new class of antiemetic drugs developed to control cancer
chemotherapy/radiotherapy induced vomiting and later found to be highly effective
in postoperative nausea and vomiting as well. It blocks the depolarizing action of 5HT through 5-HT. Oral bioavailability of ondansetron is 60-70% due to first pass
metabolism. It is eliminated in urine and faeces, mostly as metabolites; t1/2 being 35 hours and duration of action 4-12 hours. It is generally well tolerated: the only
common side effect is headache. Mild constipation or diarrhoea and abdominal
discomfort occur in few patients. Rashes and allergic reactions may occur as well
after IV. Injection.
Dose and efficacy:
For cisplatin and other highly emetogenic drugs-8 mg IV. By slow injection
over 15 min half hour before chemotherapeutic infusion followed by 2
similar doses 4 hour apart.
To prevent delayed emesis 8 mg oral is given twice a day for 3-5 days.
For postoperative nausea/vomiting 4-8 mg IV. Given before induction is
repeated 8 hourly.
For less emetogenic drug and for radiotherapy an oral dose of 8 mg is given
1-2 hour prior to the procedure and repeated twice 8 hourly.
Gastroesophageal reflux disease (GERD)
It is a very common problem presenting as heartburn, acid eructation and sensation of
stomach contents coming back in foodpipe, especially after a large meal, aggravated by
stooping or lying flat. Repeated reflux of acid gastric contents into lower l/3rd of
esophagus causes esophagitis, erosions, ulcers, pain on swallowing, dysphagia strictures
and increases the risk of esophageal carcinoma.
Drugs used to treat GERD are as follows:
i.
PPIs
ii.
H2 Blockers
iii.
Antacids
iv.
Sodium Alginate
v.
Prokinetic drugs
W
&+$37(5*$6752,17(67,1$/'58*6
(iii)
Constipation & Diarrhea
Constipation
Laxatives
Irritation or stimulant
Castor oil: Nicinoleic acid
Senna: Emodin
Aloe: Emodin
Phenolphthalein
Bisacodyl
Adverse effect: Abdominal cramp and potential for atonic colon with prolonged use.
Bulking agents
Hydrophilic colloids
Methylcellulose
Psyllium seeds
Bran
Mechanism: Water retention and intestinal distension-increasing peristaltic activity.
Osmotic
Magnesium hydroxide
Magnesium sulfate
Polyethylene glycol
Lactulose
Stool softeners
Decussate sodium
Mineral oil
Glycerine suppositories
Diarrhea
Principles of Management
Treatment of fluid depletion, shock and acidosis
Maintenance of nutrition
Drug therapy
Specific antimicrobial drugs
Nonspecific antidiarrhea drugs
W
Rehydration
Intravenous
Severe diarrhea fluid loss >10% body weight
Ringer lactate
Normal saline
Oral (ORS)
Fluid loss mild to moderate
Who formula (310 mosm/l)
NaCl 3.5gm (60mm), KCl 1.5gm (20mm), trisodium Citrate 2.9 (30mm), Glucose 20 gm
(110mm) to be dissolved in one liter of water.
New formula who ORS (245 mosm/l ) NaCl 2.6mg, Glucose 13.5gm.
Antimicrobials
Indication
Cholera
Campylobacter Jejuni
Clostridium Difficile
Diverticulitis
Antidiarrheals
Antimotility Agents
Diphenoxylate
Loperamide
Mechanism: They have opioid like action on the gut activating presynaptic opioid
receptors in the enteric nervous system to inhibit acetylcholine release and decrease
peristalsis.
Side Effects: Drowsiness abdominal cramps, dizziness, toxic megacolon - contraindicated
to young children and severe colitis.
Adsorbents
Kaolin
Pectin
Methylcellulose
Magnesium aluminum silicate
Widely used but efficacy has not been documented
Mechanism: Adsorbing intestinal toxins or microorganisms, or by coating or protecting
the intestinal mucosa.
They are much less effective than antimotility agents and can interfere with absorption of
other drugs.
Prostaglandin inhibitors: Aspirin, Indomethacin
Mechanism: Inhibition of prostaglandin synthesis. Effective in controlling Diarrhoea.
W
Antisecretory drugs
Sulfasalazine
Mesalazine
Bismuth subsalicylate
Atropin
Octreotide
Sulfasalazine
5-ASA + Sulfapyridine
Poorly absorbed from GI, Local effect is not systemic effect
5-asa acts as a local anti-inflammatory agent by inhibiting COX and LOX there by
reducing PG. lt cytokines in the gut
Use: Crohn's disease , ulcerative colitis mainly maintaining remission
Adverse effect is dur to sulfapyridine which is absorbed in colon
Rashes, fever, joint pain, hemolysis, blood dyscrasias, nausea, vomiting, headache,
malaise. Male infertility is also reported
Mesalazine
5-ASA
Formulated as a delayed release preparation
Better tolerated than sulfasalazine
Nausea, diarrhoea, abdominal pain, headache but are less frequent, rash and
hypersensitivity reaction, no bone marrow depression and decrease sperm count
Nephrotoxic potential contraindicated in renal and hepatic impairment.
Bismuth subsalicylate
Action may be its salicylate component
7UDYHOHUVGLDUUKHRD
Decrease fluid secretion in the bowel
W
&+$37(585,1$5<6<67(0'58*6
(i)
Diuretics
Figure: 7.1.1- Structure of Nephron
Diuretics
Nephron structure
Proximal Tubule
Na+ flows down concentration gradient
Na/K ATPase maintains gradient
Water follows passively
67% of Na and water reabsorption
Loop of Henle
TDL permeable to water but not Na+
TAL impermeable to water and transports Na+
Differences in permeabilities creates the countercurrent multiplier
Countercurrent multiplier creates interstitial osmolar gradient
20% of filtered load of Na absorbed by the TAL
W
Distal Convoluted Tubule

5% of filtered load of Na+ reabsorbed
Segment mostly impermeable to water
Cortical Collecting Duct
Water permeability controlled by antidiuretic hormone (ADH).
Driving force for water reabsorption is created by the countercurrent multiplier.
2-3% of filtered Na+ reabsorbed here via Na+ channels that are regulated by
aldosterone.
Major site of K+ secretion.
Diuretics
Diuretics are the drugs that increase urine and solute excretion
These drugs increase the output of sodium and water.
Agent that promotes the execration of urine through there effect on kidney function.
Classes of Diuretics by Definitions
Diuretic: substance that promotes the excretion of urine
Natriuretic: substance that promotes the renal excretion of sodium
Classification on the basis of site of action
1. Drugs acting on proximal tubule:
Osmotic diuretics: Mannitol, Glycerol
Carbonic anhydrase inhibitor: Acetazolamide
2. Drugs acting on ascending loop of Henle:
Furosemide
Bumetanide
Ethacrynic acid
3. Drugs acting on cortical diluting segment:
Thiazides: Chlorothiazide, Hydrochlorothiazide, Benzthiazide
Thiazide like: Chlorthalidone, Metolazone, Xipamide, Mefruside
4. Drugs acting on distal tubule:
Potssium sparing diuretics:
Aldosterone antagonist: Spironolactone
Directly acting: Triameterene, Amiloride
W
Figure: 7.1.2- Mechanism of Action of Cardiac Glycosides

Principles of effects of Diuretics
1. Interference with Na+ reabsorption at one nephron site interferes with other renal
functions linked to it
2. It also leads to increased Na+ reabsorption at other sites
3. Increased flow and Na+ delivery to distal nephron stimulates K + (and H +) secretion
4. Diuretics act only if Na+ reaches their site of action. The magnitude of the diuretic
effect depends on the amount of Na+ reaching that site
5. Diuretic actions at different nephron sites can produce synergism
6. All but spironolactone, act from the luminal side of the tubular cellular membrane
Thiazide diuretics
Secreted into tubular lumen by organic acid transport mechanisms in proximal tubule
Act on the distal tubule to inhibit sodium and chloride transport on the luminal
membrane and result in a moderate diuresis
Actions:
Increase excretion of Na and Cl
Increase renal excretion of K
Reduce calcium and urate excretion
Reduce peripheral vascular resistance
Not effective at low glomerular filtration rates
W
Pharmacokinetics
Rapid GI absorption
Distribution in extracellular space
Eliminated unchanged in kidney. Secreted by organic acid secretary system of the
kidney.
Variable elimination kinetics and therefore variable half-lives of elimination ranging
from hours to days.
Half life: Chlorthalidone: 40-50 hrs, Hydrochlorothiazide: 8-12 hrs, Chlorothiazide:
6-12 hrs.
Whole Body Effects of Thiazides
Increased urinary excretion of:
Na+
ClK+
Water
HCO3Reduced ECF volume (contraction)
Reduce blood pressure (lower CO)
Reduced GFR
Clinical Uses
1. Essential Hypertension:
Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension
They should be considered first-line therapy in hypertension.
Excretion of Na+1D+-Ca2+ H[FKDQJH&D2+ LQFHOOWHQVLRQRIDUWHULDO
causing vasodilation and hence decrease BP.
2. Edema:
Mild and moderate cardiac edema: first choice
Ascites due to cirrhosis
Renal edema: related to renal function
3. Idiopathic Hypercalciuria:
It is a condition characterized by recurrent stone formation in the kidneys due to
excess calcium excretion
Thiazide diuretics used to prevent calcium loss and protect the kidneys
4. Nephrogenic Diabetes Insipidus
Thiazides: causes paradoxical reduction in urine volume
So volume depletion causes decreased GFR
5. CHF (congestive heart failure)
6. Metabolic alkalosis: causes excretion of bicarbonate
W
Thiazide Use in Hypercalciuria - Recurrent Ca2+ Calculi

Thiazides promote distal tubular Ca2+ reabsorption.
3UHYHQWH[FHVVH[FUHWLRQZKLFKFRXOGIRUPVWRQHVLQWKHGXFWVRIWKHNLGQH\.
50-100 mg HCT kept most patients stone free for 3 years of follow-up in a study.
Adverse effects of Thiazides
Initially, they were used at high doses which caused a high
Incidence of adverse effects. Lower doses now used cause
Fewer adverse effects. Among them are:
1. Hypokalemia
Increased availability of na+ for exchange at collecting duct
Volume depletion induced aldosterone release
2. Hyponatremia: due to thirst, sodium loss, inappropriate adh secretion
3. Dehydration leading to postural hypotension
4. Hyperglycemia
Diminished insulin secretion
Related to the fall in serum k+
5. Hyperuricemia because thiazides compete with urate for tubular secretion
6. Hypercalcemia
7. Hyperlipidemia; mechanism unknown but cholesterol increased is usually of no
significance.
8. Hypersensitivity
9. Metabolic alkalosis
10. Impotence
Thiazides Dose
Chlorothiazide: 500-2000 mg/day
Hydrochlorothiazide: 25-100 mg/day
Chlorthalidone: 50-100 mg/day
Metolazone: 5-20 mg/day
Loop diuretics
Furosemide, Bumetanide, Torsemide, Ethacrynic acid
Secreted in proximal tubule by Organic acid mechanisms
Mechanism of Action
Act on the ascending loop of Henle to inhibit Na-K-Cl co transport. Therefore
reabsorption of Na, K , Cl is decreased and osmotic gradient is lowered
Cause a greater natriuresis than thiazides
Effective at low glomerular filtration rates, where thiazides are ineffective
Increase sodium, potassium, calcium and magnesium excretion
Decrease urate excretion
W
Additional non-tubular effects:

Renal Vasodilation ( PG synthesis) and redistribution of blood flow
Increase in renin release
Increase in venous capacitance
Pharmacokinetics
Rapid GI absorption. bioavailability ranges from 65-100%. Also given i.m. and i.v.
Rapid onset of action
Highly plasma protein bound
Secreted by proximal tubule organic acid transporters
Short half-lives in general: 2 hrs
Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile.
Clinical uses
1. Severe edema due to chf, nephrotic syndrome or cirrhosis
2. Acute heart failure with pulmonary edema
'LODWLQJDUWHULROHDIWHUORDG
EORRGYROXPHSUHORDG
Dilating pulmonary vessels
3. Hypercalcemia
4. Hypertension
5. Acute renal failure: early stage
6. Ascitis
7. Along with blood transfusion in severe anemia to prevent vascular overload.
Adverse Effects is similar to thiazides in many respects
1. Hyponatremia,hypokalemia, hypocalcemia
2. Hyperglycemia, hyperuricemia, hypercholesterolemia, hypersensitivity
3. Dehydration and postural hypotension
4. Metabolic alkalosis
5. Ototoxicity: dose-related hearing impairment: Tinnitus, hearing loss, etc.
Dose of Frusemide
20-80mg OD in the morning
In Pulmonary edema: 40-80mg IV
In Renal insufficiency: up to 200mg 6 hourly IM/IV
W
Acetazolamide: Carbonic anhydrase inhibitor

Mechanism of Action
It inhibits carbonic anhydrase enzyme located intracellularly and on the apical membrane
of proximal tubular epithelium resulting in decreased ability to exchange Na for H and is
mild diuresis.
Pharmacokinetics
Well absorbed orally
Excreted unchanged in urine
Uses
Glaucoma
Mountain (High altitude) sickness
Alkalinization of urine
Epilepsy
Periodic paralysis
i.
Potassium depletion
ii.
Hypersensitivity reaction
iii.
Metabolic acidosis
iv.
Drowsiness
v.
Paraesthesis
vi.
Renal stone formation
vii.
Bone marrow suppression
viii.
Contraindicated in liver disease
Dose: 250 mg OD or BD.
Spironolactone: potassium sparing diuretics
Mechanism of Action
It is a competitive aldosterone antagonist
It binds to the intracellular aldosterone receptor and inactivates it, thus preventing
translocation of the receptor complex into nucleus of target cells and binding to DNA.
prevents Na reabsorption and K & H secretion
Pharmacokinetics
Orally absorbed
Strongly bound to plasma protein
Extensive first pass effect in liver and enterohepatic circulation
In liver metabolised to active metabolites
Induces hepatic cytochrome P-450
W
Uses
To counteract K loss due to thiazide and loop diuretics
Edema: due to Cirrhosis and Nephrotic syndrome
HTN
CHF
Secondary hyperaldosteronism
GI upset, Drowsiness, Mental confusion, lethargy
Hyperkalemia
Hirsutism, Gynecomastia, Menstrual irregularities Impotence
Acidosis
Dose: 25-50 mg BD QID
Drug interaction
Given together with K supplements- serious hyperkalemia
Aspirin blocks action of Spironolactone by inhibiting tubular secretion of canrenone
Spironolactone increases plasma digoxin concentration
Triamterene and Amiloride
Mechanism of Action
Blockade of renal epithelial Na+ channel in the principal cells of the CCD
Amiloride: blocks the amiloride sensitive Na channels through which Na enters cell
down the electrochemical gradient generated by Na-K ATPase pump
Na entry through channel partially depolarizes luminal membrane thus promoting
secretion of K and H ions into lumen.
Blockade of the electrogenic entry of sodium causes a drop in luminal membrane
potential, hence inhibits secretion of K and H ions
Pharmacokinetics
Triamterine
50% absorption of oral dose
60% bound to plasma proteins
Extensive hepatic metabolism with active metabolites
Secreted by proximal tubule via organic cation transporters
Amiloride
50% absorption of oral dose
not bound to plasma proteins
not metabolized, excreted in urine unchanged
Secreted by proximal tubular cation transporters
W
Therapeutic Uses
i.
To counteract K loss due to other diuretics
ii.
Edema
iii.
HTN
Mannitol: Osmotic diuretic
Mechanism of Action
Mannitol is small molecular weight substances that are filtered by glomerulus but are
not absorbed by the renal tubule and thus increase the osmolarity of the tubular fluid.
The result is increased urine volume
They act in proximal tubule , where they prevent the absorption of water and sodium.
Also increases movement of water from inside of cells to the extracellular fluid .
Maintains urine flow and prevents Renal tubular necrosis.
Pharmacokinetics
Not absorbed orally
Given intravenously
Plasma half life is 0.5-1.5 hour
Uses
Acute renal failure due to shock
Increased intracranial pressure
Drug toxicity (hypnotic drug poisoning)
Nausea, Vomiting, Headache
Hyponatremia
Hypersensitivity
Dose: 1-1.5gram/kg infusion over 20 min. as 20% solution of Mannitol (5ml/kg weight).
Contraindication
Acute tubular necrosis, Anuria.
Pulmonary edema, heart failure, cerebral haemorrhage.
Conditions treated with Diuretics
i.
Edema
ii.
Hypertension
iii.
Nephrogenic Diabetes Insipidus
iv.
Syndrome of Inappropriate ADH Secretion (SIADH)
v.
To increase or decrease Ca++, K+ or H+ ion excretion.
W
Edema: Therapeutic Considerations

i.
Therapy is palliative (except with pulmonary edema).
ii.
Need a mild sustained response.
iii.
Therefore, in most cases start with a thiazide.
iv.
If resistant, move to Loop diuretic.
v.
Specific consideration to potassium homeostasis, i.e. supplement with K-salt or use
K-sparing diuretic.
Diuretic Resistance
1. Compensatory Mechanisms (RAAS, SNS)
2. Failure to reach tubular site of action
Decreased G.I. absorption eg. diarrhea
Decreased secretion into tubular lumen (e.g. uremia, decreased kidney perfusion)
Decreased availability in tubular lumen (e.g. nephrotic syndrome)
3. Interference by other drugs (e.g. NSAIDV
4. Tubular adaptation (chronic Loop diuretic use)
W
&+$37(585,1$5<6<67(0'58*6
(ii)
Anti-Diuretics
Anti-Diuretics
These are drugs that reduce urine volume, particularly in diabetes insipidus (DI) which is
their primary indication.
1. Antidiuretic hormone (ADH), Desmopressin, Lypressin, Terlipressin
2. Thiazide diuretics, Amiloride.
3. Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine.
Antidiuretic Hormone
It is a nonapeptide secreted by posterior pituitarv along with oxytocin. It is synthesized in
the hypothalamic nerve cell bodies as a large precursor peptide along with its binding
protein - neurophysin and is transported down the axons to nerve endings in the median
eminence and pars nervosa.
ADH (Vasopressin) receptors
These are G protein coupled cell membrane receptors; two subtypes V1 and V2 have been
identified, cloned and structurally characterized.
Pharmacokinetics
AVP is inactive orally because it is destroyed by trypsin. It can be administered by any
parenteral route or by intranasal application. The peptide chain of AVP is rapidly cleaved
enzymatically in many organs, especially in liver and kidney; plasma t1/2 is short.
Vasopressin Analogues: Lypressin, Terlipressin, Desmopressin.
Uses
1. Based on V2 actions
i.
Diabetes insipidus
ii.
Bedwetting in children and nocturia in adults
iii.
Renal concentration test
iv.
Haemophilia, Von Willebrand's disease
2. Based on V1 actions
i.
Bleeding esophageal varices
ii.
Before abdominal radiography: drive out gases from bowel occasionally.
Adverse Effects
Because of V2 selectivity desmopressin produces fewer adverse effects than Vasopressin,
lypressin or terlipressin. However, transient headache and flushing are frequent. Nasal
irritation, congestion, rhinitis, ulceration and epistaxis can occur on local application.
Systemic side effects are: belching, nausea, abdominal cramps, pallor, urge to defecate.
W
&+$37(5$17,&$1&(5'58*6
Anti-Cancer Drugs
Introduction
A neoplasm is an abnormal mass of tissues, the growth of which exceed and is
uncoordinated with that of normal tissues and persist in the same excessive manner after
cessation of stimuli which evoke the change.
Classification
Benign: no too much harm and can be cured by surgery
Malignant: very lethal. It is treated with Surgery, Radiotherapy, Chemotherapy,
Hormonal therapy.
Anti-Cancer Drugs: Either kill the cell or modify their growth.
Aim: Cure or prolong remission, Palliation, Adjuvant chemotherapy.
General Principles
Malignant cell viewed as invader: bacterial metabolism differs markedly from that of
host, while malignant cells are in fact host cells.
A single colonogenic malignant cells capable of producing progeny that can kill host.
Drugs kill the cell by first order kinetics, i.e. certain fraction of the cell present is
killed by one treatment.
Drugs regimens which are effectively palliate large tumors burden may be curative
applied to minute residual tumor cell population.
To get effective cure all malignant cells must be killed When ever possible complete
remission should be the goal of the cancer therapy.
Cytotoxic drugs
Cell cycle nonspecific: Kills resting as well as dividing cells. E.g. Cisplatin
Cell cycle specific: kills only dividing cells. E.g. Vinblastine, Methotrexate
General toxicity of the cytotoxic drugs
1. Profound effect on rapidly multiplying cell
Bone marrow Depression: Granulocytopenia, agranulocytopenia,
thrombocytopenia, aplastic anmeia, infection, bleeding.
Lymphocytopenia.
G I symptoms: Stomatitis, diarrhoea, nausea, vomiting, hemorrhage.
2. Skin: Alopecia, Dermatitis
3. Gonads
Impotence in males
Oligospermia, sterility
Inhibition of ovulation and amenorrhoea
W
4. Foetus: Abortion, fetal death, teratogenesis

5. Carcinogenecity: Secondary cancers, leukemia, lymphomas
6. Hyperuricemia
Toxicity Amelioration
1. Toxicity blocking drugs:
Folinic acid rescue
Cystitis caused by cyclophosphamide: Mesna, Acetylcystine
Antiemetics: Ondansetron, Metoclopramide
2. Lithium carbonate: stimulates bone marrow
3. Hyperuricaemia:
Allopurinol
Alkalinization of urine
Plenty of fliuld
Corticostriods
4. Drugs given in pulses with 2-3 weeks interval
5. Selective exposure of tumour cell
Intra-arterial
Intraperitoneal
Topical
6. Platelet and granulocyte transfusion
7. Use of biological response modifiers: Interleukin 2, GM-CSF/G-CSF
8. Bone marrow transplantation
Classification of Anti-Cancer Drugs
A. Drug acting directly on cells (Cytotoxic drugs)
1. Alkylating agents:
a. Nitrogen mustards: Mecholrethamine (Mustine HCl), Cyclophosphamide,
Ifosfamide, Chlorambucil, Melphalan.
b. Ethylenimine: Thio-TEPA
c. Akly sulfonate: Busulfan
d. Nitrosoureas: Carmustine, Lomustine, Semustine.
e. Triazine: Dacarbazine
2. Anti metabolites:
a. Folate antagonist : Methotrexate
b. Purine antagonist :6 Mercaptopurine, Azathioprine
c. Pyrimidine antagonist : 5 Flourouracil, Cytarabine
3. Vinica alkaloids: Vincristine, Vinblastine
4. Texanes: Paclitaxen, Docetaxel
5. Antibiotics: Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitoxantrone
6. Epipodophyllotoxins: Etoposide
7. Miscellaneous: Hydroxyurea, Procarbazine, L-Asparaginase, Cisplatin & Carboplatin.
W
B. Drugs altering the hormone milieu

1. Glucocortiocoids: Prednisolone and others
2. Estrogenes: Diethylstilbestrol, Ethinyl estradiol
3. Anti- Androgen: Testosterone, Fluoxymesterone
4. Anti estrogenes: Tamoxifen
5. 5 v reductase inhibitors: Finasteride
6. GnRH analogue: Naferelin, Goserelin
7. Progestins: Hydroxyprogesterone acetate
Alkylating agents
Its active metabolite transfers alkyl groups to DNA and results in cross linking/
abnormal base pairing/scission of DNA strand
Cytotoxic and radiomimetic action.
Cell cycle nonspecific
Also CNS stimulant and cholinergic property
Cychlophosphamide
Wide range of anti tumor action
Prominent immuno suppressant
Less damaging to platelet
Alopecia and cystitis
Chloramphenicol inhibit the metabolism of cyclophosphamide
Chlorambucil
Maintenance therapy for chronic lymphatic leukemia.
+RGJNLQVGLVHDVH
Also got some immunosupressants property
Melphalan
Multiple myeloma
Advance ovarian cancer
Bone marrow depression
Infection, diarrhoea and pancreatitis
Busulfan
Chronic myeloid leukemia
Hyperuricemia
Pulmonary fibrosis
W
Anti-metabolites
Analogues related to normal component of the DNA
Competitively inhibits the utilization of the substrate.
Folate Antagonist: Methotrexate
Highly efficacious anti-neoplastic drugs
Primarily inhibits DNA synthesis
Inhibits dihydrofolate reductase
DHFA THFA
Cell Cycle specific
Therapeutic uses
Choriocarcinoma
Maintenance of the remission in acute leukemia
Rheumatoid arthritis
Psoriasis
Purine Antagonist
Mercaptopurine uses:
Childhood Acute leukemia
Choriocarcinoma
Azathioprine uses:
Immuno suppressants in organ transplantation
Pyrimidine Antagonist: neoplastic, antifungal and antipsoriatic agents.
5 Fluorouracil
Tumors of breast, colon, urinary bladder, liver
Topical application in cutaneous basal cell carcinoma
Cytarabine
Cell cycle specific
Induce remission in acute leukemia
+RGJNLQVGLVHDVHDQGQRQ+RGJNLQO\PSKRPD
Vinica Alkaloids
These are the mitotic inhibitors binds to micro- tubular protein tubulin and prevents
its polymerization and assembly of microtubules.
Cell cycle specific
Acts in mitotic phase
W
Vincristine
Childhood Acute leukemia
Lymphosarcoma
+RGJNLQVGLVHDVHV
Carcinoma of the lungs
Perpheral neuropathy, alopecia
Bone marrow depression are minimal
Vinblastine
+RGJNLQVGLVHDVHV
Testicular carcinoma
Bone marrow depression more prominent
Neurotoxicity and alopecia less marked
Texanes
Paclitaxel:
Enhances polymerization of tubulin
Indications
Ovarian and breast carcinoma
Advances cases of head and neck cancer
Esophageal adenocarcinoma
Docetaxel:
Breast and ovarian cancer
Pancreatic, gastric and head and neck cancer
ADR: Arrhythimias, fall in BP, heart failure
Antibiotics
Actinomycin D:
Rhabdomyosarcoma
:LOPVWXPRXU
Methothexate resistant choriocarcinoma
ADR: Vomiting, stomatatis, desquamation of skin, bone marrow depression.
Doxorubicin
Acute leukemia
Mutagenic and carcinogenic potential
ADR: Cardiotoxicity, CHF, Bone Marrow depression, Alopecia, stomatitis, and local
tissue damage.
W
Bleomycin
Testicular tumor, Squamous cell carcinoma of skin, head and neck, G U tract
+RGJNLQVGLVHDVHV: Mucocutaneous toxicity and pulmonary fibrosis
L Asparaginase: Used when other drug failed to induce remission.
Liver damage, pancreatitis, CNS symptoms
Anaphylaxis
Cisplatin
Metastatic testicular and ovarian carcinoma
It is a platinum coordination complex
Highly emetic drugs
Tinnitus, Deafness, neuropathy
Shock like stage
Hormones
Not cytotoxic
Modify the growth of hormone dependent tumour.
Glucocorticoids
Marked lympholytic action
Primarily use in acute leukemia and lymphomas. E.g. Prednisolone, Dexamethasone.
Estrogens
Carcinoma of the prostate
Carcinoma of the male breast
Anti- Estrogens
Tamoxifen
Carcinoma of the breast
Anti androgens: Flutamide
Carcinoma of the prostate
Advance/ metastatic carcinoma
5 v reductase inhibitors: Finasteride
Advance carcinoma of the prostate
W
&+$37(51(592866<67(0'58*6
i.
General Anesthetic Agents
General Anesthetic Agents (GA)

These are drugs which produce reversible loss of all sensation and consciousness.
Cardinal features of GAs are: Loss of all sensation, Sleep (unconsciousness), Muscle
relaxation, Abolition of reflexes.
Classification of GAs
A. Inhalational:
Gas: Nitrous oxide
Liquids:
Ether
Halothane
Enflurane
Isoflurane
Desflurane
Sevoflurane
B. Intravenous
Inducing agents:
Thiopentone sod.
Propofol
Etomidate
Slower acting:
Benzodiazepines: Diazepam, Lorazepam, Midazolam
Dissociative anesthesia: Ketamine
Neurolept analgesia: Fentanyl + Droperidol
Mechanism of Action
Not precisely known
GA interacts with lipid matrix of membrane and with hydrophobic regions of
specific membrane protein
alteration of neuronal cell membrane
permeability
prevent ionic Na influx
rate of rise of action
potential
fail to induce depolarization
Anesthesia
GA acts on substantia gelatonisa of spinal cord
Analgesia
GA acts on hippocampus of cerebral cortex
Amnesia
GA acts on reticular activating system
loss of consciousness
GA depresses vasomotor centre and respiratory centre in brain stem
cardio-respiratory depression.
W
MAC value
It is the minimum alveolar anesthetic concentration at which 50% of patient do
not respond to a surgical stimulus
A measure of anesthetic potency
Nitrous oxide: 105%
Halothane : 0.8%
Enflurane : 17%
Stages of GA
i.
Stage of Analgesia
ii.
Stage of delirium
iii.
Stage of surgical anesthesia
iv.
Stage of medullary paralysis
Stage of analgesia
Starts from beginning of anesthetic inhalation and last upto loss of consciousness
Patients remains conscious, can hear, see and feels a dream like state
Reflexes and respiration remains normal
Stage of Delirium
From loss of consciousness to beginning of regular respiration
Apparent excitement is seen: shout, struggle, hold his/her breath, muscle tone
increased, jaws tightly closed, vomiting, urinary/defecation incontinence
HR and BP may rise and pupils dilate due to sympathetic stimulation
No stimulus should be applied or operative procedure carried out during this stage
Stage of surgical anesthesia
Extends from onset of regular respiration to cessation of spontaneous breathing.
It is divided into 4 planes:
Plane 1: roving eye balls, the plane ends when eyes become fixed
Plane 2: loss of corneal and laryngeal reflex
Plane 3: pupils start dilating and light reflex is lost
Plane 4: intercostal paralysis, shallow abdominal respiration, dilated pupils
Stage of medullary paralysis
Vasomotor and respiratory failure.
Cessation of breathing to failure of circulation and death.
Pupil widely dilated, muscles are totally flabby, pulse is thready, BP is very low.
W
Properties of an ideal anesthetic

A. For patients:
It should be pleasant, non irritating, non-toxic
Should not cause nausea and vomiting
Induction and recovery should be fast with no after effects
Cost effective and available
B. For surgeon:
It should provide adequate analgesia, immobility and muscle relaxation
It should be noninflammable and nonexplosive
C. For anesthetist:
Easy administration , controllable
Margin of safety should be wide no fall in BP
Heart, liver and other organs should not be effected
Should be potent- so low dose is required and oxygenation of patient not affected
Rapid adjustment of depth of anesthesia should be possible
Cheap, stable and easily stored
Should not be reacting with rubber tubing and soda lime
Balanced anesthesia
The anesthesia in which each drug being selected for one specific purpose and whole
combination providing desirable quantities of unconsciousness, analgesia and muscle
relaxant which is most effective and comfortable but minimum disturbances for patient
and best operating condition for surgeon is known as balanced anesthesia.
Nitrous oxide (N2O)
Also known as Laughing gas
Low potency anesthetic: MAC 105%
Poor muscle relaxant
Nonirritating, noninflammable, nonexplosive
Advantages:
Strong analgesic action
It can be given in combination with another anesthetic and reduces the
required dose of other toxic anesthetic agent. 70% N2O + 25-30% O2 +
0.2 -2% potent anesthetic
Little effect on respiration, heart, BP, non toxic to liver, kidney and brain
Induction is rapid and not unpleasant. Recovery occurs within 4 minutes.
Cheap and easy to use
Uses:
Dental and obstetric analgesia
It is used in combination with O2. 50% N2O + 50% O2
W
Contraindication:
Pneumothorax, pneumopericardium, pneumoperitonium
Emphysema
Intestinal obstruction
Middle ear occlusion
Arterial air embolism
Decompression sickness
Chronic obstructive airway disease
Ether (Diethylether)
Highly volatile liquid, irritable, inflammable, explosive
Potent anesthetic , produces good analgesia and muscle relaxation
Highly soluble in blood induction is prolonged and unpleasant
Irritant to airway, increase bronchial and salivary secretion.
Recovery is slow
Post-anesthetic nausea and vomiting
Cheap and easy to administer (open drop)
Safe even in inexperienced hands
Halothane
Colorless volatile liquid with sweet smell
Nonirritant and noninflammable
Intermediate soluble in blood induction fast and pleasant
Potent anesthetic but not good analgesic or muscle relaxant
Sensitizes heart to adrenaline
Advantages:
High therapeutic efficacy
Induction is rapid
Does not increase salivary and bronchial secretion
Recovery time is rapid and incidence of post operative nausea and
vomiting is low
Disadvantages:
Little margin exist between doses needed to produce respiratory and
vasomotor depression
Is cardio-depressant
20% halothane metabolized in liver and induces hepatic enzymes
Contraindication: Jaundice, malignant hyperthermia, Inc. CSF pressure.
Adverse Drug Reaction:
Hepatic damage, transient jaundice, fetal hepatic jaundice
Anorexia, nausea, vomiting
Fever, malignant hyperthermia
Cardiac dysrrhythmia
W
Enflurane
Nonirritating , noninflammable liquid
Less potent than halothane
Rapid induction and recovery
HR and cardiac output reduction is less
Fall in BP is same as Halothane
Enflurane anesthesia exhibits following differences from halothane:
Fewer arrhythmias
Less sensitization of heart to catecholamines
Greater potentiating of muscle relaxants
Greater depressant on respiration
Brief clonic seizure. So C/I in epilepsy
Isoflurane: Isomer of enflurane
More potent, more volatile , less soluble than enflurane
Rapid induction and recovery
Fall in BP is same as enflurane
HR increased stimulation of beta adrenergic receptors
Does not sensitize heart to catecholamines
Safer in MI
Respiratory depression is more and secretions slightly increased.
Good skeletal muscle relaxant
Metabolism of isoflurane is negligible
No hepatic and renal toxicity
Postanesthetic nausea and vomiting is low
Pupils do not dilate and light reflex is not lost even at deeper depths
Does not provoke seizure, So preferred for neurosurgery.
Thiopentone Sodium
It is a very short acting barbiturates given I/V
Uses: induction of general anesthesia and short duration anesthesia
Highly soluble in water
It produces unconsciousness in 15-20 sec. when given I/V (3-5mg/kg as 2.5% sol)
Patient regains consciousness in 10-20 minute
On I/V administration it quickly enters CNS in less than 1 min and also
immediately diffuses out of brain and redistributed to skeletal muscles and
adipose tissues.
Metabolism is slower than tissue redistribution
Hepatic metabolism (Elimination T1/2: 7-10 hrs)
W
Advantages:
Single dose is required
No irritation of air passages
Smooth induction and rapid action
Rapid recovery
No excitement and pleasant anesthetized
Does not sensitize heart to ADR.
Disadvantages:
Poor analgesia and weak muscle relaxant
It cannot be given in large and repeated dose as it accumulates in fatty
tissues and then subsequently release and causes prolonged anesthesia with
cardio-respiratory depression
Laryngospasm, apnea
Shivering
Delirium
Nausea and vomiting
C/I of Thiopentone Sodium.
Hepatic dysfunction
Myxoedema
Status asthmaticus
Severe cardiovascular disease
Hypotension
$GGLVRQVGLVHDVH
Acute intermittent porphyria (AIP)
Allergy to barbiturate
Propofol
It is a phenol derivative (oily liquid) and used as 1% emulsion for I/V induction
Uses: induction and short duration anesthesia
Unconsciousness occurs in 15 - 45 sec and lasts about 15 min
Quick recovery (4min) from a single dose
Distribution is rapid T1/2 distribution 2-4 min
Rapid metabolism. Elimination T1/2 100 min (shorter than Thiopentone Sod.)
ADRs: hypotension, bradycardia, respiratory depression
Etomidate: newer anesthetic
Short duration of action (5-10) min.
Little respiratory and cardiovascular depression
Motor restlessness and rigidity more prominent
Post anesthetic Nausea and vomiting more
Poor analgesic
Suppresses steroids production from adrenals
W
Ketamine: Dissociative anesthesia

It is a hallucinogen (phencyclidine derivative)
It produces dissociative anesthesia sedation, amnesia and feeling of dissociation
from environment
Primary site of action is cortex and sub cortical area
Inc HR, BP and cardiac output
Respiration is not depressed
Reflexes not abolished and muscle tone increased
It is preferable for children and asthmatic patient.
Emergence delirium
Hallucinations
Increased salivation
Involuntary movements
Inc BP, HR
Contraindication:
Moderate to severe hypertension
CHF
Acute or chronic alcoholic intoxication
Cerebral trauma
Pregnancy before term.
Fentanyl: droperidol combination
It is a neuroleptic analgesia
Fentanyl is a potent opioid analgesia and droperidol is a rapidly acting neuroleptic
No loss of consciousness
Actions last for 30-40 min
Uses:
Endoscopies, angiographies, burn dressing
Minor surgical procedures
ADRs: nausea, vomiting, muscle dystonia, abnormal movements
&,3DUNLQVRQVSDWLHQWV
Complications of general anesthesia
A. During anesthesia
Respiratory depression, Salivation, respiratory secretions
Cardiac arrhythmias, Asystole, Fall in BP
Aspiration of gastric contents- acid pneumonitis
Laryngospasm and asphyxia
Delirium, convulsions
Fire and explosion
W
B. After anesthesia:
Nausea and vomiting
Persistent sedation: impaired psychomotor function
Pneumonia, atelectasis
Organ toxocities: liver, kidney damage
Nerve palsies: due to faulty poison
Emergence delirium
Preanesthetic medication: used before anesthesia to make it more pleasant and safe.
a. Opioids: Morphine, Pethidine
b. Antanxiety drugs: diazepam, lorazepam
c. Sedative hypnotics: Pentobarbitone, secobarbitone
d. Anticholinergics: Atropine, Hyoscine
e. Neuroleptics: Chlorpromazine, Haloperidol
f. H2 blockers: Ranitidine, famotidine
g. Antiemetics: Metochlopromide, Domperidone, Ondansetron
W
&+$37(51(592866<67(0'58*6
ii.
Anti-Epileptic Drugs
Anti-Epileptic Drugs
Epilepsy
It is defined as a group of disorders in which there are recurrent episodes of altered
cerebral function associated paroxysmal excessive and hyper synchronous discharge of
cerebral neurons which may or may not be associated with loss of consciousness
Classification of Seizure Types
A. Partial Seizures
a) Simple partial (cortical focal epilepsy): lasts 1/2 1 min. often secondary, no loss of
consciousness, convulsion group of muscles or localized sensory disturbance.
b) Complex partial (temporal lobe epilepsy, psychomotor): lasts 1-2min, aura often
precedes. Impaired consciousness, purposeless motor movement, confused state.
c) Partial seizures secondarily generalized.
B. Generalized seizures
a) Generalized tonic-clonic (grand mal) seizures: They are the most dramatic of all
epileptic seizures and are characterized aura cry unconsciousness tonic spasm
of all body muscles clonic jerking prolonged sleep. Lasts 1-2 min.
b) Absence (petit mal) seizures: common in children. Momentary loss of
consciousness, freeze and stares in one direction, no convulsion. Lasts <30 sec.
c) Atonic seizures: unconsciousness, all muscles relaxed, patient may fall.
d) Myoclonic seizures: contraction of muscles of a limb or whole body.
e) Infantile spasm: intermittent muscle spasm in infant.
C. Status epilepticus
The term status epilepticus denotes seizures that are repeated frequently enough that
recovery between attacks does not occur.
Refractory epilepsy: Failure of two or more drugs and occurrence of one or
more seizures per month over 18 months.
Causes of epilepsy
Primary cause: idiopathic, 60-75%
Secondary cause: Due to other diseases
Head injury
Brain tumor
Hypoglycemia
Infection meningitis
W
Classification
i.
Barbiturates: Phenobarbitone, Mephobarbitone
ii.
Deoxybarbiturate: Primidone
iii.
Hydantoins: Phenytoin
iv.
Iminostilbene: Carbamazepine
v.
Succinimide: Ethosuximide
vi.
Aliphatic carboxylic acid: Sodium valproate
vii.
BZDs: Clonazepam, CLobazam, Diazepam
viii.
Newer drugs: Lamotrigine, Gabapentin, Vigabatrin
Phenytoin (Diphenylhydantoin): oldest nonsedative antiseizure drug.
Mechanism of Action
Phenytoin stabilizes neuronal membranes to depolarization by decreasing influx of Na
ions in neurons in resting state or during depolarization.
It also reduces influx of Calcium ions during depolarization and suppresses repetitive
firing of neurons.
At high concentration, it potentiates the effect of GABA. At therapeutic
concentrations, the major action of phenytoin is to block sodium channels and inhibit
the generation of repetitive action potentials
Pharmacokinetics
Oral absorption is slow but once absorbed distribution is rapid and brain
concentration is high
Chronic administration- oral; status epilepticus I/V
Plasma protein binding- 90%
Metabolized in liver - hydroxylation, glucoronide conjugation
Kinetics: 1st order to 0 orders from low dose to high dose over therapeutic range.
5% phenytoin excreted unchanged in urine
T1/2: 12-24 hrs may increase up to 60 hrs.
Phenytoin causes hepatic enzymes induction.
i.
Gum hyperplasia
ii.
iii.
Osteomalacia
iv.
Hirsutism
v.
Dose related toxicity: Nystagmus, diplopia, ataxia, vertigo , drowsiness,
confusion, hallucination, nausea, vomiting, Hypotension
vi.
Hyperglycemia
vii.
Hypersensitivity rxn: rash, fever, neutropenia, lymphadenopathy
viii.
Teratogenicity: Fetal hydantoin syndrome - cleft palate, hair lip, hypoplastic
phalanges, microcephaly.
W
Uses
Antiepileptic:
Generalized tonic clonic seizure (grand mal)
Simple and complex partial seizures
Status epilepticus
Not used in absence seizure (petit mal)
Trigeminal neuralgia: second choice to carbamazepine
Cardiac arrhythmia- digitalis induced.
Contraindication
Hepatitis
Pregnancy
H/O hypersensitivity to phenytoin
Febrile convulsion
Drug Interaction
&DUEDPD]HSLQHDQGSKHQ\WRLQLQFUHDVHVHDFKRWKHUVPHWDEROLVP
Inhibition of phenytoin metabolism:
Chloramphenicol
INH
Cimetidine
Dicumoral
Warfarin
Phenytoin induces P-450 system and increases metabolism of OCP, digitoxin,
doxycycline, theophylline, levodopa, etc
Valproate displaces phenytoin from PBS and dec. its metabolism- phenytoin level inc.
Phenobarbitone: barbiturate, oldest of the currently available antiepileptic drug.
Mechanism of Action
Facilitates GABA-A action by increasing duration of chloride channel opening thus
decreasing neuron firing. At high dose also blocks Sodium ion channels.
Sedation
Behavioral abnormality
Diminition of intelligence
Impairement of learning memory
Hyperactivity in children
Mental confusion in old
Rashes
Osteomalacia
W
Uses
Generalized tonic clonic seizure
Simple partial seizure
Complex partial seizure
Primidone
It is effective against partial and secondarily generalized tonic-clonic seizures but
is not useful for absence seizures. It has two active metabolites, phenobarbital and
phenylethylmalonamide.
Although primidone is converted to phenobarbital, the mechanism of action of
primidone itself may be more like that of phenytoin.
Side effects are drowsiness, weakness, dizziness, nausea, nystagmus, diplopia,
ataxia, agranulocytosis, thrombopenia and anemia.
Carbamazepine
It is tricyclic drug but has no sedation in its therapeutic range. Reduce propagation of
abnormal impulses in brain by blocking Sodium channels.
Stupor
Coma
Respiratory depression
Drowsiness
Vertigo
Ataxia
Blurred vision
Nausea , vomiting
Aplastic anemia
Agranulocytosis
Thrombocytopenia
Liver toxicity
Uses
Epilepsy: partial seizure, tonic-clonic generalized seizure
Trigeminal neuralgia - DOC
Mania (Bipolar depression) alternative to lithium
Drug interactions
Phenobarbitone, phenytoin and valproate induce its metabolism and vice versa.
Induces metabolism of haloperidol and OCP.
W
Valproic acid (Sodium Valproate)

Anorexia, vomiting
Drowsiness, ataxia, tremor
Thrombocytopenia
Teratogenicity
Hepatoxicity
Uses
Highly effective in absence seizure
Alternative/adjuvant drug for generalized tonic clonic seizure, simple partial seizures,
complex partial seizures
Myoclonic and atonic seizures
Mania and bipolar illness as alternative to Lithium
Ethosuximide
Reduces propagation of abnormal electrical activity in brain and is first choice in absence
seizure. Good oral absorption and metabolized in liver through P-450 system. 25%
excreted unchanged through urine.
GI intolerance
Mood changes
Headache, tiredness, agitation, drowsiness
Inability to concentrate
Uses: only in absence seizures
Benzodiazepines
A. Diazepam and Lorazepam: Used IV for status epilepticus, not used chronically, rapid
development of tolerance.
B. Clonazepam and Clorazepate: Effective for absence seizures, they have sedative
effects, Hyperactivity, and tolerance limit chronic use.
Lamotrigine: Newer anticonvulsant
Blocks voltage sensitive Na channels.
Stabilizes presynaptic membrane.
Prevents release of excitatory neurotransmitter (glutamate).
ADRs: Sleepiness, dizziness, diplopia, ataxia, vomiting, rash.
Uses: Partial seizures, Generalized tonic-clonic seizures.
W
Vigabatrin
Inhibitor of GABA transaminase, which degrades GABA, thus GABA conc. increases in
synapsis. Well oral absorption and excreted unchanged in urine.
ADRs: Behavioral changes, psychosis, amnesia, depression, drowsiness, agitation.
Uses: Refractory epilepsy, Partial seizures.
Selectivity of Antiepileptic Drugs
A. Grand Mal epilepsy
i.
Carbamazepine
ii.
Phenobarbital
iii.
Phenytoin
iv.
Primidone
v.
Sodium valproate
B. Petit Mal epilepsy
i.
Clonazepam
ii.
Ethosuximide
iii.
Sodium valproate
iv.
Lamotrigine
C. Psychomotor
i.
Carbamazepine
ii.
Phenytoin
iii.
Phenobarbital
iv.
Primidone
v.
Sodium valproate
vi.
Lamotrigine
D. Status Epilepticus
i.
Diazepam IV
ii.
Lorazepam IV
iii.
Phenytoin IV
iv.
Phenobarbital IV
W
&+$37(51(592866<67(0'58*6
iii.
Anti-3DUNLQVRQV'UXJV
Anti-3DUNLQVRQV'UXJV
Parkinsonism
It is a degenerative disease of basal ganglia
It is an extrapyramidal motor disorder characterized by muscle rigidity, tremor at rest
and hypokinesia often with dementia.
Other symptoms are facial masking, drooling, gait disorder, and slurred speech
Associated with marked loss of dopamine from basal ganglia.
Caused by progressive degeneration of dopamine neurons in the substantia nigra and
nigrostriatal tract that leads to an imbalance in the activity of dopamine and ACh in
the basal ganglia
Often idiopathic, but may follow stroke, virus infection, can be drug-induced.
3DWKRJHQHVLVRI3DUNLQVRQVGLVHDVH
3DUNLQVRQVGLVHDVH3'LVDSURJUHVVLYHGLVRUGHURIPRYHPHQWWKDWRFFXUVPDLQO\LQWKH
elderly. The chief symptoms are:
7UHPRUDWUHVWXVXDOO\VWDUWLQJLQWKHKDQGVSLOO- UROOLQJWUHPRUZKLFK tend to
diminish during voluntary activity
Muscle rigidity, detectable as an increased resistance in passive limb movement
Bradykinesia
Classification
A. Drugs affecting brain dopaminergic system:
i.
Dopamine precursor: Levodopa
ii.
Dopaminergic agonists: Bromocriptine, Lisuride, Pergolide, Piribedil
iii.
Peripheral decarboxylase inhibitor: Carbidopa, Benserazide
iv.
Facilitate dopaminergic transmission: Amantadine, Selegiline
B. Drugs affecting brain cholinergic system
i.
Central anticholinergics: Trihexphenidyl, Procyclidine, Biperiden
ii.
Antihistaminics: Orphenadrine, Promethazine
W
Figure: 9A.3- Effects of Antiparkinsonism drugs

Levodopa
Dopamine does not cross the blood-brain barrier so levodopa, the precursor of
dopamine, is given instead.
Levodopa is formed from L-tyrosine and is an intermediate in the synthesis of
catecholamines.
Mechanism of Action
It is natural amino acid, precursor of dopamine, replenish dopamine in basal ganglia
Dopamine is poorly lipid soluble. It does not cross BBB and hence cannot enter CNS.
Levodopa can cross BBB
>90% Levodopa is metabolized to dopamine in peripheral tissues (gut and liver) and
only 5% of oral dose reach CNS.
Carbidopa prevents the peripheral metabolism of levodopa by inhibiting DOPA
decarboxylase enzyme which converts levodopa to dopamine.
So Levodopa- carbidopa combination is better.
W
Actions of levodopa
i.
CNS: no effect in normal or other disease person. In parkinsonian patient:
hypokinesia and rigidity resolve first and then tremor. Others like posture, gait,
handwriting, speech, facial expression, mood, self care and interest in life also
becomes normal.
ii.
CVS: peripherally formed DA acts on beta adrenergic receptor on heart causing
tachycardia and in brain DA dec. sympathetic outflow causing postural hypotension.
iii.
CTZ: peripherally formed DA can reach CTZ and causes nausea and vomiting.
iv.
Endocrine: DA inhibit prolactin release.
Pharmacokinetics
Levodopa is rapidly absorbed from small intestine
Levodopa has short half life (1-2 hrs)
Gastric emptying: if slow, less levodopa is available to penetrate BBB
Aminoacids present in food: amino acids of food compete with levodopa for
absorption from gut and for transport across BBB
Levodopa undergoes high first pass metabolism
Metabolites are excreted in urine after conjugation
A. Peripheral effects:
i.
Anorexia, nausea, vomiting
ii.
iii.
Tachycardia and ventricular extra systoles
iv.
Altered in taste sensation
B. CNS effects: on prolong use
i.
Visual and auditory hallucinations
ii.
Abnormal voluntary movement (Dyskinesia)
iii.
Mood change, depression, anxiety, nightmares
iv.
Fluctuation in motor performance: In the beginning it is End of dose or wearing
off effect which gradually changes to On-Off phenomenon.
Drug interactions
i.
Pyridoxine (Vitamin B6): increase peripheral breakdown of levodopa and diminish its
effectiveness
ii.
Non-selective MAO (Monoamine oxidase) inhibitors: prevents degradation of
dopamine and can cause hypertensive crisis. Therapy with MAO inhibitors must be
stopped 14 days prior to the initiation of levodopa therapy
iii.
Atropine: have additive antiparkinsonian action but retard its absorption
iv.
Antihypertensive: postural hypotension
v.
Antipsychotics: reverse therapeutic effect by blocking DA receptors.
W
Carbidopa
Carbidopa is an inhibitor of DOPA decarboxylase. Since it is unable to penetrate the
BBB, it acts to reduce the peripheral conversion of levodopa to dopamine.
Sinemet is the trade name of a preparation that combines carbidopa and levodopa in
fixed proportions (1:10). It decreases 75% dosage of L-dopa.
Madopar contains L-dopa and benserazide (100:25 or 200:50).
Carbidopa-Levodopa Combination
i.
T1/2 of levodopa prolong and dose reduced to 25% of the required
ii.
Systemic concentration of DA reduced - so less nausea and vomiting
iii.
Cardiac complication dec.
iv.
Pyridoxine reversal of levodopa effect does not occur
v.
On-Off phenomenon is minimized
vi.
Higher degree of improvement
Dose: Levodopa- carbidopa
Preparations:
Sinemet (10:1); Levodopa 100mg + carbidopa 10mg
Syndopa; Levodopa 250mg + carbidopa 25mg
Tridomet plus (4:1); Levodopa 100mg + carbidopa 25mg
Levodopa 100mg + Benserazide 25mg
Dose: levodopa 400-800 mg + carbidopa 75-100mg TID (maintenance dose).
Bromocriptine
It is an ergotamine derivative. It is potent agonist on D2 and partial agonist or antagonist
on D1 receptors.
Nausea, vomiting
Confusion, delirium, Hallucinations
Orthostatic hypotension, Nasal stuffiness
Uses
It is used to treat parkisonism, especially for the patients develop tolerance or failure
to levo-dopa treatment.
It is also used to treat hyperprolactinemia by inhibiting prolactin secretion, and used
to treat acromegaly by inhibiting growth hormone.
Amantadine
It was introduced as an antiviral agent for the prophylaxis of A2 influenza.
It stimulates the release of dopamine from dopaminergic nerve terminals in the
nigrostriatum and delays its reuptake.
It also has direct effect on dopamine receptors.
W
Amantadine may be more efficacious in parkinsonism than the anticholinergic drugs,

but is less effective than levodopa.
Its benefits may be short-lived, often disappearing after only a few weeks of
treatment.
It may favorably influence the bradykinesia, rigidity, and tremor of parkisonism.
Restlessness, depression, irritability, insomnia, agitation, excitement, nightmares,
hallucinations and confusion.
Long-term use can produce livedo reticularis in the lower extremities, ankle edema.
Convulsions rarely occur.
Contraindicated in epilepsy, cerebral atherosclerosis and pregnancy.
Dose: 100mg BD (fixed dose).
Selegiline (Deprenyl)
Selegiline is a selective inhibitor of MAO-B. The isoenzyme MAO-B is the
predominant form in the striatum and is responsible for the majority of oxidative
metabolism of dopamine in the striatum.
So, selegiline increases the dopamine level in brain and enhances action of levodopa
ADRs: postural hypotension, nausea, confusion, Psychosis.
Contraindication: convulsion disorders.
Interaction with pethidine: excitement, hyperthermia, respiratory depression.
Anticholinergic (antimuscarinic) drugs:
Dry mouth
Blurred vision
Constipation
Urinary retention
Mental confusion, delirium
Hallucinations
Increased intraocular pressure (glaucoma)
Palpitations and cardiac arrhythmias.
Contraindication
Prostatic hyperplasia
Obstructive gastrointestinal disease
Angle-closure glaucoma.
Dose:
Trihexyphenidyl (Benzhexol) 2-10mg/day per oral.
Procyclidine 5-20mg/day per oral.
W
&+$37(51(592866<67(0'58*6
iv.
Sedative
A drug that subdues excitement and calms the subject without inducing sleep, though
drowsiness may be produced. Sedation refers to decreased responsiveness to any level of
stimulation; is associated with some decrease in motor activity and ideation.
Hypnotic A drug that induces and/or maintains sleep, similar to normal arousable sleep.
This is not to be confused with 'hvpnosis' meaning a trans-like state in which the subject
becomes passive and highly suggestible.
Classification
1. Barbiturates
Long acting: Phenobarbitone
Short acting: Butobarbitone, Pentobarbitone
Ultra-short acting: Thiopentone, Methohexitone
2. Benzodiazepines
Hypnotic: Diazepam, Flurazepam, Nitrazepam, Alprazolam, Temazepam,
Triazolam
Anti-anxiety: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam,
Alprazolam
Anticonvulsant: Diazepam, Lorazepam, Clonazepam, Clobazam
3. Newer non-benzodiazepine hypnotics: Zopiclone, Zolpidem Zaleplon
Barbiturates
Barbiturates have been popular hypnotics and sedatives of the last century up to 1960s,
but are not used now to promote sleep or to calm patients. However, they are described
first because they are the prototype of CNS depressants.
Barbiturates are general depressants for all excitable cells, the CNS is most sensitive
where the effect is almost global, but certain areas are more susceptible.
1. CNS Barbiturates produce dose-dependent effects:
Sedation
Sleep
Anaesthesia
Coma.
2. Other systems
Respiration is depressed by relatively higher doses.
CNS Hypnotic doses of barbiturates produce a slight decrease in BP and HR.
Skeletal muscle Hypnotic doses have little effect but anaesthetic doses reduce
muscle contraction by depressing excitability of neuromuscular junction.
Smooth muscles tone and motility of bowel is decreased slightly by hypnotic
doses; more profoundly during intoxication.
Kidney Barbiturates tend to reduce urine flow by decreasing BP and
increasing ADH release. Oliguria attends barbiturate intoxication.
W
Pharmacokinetics
Barbiturates are well absorbed from the GIT. They are widely distributed in the body. The
rate of entry into CNS is dependent on lipid solubility.
Uses
Barbiturates are seldom used now.
They are occasionally employed as adjuvants in psychosomatic disorders. The
enzyme inducing.
Dose: Phenobarbitone 30-60 mg oral OD-TDS; 100-200 mg IM./IV.
Hangover was common after the use of barbiturates as hypnotic.
In occasional patient barbiturates produce excitement.
Hypersensitivity: Rashes, swelling of eyelids, 1ips, etc.
Acute Barbiturate Poisoning: Mostly suicidal, sometimes accidental; infrequently
encountered now due to inavailability of barbiturates However, the principles of
treatment apply to any CNS depressant poisoning.
Contraindication
i.
Acute intermittent porphyria (AIP)
ii.
Liver and kidney disease
iii.
Severe pulmonary insufficiency
iv.
Obsiructive sleep apnoea
Drug Interaction
Barbiturates induce the metabolism of many drugs and reduce their effectiveness.
Additive action with other CNS depressants.
Sodium valproate increases plasma conc. of phenobarbitone.
Phenobarbitone competitively inhibits as well as induces phenytoin and imipramine
metabolism: complex interaction.
Phenobarbitone decreases absorption griseofulvin from the GIT.
Benzodiazepines (BZD)
Chlordiazepoxide and diazepam were introduced around 1960 as anti-anxiety drugs.
Pharmacokinetics
There are marked pharmacokinetic difference among BZDs because they differ in lipid
solubility by > 50 fold. Oral absorption of some is rapid while that of others is slow.
Widely distribute in body. They cross placenta and secreted through milk as well.
Benzodiazepines are relatively safe drugs. Side effects of hypnotic doses are dizziness,
vertigo, ataxia, disorientation, amnesia, prolongation of reaction time-impairment of
psychomotor skills.
Drug Interactions
They are synergise with alcohol and other CNS depressants leading to excessive
impairment. Concurrent use with Sod. Valproate has provoked Psychotic symptoms.
W
Non-benzodiazepines hypnotics
Zopiclone
This newer cyclopyrrolone hypnotic. It is an agonist at a subtype of BZD receptor
involved in the hypnotic action.
Zolpidem
It is an imidazopyridine which preferentially acts on the cr1 subunit containing subtype of
BZD receptors that are important in mediating the hypnotic effect.
Zaleplon
It is the shortest acting of the newer Non-BZD hypnotics that selectively act on a subset
of BZD receptors containing alpha1 subunit which appear to mediate hypnotic action.
Uses
Currently, BZDs are one of the most frequent prescribed drugs. They have also been
combined with many other categories of drugs with a view to improve efficacy by
relieving attendant anxiety.
Benzodiazepines antagonist
Flumazenil
It is a BZD analogue which has little intrinsic activity, but competes with BZD agonists
as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant
effects respectively.
Uses
i.
Ta reverse BZD anaesthesia
ii.
BZD overdose
W
&+$37(51(592866<67(0'58*6
v.
Anti-Psychotic Drugs
Psychosis: is a condition characterized by a loss of contact with reality.
Hallucinations: false perceptions
Delusions: false beliefs
Types
a. Functional psychosis: having no identifiable cause
b. Organic psychosis: an identifiable cause in brain, E.g. tumour in brain.
Hallucinations
Hearing voices
Seeing visions
Experiencing odd tastes, smells
Experiencing odd feelings
Delusions
Persecution
Jealousy
Erotomania
Thought control
Behavior control
Causes
Drugs: E.g., Lysergic Acid Diethylamide, Amphetamines, Cocaine
Brain Diseases: EJ$O]KHLPHUV'LVHDVH
Brain Injuries: E.g., trauma, stroke
Extreme stress: E.g., war, kidnapping
Bipolar and major depressive disorders
Schizophrenia; most common cause
Positive Symptoms
Delusions
Hallucinations
Disorganized speech/thinking
Grossly disorganized behavior
Catatonic behaviors
W
Negative symptoms
Affective flattening
Alogia
Avolition
Figure: 9A.5- Features of Schizophrenia
Diagnostic Criteria for Schizophrenia

Delusions
Hallucinations
Disorganized Speech
Disorganized or catatonic behavior
Negative Symptoms
Two or more of the above must be present for at least one month and some
disturbance for six months
Significant impairment in social/occupational functioning
Dopamine theory of Schizophrenia

Excess dopamine binds to post-synaptic D2 receptors on neurons located within
the limbic system and nucleus accumbens
D2 receptors are over-stimulated
Ca++ channels are closed whereas K+ channels are opened
Decreased flow Ca++ into the neuron and increased flow of K+ out of the neuron
prevents depolarization
Activity of neuron is inhibited
Pleasure sensation is decreased, psychosis occurs
W
i.
Phenothiazines: Chlorpromazine (CPZ), Triflupromazine, Thioridazine,
Trifluoperazine, Fluphenzine, Thioproperazine
ii.
Butyrophenones: Haloperidol, Trifluperidol, Droperidol, Penfluridol
iii.
Thioxanthenes: Chlorprothixene, Thiothixene, Fluphenthixol
iv.
Others: Loxapine, reserpine, sulpiride, pimozide
v.
Atypical neuroleptics: Clozapine, Risperidone, Olanzapine
Chlorpromazine (CPZ)
It is the prototype of phenothiazines. The phenothiazines have a three-ring structure in
which two benzene rings are linked by sulfur and a nitrogen atom.
i.
Decreases prolactin inhibitory factor
ii.
Inhibits the secretion of GnRH, decreases FSH and LH
iii.
Inhibits the secretion of ACTH, decreases corticosteroids
iv.
Inhibits growth hormone
Pharmacokinetics
Absorption absorbed well in GI tract
Distribution: highly protein bound (92-99%)
Metabolism metabolized in the liver
Half Life Adults (20 40 hours)
Half Life Elderly patient may be doubled
Adult steady state 4-7 days
Monitor liver functions esp. elderly and physically compromised
Elimination: kidney
i.
Extrapyramidal system (EPS) reactions
a) Parkinsonian syndrome:
Tremors
Bradykinesia/akinesia [slowness, absence of movement]
Cogwheel rigidity[slow regular muscular jerks]
Postural instability
Stooped/hunched posture, Shuffling gait
Restricted movements, Masked face
Hypersalivation & drooling
b) Akathisia: QRWVLWWLQJ
Pacing, Motor restlessness, Foot taping
restlessness, irritability, inability to sit still or lie down.
W
c) Acute dystonic reactions:

Muscle spasm
Dramatic and painful
d) Tardive dyskinesia:
Effects 4% of persons taking antipsychotics
Choreoathetoid movements [rapid, jerky and slow, writhing movements]
may occur anywhere in the body arms, feet, legs, trunk
ii.
Cardiovascular effects: Orthostatic hypotension, which can result in syncope, and
reflex tachycardia.
iii.
Autonomic side effects:
Anticholinergic: dry mouth, blurred vision, constipation, urine retention,
increase intraocular pressure.
-receptor blocking effects: Inhibition of ejaculation, stuffy nose.
iv.
Endocrine side effects: galactorrhea, amenorrhea, decreased libido, impotence and
inhibition of growth.
v.
Allergic reactions: Cholestatic jaundice, agranulocytosis and eosinophilia (rare)
dermatitis, urticaria, photosensitization, pigmentation.
vi.
Ocular side effects: Opaque deposits in lens and cornea.
vii.
Metabolic effect: Weight gain
viii.
Neuroleptic malignant syndrome (NMS):
This life-threatening disorder occurs in patients who are extremely
sensitive to the extrapyramidal effects of antipsychotics.
The main presentations are marked muscle rigidity, high fever and high
blood pressure, delusions, accompanied with elevated creatine kinase
isozymes, that reflects muscle damage.
This syndrome is believed to result from an excessively rapid blockade of
postsynaptic dopamine receptors.
The treatment is discontinuation of antipsychotics, the use of DA agonistbromocriptine or CNS dopamine releaser- amantadine; the use of muscle
relaxants, - dantrolene or diazepam.
ADRs of neuropeltics: Tremors, Constipation, Confusion, Postural
Hypotension, Urinary retention, Sexual dysfunction.
Uses
i.
As Anti-psychosis: Schizophrenia, Mania, Psychosis associated with chronic
alcoholism.
ii.
As anti-anxiety
iii.
As antiemetic: Nausea and vomiting induced by uremia, cancer, pregnant toxemia,
radiation.
iv.
Other uses: Preanesthetic medication; to potentiate hypnotics, analgesics and
anesthetics; intractable hiccough; Tetanus.
W
Atypical Anti-psychotics
Lower ratio of D2 and 5-HT2A receptor antagonism
Lower propensity to cause EPS
Effective for positive symptoms: - equal or better than typical antipsychotics
Clozapine is more effective than conventional antipsychotics.
Clozapine
Atypical anti-psychotic drug. It belongs to dibenzodiazepine. It has medium antipsychotic
effect, low sedative effect. Clozapine has low affinity for D 2 receptors and little
propensity to produce extrapyramidal side effects. It is more 5-HT receptor antagonist. It
has greater efficacy for reducing negative symptoms of schizophrenia. It is used to treat
psychoses, chronic schizophrenia.
a) Common side effects
Tachycardia
Sedation
Hypotension
Hypersalivation
Sedation
b) Serious Side Effects
Agranulocytosis 1-2% incidence
Seizures 3% incidence related to dosage
Risperidone
No agranulocytosis
Low EPS
Less tardive dyskinesia
Insomnia, agitation, anxiety
Orthostatic hypotension
Weight gain
EPS
Headache
Rhinitis
Olanzapine
Once a day dosing, long half life
Greater compliance
No cardiac or hematological problems
W

Weight gaincan be excessive
Elevated glucose, cholesterol, triglycerides
Other side effects similar but milder than risperidone
Advantages of atypical anti-psychotics
More selective to mesolimbic pathway
Less Extra pyramidal side effects
They are more effective than older ones in treating negative symptoms
They have an effect on central neurotransmitter receptors which is a target of
antipsychotic action.
W
&+$37(51(592866<67(0'58*6
vi.
Anti-Depressant Drugs
Figure: 9A.6- Major Affective Disorders
Anti-Depressant Drugs
Affective disorders
Depression
Mania
Anxiety
Tension
Obsessive compulsive disorder
Depression
It is a psychological disease in which the patient complains of- Helplessness, Apathy,
Loss of sexual desire and activity.
Reactive (episodal) Depression: More than 60% of all depressions. Core symptoms:
Feelings of misery
Apathy
Inadequacy
Pessimism
Anxiety, tension
Guilty feeling
W
Major Endogenous Depression: Core Symptoms:

Feeling of misery, apathy and pessimism.
Withdrawn.
Low self esteem, feelings of guilt, inadequacy and ugliness.
Loss of interest in pleasurable activities like sex, etc.
Indecisiveness, loss of motivation.
Retardation of thought and action.
Sleep disturbance and significant weight change.
Psychomotor agitation or retardation.
In severe cases, it is accompanied by hallucinations and delusions.
Recurrent suicidal ideation, a suicide attempt or a specific suicide plan.
Mania
Bipolar disorder characterized by expansiveness, elation, hyper-excitability, hyperactivity and Inc. speed of thought and speech. Core symptoms:
(OHYDWHGKLJKPRRG
Talkative, go on-and-on about the things they will do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep.
Lack judgment
Causes of depression
Primary cause: Idiopathic
Secondary cause:
Drugs: reserpine, propranolol, alpha-methyldopa
Alcohol
Diseases: parkinsonism, MI, LVF
Vit. deficiency: Vit B1
Post partum
Symptoms of depression
Ongoing sad, anxious or empty feelings, Feelings of hopelessness
Feelings of guilt, worthlessness, or helplessness, Feeling irritable or restless
Loss of interest in activities or hobbies that were once enjoyable, including sex
Feeling tired all the time
Difficulty concentrating, remembering details, or difficulty making decisions
Not able to go to sleep or stay asleep (insomnia); may wake in the middle of the
night, or sleep all the time
Overeating or loss of appetite
Thoughts of suicide or making suicide attempts
Aches, pains, headaches, cramps or digestive problems that do not go away.
W
Classification of Anti-Depressants
1. Trcyclic/polycyclic antidepressants:
Amitriptyline
Desipramine
Imipramine
Trimipramine
Amoxapine
Doxepin
2. SSRIs (selective serotonin reuptake inhibitors)
Fluoxetine
Sertraline
Venalafaxine
Paroxetin
Nefazodone
Trazodone
3. MAO (monoamine oxidase) inhibitors :
Non-selective:
Hydrazines: Phenelzine, Isocarboxazid
Nonhydrazines: Tranylcypromine
Isoenzyme selective:
MAO-A: Clorgiline, Moclobemide
MAO-B: Selegiline (Deprenyl)
4. Drugs used to treat Mania: Lithium
MAO inhibitors
Monoamine oxidase (MAO) is a mitochondrial enzyme found in neural and other tissues.
,QQHXURQ0$2IXQFWLRQVDVDVDIHW\YDOYHWRR[LGDWLYHO\GHDPLQDWHDQGLQDFWLYDWe any
excess neurotransmitters in presynaptic neurons. MAO inhibitors reversibly or
irreversibly inactivate the enzyme, permitting neurotransmitters to escape degradation and
thus accumulate in presynaptic neurons and leak into synaptic space.
Tyramine causes release of large amount of stored neurotransmitters from nerve
terminals, resulting in: Headache, nausea, Tachycardia, HTN, cardiac arrhythmias.
Stroke
Drowsiness
Orthostatic hypotension
Blurred vision
Dryness of mouth
Dysuria
Constipation
W
Uses
Not commonly used
Depressed patient who are unresposive or allergic to TCAs
Low psychomotor activity
Phobic state
Atypical depression
Tricyclic / polycyclic antidepressants: block NA and serotonin uptake in neuron.
Classification
1. NA and serotonin (5HT) reuptake inhibitors: Imipramine, Amitriptyline,
Trimipramine, Doxepin, Clomipramine, Dothepin
2. NA (> 5-HT) reuptake inhibitors: Nortryptyline, Desipramine, Protriptyline,
Amoxapine.
3. Selective Serotonin (5-HT) reuptake inhibitors: Fluoxetine, Fluvoxamine, Paroxetine
4. Atypical antidepressants: Trazodone, bupropion, mianserin, tianeptine
1. CNS:
Inhibit DA reuptake stimulant action
Inhibit 5-HT and NA reuptake antidepressant action
Inhibit 5-HT reuptake sadative action
2. ANS:
Potent anticholinergics dry mouth, blurred vision, constipation, urinary retention
Weak alpha-1 blocking action
Block reuptake of NA
3. CVS:
Tachycardia anticholinergic and NA potentiating actions
Postural hypotension alpha blockade
Arrhythmias in overdose
Pharmacokinetics
Widely distributed
Readily penetrates into CNS
High first pass effect
High protein binding
Metabolized by hepatic microsomal system and conjugated with glucoronic acid
Excreted as inactive metabolites through urine
W

Anticholinergic: dry mouth, bad taste, constipation, epigastric distress, urinary
retention, blurred vision, palpitation
Sedation ,mental confusion, weakness
Increased appetite, Weight gain
Hypomania or mania
Sweating and fine tremors
Postural hypotension blocking of D receptors
Palpitation, Tachycardia, Cardiac arrhythmias
Hypersensitivity like rashes and jaundice
Sexual dysfunction
Uses
Endogenous (major) depression
Obsessive compulsive and phobic state
Attention deficit hyperactive disorder in children
Eneursis in children above 5 yrs
Dose
Amitryptline:
Adult: oral 50-100 mg /day; 10 mg inj.
Child: not used
Imipramine:
25 mg X TDS X PO (Max. 150-200mg/day)
Not used in children < 6yrs
Drug Interactions
All TCAs potentiate CNS depressants to coma and death.
Phenytoin, phenylbutazone, aspirin, CPZ can displace TCAs from PBS to toxicity.
SSRIs
Selective Serotonin reuptake inhibitors
New groups of antidepressants
SSRIs selectively inhibits Serotonin reuptake
It includes: Fluoxetine, Sertraline, Paroxetine, Citalopram, Flavoxamine.
ADR of Fluoxetine: Nausea, Anorexia, Anxiety, Weight loss, Insomnia, Tremors.
Doses of SSRIs
Fluoxetine: 20-60 mg /day at morning
Sertraline: 50-200 mg /day
Citalopram: 20-40 mg/day
Fluvoxamine: 50-200 mg/day
W
Anti-Manic Drugs: Lithium (Li+) salts

Lithium (Li+) remains the drug of choice for the treatment and prophylaxis of mania.
Nausea, vomiting, mild diarrhea
Thirst and polyuria
Cardiac arrhythmias
Drowsiness, delirium
Diabetes insipidus (on long term use)
Contraindicated in Pregnancy and Sick sinus syndrome
Drug Interactions
Neuroleptics are potentiated by lithium salts
Diuretics, NSAIDs potentiate lithium by reducing elimination
Uses
Acute manic episode
Prophylaxis of MDI (manic depressive illness)
Recurrent neuropsychiatric illness
Inappropriate ADH secretion syndrome
Cancer chemotherapy induced leukopenia and agranulocytosis
Alternative drugs for manic depression
Sodium valproic acid
Carbamazepine
Clonazepam
Gabapentin
W
&+$37(51(592866<67(0'58*6
i.

Anesthetics
These are the drugs which upon topical application or local injection cause reversible
loss of sensory perception, especially of pain, in a restricted area of the body.
They block generation and conduction of nerve impulse at all parts of neuron where
they come in contact, without causing structural damage.
Chemically local anesthetics are weak bases with amphiphilic property.
Classification
A. Injectable:
Low potency, short duration (1-2 hrs): Procaine, chloroprocaine
Intermediate potency and intermediate action (2-4hrs): Lidocaine, Prilocaine
High potency, long duration (16 hrs): Tetracaine, Bupivacaine, Ropivacaine,
Dibucaine.
B. Surface anaesthetic:
Soluble: cocaine, lidocaine, tetracaine
Insoluble: benzocaine, butylaminobenzoate, oxethazine
Mechanism of Action
Local anesthetics bind directly to the intracellular voltage-dependent sodium
channels and block open and inactive sodium channels, at specific sites
Local anesthetics work to block nerve conduction by reducing the influx of
sodium ions into the nerve cytoplasm.
Sodium ions cannot flow into the neuron, thus the potassium ions cannot flow out,
thereby inhibiting the depolarization of the nerve.
Can be inhibited for just a few nodes of ranvier along way, then nerve impulses
generated downstream from the blocked nodes cannot propagate to the ganglion.
Actions of LA
Locally
Different nerves have different sensitivity to LA.
More easily blocked by LA: Smaller, less heavily myelinated and more rapidly
firing fibers.
Order of loss of sensory function: First pain, then cold, then warmth, then touch,
then deep pressure.
W
Systemic
CNS: Local anesthetics, if absorbed systematically in excessive amounts, can
cause central nervous system (CNS) excitement or, if absorbed in even higher
amounts, can cause CNS depression.
CVS: LAs are cardiac depressants. Has quinidine like antiarrhythmic actions. LAs
causes fall in BP.
Pharmacokinetics
Soluble surface anesthetics are rapidly absorbed from mucous membranes and
abraded areas but absorption from intact skin poor.
Rate of absorption depends upon blood flow to that area.
Amide LA are bound to plasma glycoprotein, ester LA negligibly bound to plasma
protein. LAs are temporarily bound to nerves at site of injection.
CNS: Light headache, dizziness, mental confusion, disorientation. Auditory and
visual disturbances. Shivering, tremors, twitching.
CVS: Bradycardia, hypotension, cardiac arrhythmias and vascular collapse.
Injection of LA may be painful.
Rashes, angioedema, dermatitis, asthma, rarely anaphylaxis.
Cocaine
It is a natural alkaloid from leaves of Erythroxylon coca
surface anesthetic and is rapidly absorbed from buccal mucous membrane
Cocaine should never be injected, it can cause tissue necrosis
It produces prominent CNS stimulation
It induces a sense of well being, delays fatigue and increases power of endurance
In periphery, it blocks uptake of NA and Adrenaline into adrenergic nerve
endings, resulting in higher concentration of transmitter around receptors
sympathomimetic effect
Local vasoconstriction, tachycardia, rise in BP and mydriasis
Use: ocular anesthesia.
Procaine
First synthetic local anesthetic
Not surface anesthetic
Low potency, onset of action- slow 15 min
Duration of action: 30-60 min
Forms poorly soluble salt with benzyl penicillin.
W
Lignocaine/ Lidocaine/Xylocaine
Most widely used LA
Duration of action: 1-2 hr
Onset of action: 3 min
Good for both surface application and inj
Most refined preparation used as antiarrhythmic
Uses: Surface anesthesia, infiltration, nerve block, epidural, spinal, intravenous
regional block anesthesia.
ADR: Drowsiness, mental clouding, altered taste, Tinnitus, Muscle twitching,
Convulsions, Cardiac arrhythmias, Fall in BP, Coma and respiratory arrest.
Bupivacaine
Long acting amide linked LA
More potent and more toxic
Injected epidurally produces good analgesia without significant motor blockade.
Long duration of action: > 3 hrs
Uses: infiltration, nerve block, epidural and spinal anesthesia
ADR: more chance of ventricular tachycardia and cardiac depression if used I/V
regional anesthesia.
Uses of LA
1. Surface anesthesia: topical use; Urethra, anal canal, rectum, throat, pharynx, larynx,
trachea, bronchi, esophagus, abraded skin, eye, nose, ear.
2. Infiltration anesthesia: under skin, for minor operation. Paralyse sensory nerve
endings and small cutaneous nerve; Incision, excision, hydrocele, herneorraphy.
3. Conduction block: LA injected around nerve trunk, area distal to inj anesthetized
Filed block (all nerve coming to a particular filed block)
Nerve block particular nerve trunks or plexus block
Intercostal nerves, Brachial plexus, Ulnar nerve, femoral nerve
4. Spinal anesthesia:
Inj of LA in subarachnoid space between L2-3 or L3-4
Primary site of action is nerve route
Use: operation of lower limbs, pelvis, obstetric procedures, caesarian.
5. Epidural anesthesia:
Inj. into spinal dural space. Acts mainly on nerve roots
Use: relief of pain, operations
6. Intravenous regional anesthesia
Indications of LA
As local anesthetic agent.
As antiarrhythmic drug.
As anticonvulsant drug.
W
&+$37(51(592866<67(0'58*6
ii.
Cholinergic Drugs
Figure: 9B.2- Major Affective Disorders
Cholinergic Drugs
These are drugs which produces actions similar to that of Ach, either by directly
interacting with cholinergic receptors or by increasing availability of Ach at these sites.
Cholinergic Agonists
Choline esters: Acetycholine, Methacholine, Carbachol, Bethanecol.
Alkaloids: Muscarine, Pilocarpine, Arecoline.
Muscarinic Actions
1. Heart:
Bradycardia or even cardiac arrest
Force of contraction is reduced.
Increase PR interval, partial to complete A-V block
W
2. Blood Vessels:
Blood vessels dilated
Fall in BP, Flushing
3. Smooth muscle:
Smooth muscles in most organs contracted
Tone and peristalsis in GIT increased and Sphincters relax: causes
Abdominal cramps and Evacuation of bowel
Bladder: constricts detrusor muscles and relaxes trigones and sphincters:
voiding of bladder
Brocnhi muscle contraction: precipitates asthma
4. Glands:
Secretion increased
Sweating, salivation, lacrymation, tracheobronchial and gastric secretion
increased
Milk and bile secretion: unaffected
5. Eye:
Miosis: due to contraction of circular muscle of iris
Reduction in intraocular tension: due to spasm of ciliary muscle.
Nicotinic actions of ACh
1. Autonomic ganglia:
Both sympathetic and parasympathetic ganglia stimulated when given high
dose Ach
High dose Ach given after atropine causes tachycardia and rise in BP
2. Skeletal muscles:
Contraction of skeletal muscle fibers
Twitching and fasciculation at high intra-arterial dose
3. CNS:
It does not Penetrate BBB
Stimulation followed by depression
R Uses
Acetylcholine not used: non selective
Bethanecol uses: Postoperative, Postpartum non obstructive urinary retention,
Bladder atony, Congenital megacolon.
Pilocarpine
Prominent muscarinic effect, Causes miosis.
Causes marked sweating, salivation and increase other secretion as well.
Small dose: fall in BP (muscarinic); high dose: tachycardia and rise in BP.
Uses: 0.5- 4% drops in open angel glaucoma and to counteract mydriatics.
ADR: Stinging sensation in eye, Painful spasm of accommodation.
W
&+$37(51(592866<67(0'58*6
iii.
Anti-Cholinergic Drugs
Anti-Cholinergic Drugs
Block action of Ach on autonomic effectors and in the CNS excreted through
Muscarinic receptor
Nicotinic antagonist also block certain action of Ach known as ganglion blockers, and
neuromuscular blocker
All are competitive antagonist
Classification
1. Natural Alkaloids: Atropine, Hyoscine (Scopolamine)
2. Semi synthetic derivatives: Homatropine, Atropine methonitrate, Ipratropium
bromide, Tiotropium bromide
3. Synthetic compounds:
Mydriatics: Cyclopentolate, Tropicamide
Antisecretory- Antispasmodics: Propantheline, Oxyphenonium, Dicyclomine,
Pirenzepine
Antiparkinsonian drug: Trihexyphenidyl, Benztropine
Pharmacological Actions of Anticholinergics (Atropine)
1. CNS actions:
Overall CNS stimulant action high dose
Stimulate medullary centers (Vagal, respiratory, Vasomotor)
Depresses vestibular excitation and has anti motion sickness property
Suppresses tremor and rigidity of parkinsonism
High doses cause cortical excitation, restlessness, disorientation,
hallucinations, respiratory depression and finally coma
2. CVS actions:
Tachycardia
Atropine does not have any consistent or marked effect on BP as
cholinergic impulse is not involved in maintenance of vascular tone.
3. Action on Eye:
Mydriatics (dilatation of pupil)
Abolition of light reflex & Cycloplegia for 7-10 days
Photophobia and blurring of near vision
Intraocular tension rise
W
4. Smooth muscles:
All visceral smooth muscle relax by atropine
M3 blockade
Decrease tone and amplitude of contractions of stomach and intestine
Constipation
Bronchodilatation
Relaxation of ureter and urinary bladder: urinary retention in older male
with prostate hypertrophy.
5. Glands:
Decreases sweat, salivary, tracheobronchial and lachrymal secretion
through M3 blockade
Skin and eye become dry, talking and swallowing difficult.
Decreases secretion of acid, pepsin and mucus in stomach
6. Body temperature: Rise in body temperature at easing swhigh dose (by decreasing
sweating & stimulation of temp. regulation centre
7. Mild anaesthetic action on the cornea
Pharmacokinetics
Atropine and hyoscine- rapid oral absorption
Freely penetrate cornea
Partly crosses BBB (hyoscine better)
Partly Metabolized in liver and rest is excreted unchanged in urine
T1/2: 3-4 hours
Dose: Atropine sulfate 0.6-2 mg I/M or I/V, 1-2% eye drop/ointment.
Mydriatics
Atropine: potent mydriatic but slow and long lasting. Pupil dilates in 30 min,
cycloplegia within 1-3 hrs and lasts for 7-10 days
Homatropine: less potent than atropine. acts in 40-60 min and lasts for 1-3 days
Cyclopentolate: acts in 30-60 min and lasts for a day
Tropicamide: quickest action (20-40 min) and only for short period (3-6 hrs). But
unreliable cycloplegic action.
Uses
1. As Antisecretory
Preanaesthetic medication
Peptic ulcer
Pulmonary embolism
To check excessive sweating or salivation as in parkinsonism
W
2. As Antispasmodic
Intestinal and renal colic, abdominal cramps
Nervous and drug induced diarrhoea, functional diarrhoea
Spastic constipation, irritable colon
Pyloropasm, gastric hypermotility, gastritis, nervous dyspepsia
To relieve urinary frequency and urgency
Dysmenorrhoea: not so effective
3. Bronchial asthma, asthmatic bronchitis, COPD
4. As mydriatic and Cycloplegic
5. Central action
Parkinsonism
Motion sickness: Hyoscine 0.6 mg orally as prophylaxis. Action lasts for 4- 6 hrs.
Transdermal preparation (applied behind pinna 4 hours before journey) action
lasts for 3 days
Hyoscine produce sedation and amnesia during labour
lie detector
6. To antagonize muscarinic effects drugs and poison
7. As cardiac vagolytic.
Side Effects and Toxicity
Dry mouth, difficulty in swallowing and talking, dry flush and hot skin
Difficulty in micturation
Dilated pupil, photophobia, blurring of near vision, palpitation
Excitement, psychotic behavoiur, ataxia , delirium, hallucination
Hypotension, weak-rapid pulse, cardiovascular collapse and respiratory depress.
Contraindications
Narrow iridocorneal angle.
Caution in elderly male with prostatic hypertrophy.
W
&+$37(51(592866<67(0'58*6
iv.
Figure: 9B.4- Response to sympathetic activation
Catacholamines
Adrenaline (Adr.)- From adrenal medulla, brain transmitter.
Dopamine- Major transmitter- basal ganglia, limbic system, CTZ, anterior
pituitary, kidney.
Noradrenaline (NA)- Major transmitter.
W
Classification
Direct acting- via receptors: E.g. Adr, NA, salbutamol
Indirect Acting- act on adrenergic neurons to release NA which acts on receptors;
E.g. tyramine.
Mixed action - ephedrine, amphetamines
Administration
Adrenaline- SC, aerosol, intracardiac, used only in CPR
Nordrenaline-iv infusion, oxidizes rapidly causes extravasations
Isoprenaline -sublingual, IV.
Adverse Drug Reactions
Transient restlessnesss, palpitation, anxiety, tremor after s.c. inj of Adr.
Large IV. dose:
Acute rise in blood pressure: cerebral haemorrhage,
Ventricular tachycardia
Contraindicated in HTN, hyperthyroidism, angina.
Dopamine
D1, D2 and D and 1 ( But no 2)
Used in patient of cardiogenic shock and severe CHF
Dobutamine
Derivative of dopamine (DA)
No D1 and D2 action
Acts on alpha and beta receptors
Selective 1 agonist: increases force of cardiac contraction & output without
significant change in HR, peripheral resistance and BP.
Used as inotropic agents in pump failure accompanying MI, cardiac surgery.
Amphetamines
Alertness, increased concentration, euphoria, talkativeness, increased work capacity.
Fatigue is allayed; Dope test
Marked psychological symptoms
Hunger is suppressed
Weak anticonvulsant, antiemetic and analgesic and anti-motion property.
Uses
I.
II.
Vascular
Hypotenive states-shock
Pressor agent with volume replacement. Not in cardiogenic shock.
Adr for anaphylactic shock
Dopamine, dobutamine
W
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
XII.
XIII.
XIV.
With local anaesthetics

Adr with lignocaine-increase duration, reduces toxicity
Epistaxsis-local PE or adr
Nasal decongestant-decongests mucosa, reduces secretion
Cardiac arrest-adr stimulates heart
Av block-isoprenaline
Ccf-not used aggravates it
Bronchial asthma-beta 2 stimulants relax bronchioles
Allergic disorder-adr antagoniss histamine effects, acute hypersensitivity
reactions,anaphylactic shock ,lifesaving drug
Ocular- mydriatic in elderly, does not interfere with vision, reduces intraocular
pressure in open angle glaucoma
Narcolepsy-by amphetamines, limitation- development of tolerance, abuse,
behavioral abnormalities
Hyperkinetic children
Obesity
Nocturanal enuresis-amphetamines increase the tone of vesical sphincters
Uterine relaxants-to delay preterm labor but increased incidence of cardiac
adverse effects.
W
Specific Agents
Phentolamine
Tolazoline
Phenoxybenazmine
Prazosin
Terazosin
Doxazosin
Afuzoxin
Tamsulosin
Indoramin
Urapidil
Labetalol
Therapeutic Uses
Pheochromocytoma
Hypertensive emergencies
Chronic hypertension
Peripheral vascular disease
Local vasoconstrictor excess
Urinary obstruction (BPH)
Male sexual dysfunction
Migraine
blockers
Useful in wide variety of clinical condition
Established in the treatment of HTN, IHD, Arrhythmias, Endocrinologic and
neurologic disorders and other conditions.
Non Selective
Propranolol
Pinlolol
Nadolol
Timolol
Selective
Acebutolol
Atenolol
Metoprolol
Esmolol
Betaxolol
W
Propranolol
Therapeutic Uses
Hypertension
Glucoma
Migraine
Hyperthyroidism
Angina pectoris
MI
Bronchoconstriction
Arrythinias
Sexual impairment
Disturbance in metabolism
Timolol & Nadolol
More potent
Nadolol long duration of action
Timolol decreases production of aqueous humor.
Half life
Acebutolol:
Pindolol:
Metopolol:
Proprenolol:
Timolol:
Labetalol:
Nadolol:
3-4 hours
3-4 hours
3-4 hours
4-6 hours
4-6 hours
3-4 hours
3-4 hours
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(i)
Histamines & Anti-Histamines
Histamines
It is almost ubiquitously present in animal tissues and in certain plants, E.g. stinging
nettle. It is implicated as a mediator of hypersensitivity phenomena and tissue iniurv
reactions. It is present mostly within storage granules of mast cells. Tissues rich in
histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta. Nonmast cell
histamine occurs in brain, epidermis, gastric mucosa and growin regions. Turnover of
mast cell histamine is slow, while that of nonmast cell histamine is fast.
1. Blood vessels: Histamine causes marked dilatation of smaller blood vessels, include
arterioles, capillaries and venules.
2. Heart: Direct effects of histamine on in situ heart are not prominent, but the isolated
heart especially of guinea pig, is stimulated rate as well as force of contraction is
increased.
3. Visceral smooth muscle: Histamine causes bronchoconstriction; guinea pigs and
patient of asthma are highly sensitive. Large doses cause abdominal cramps and colic
by increasing intestinal contractions.
4. Glands: Histamine causes marked increase in gastric secretion-primarily of acid but
also of pepsin.
5. Sensory nerve endings: Itching occurs when histamine is injected i.v. or
intracutaneously.
6. Autonomic ganglia and adrenal medulla: These are stimulated and release of Adr
occurs. This can cause a secondary rise in BP.
7. CNS: Histamine does not penetrate blood brain barrier-no central effects are seen on
i.v. iniection. However, intracerebroventricular administration produces rise in BP,
cardiac stimulation, behavioural arousal, hypothermia, vomiting and ADH release.
These effects are mediated through both H1 and H2 receptors.
Uses: it has no therapeutic use. In the past it has been used to test acid secreting capacity
of stomach, bronchial hyperreactivity in asthmatics and for diagnosis of peochromocytoma, but these pharmacological tests is risky and obsolete now.
Anti-Histamines
H1 antagonists
These drugs competitively antagonize actions of histamine at the H1 receptors. The first
compoundsmof this type were introduced in the late 1930s and have subsequently
proliferated into unnecessary motley of drugs. Nevertheless, they are frequently used for a
variety of purposes.
W
Qualitatively all H1 antihistaminics have similar actions, but there are quantitative
differences, especially in the sedative property.
1. Antagonism of histamine
2. Antiallergic action
3. CNS: The older antihistamines produce variable degree of CNS depression. This
appears to depend on the compound's ability to penetrate BBB and its affinity for the
central H1 receptors.
4. Anticholinergic action
5. Lccal anaesthetic
6. BP Most antihistaminics cause a fall in BP on i.v. injection.
Pharmacokinetics
The classical H1 antihistaminics are well absorbed from oral and parenteral routes,
metabolized in the liver and excreted in urine. They are widely distributed in the body and
enter brain.
Side effects with first generation Hi antihistaminics are frequent, but are generally mild.
Individuals show marked differences in susceptibility to side effects with different drugs.
Some tolerance to side effects develops on repeated use.
Second Generation antihistaminics
The second generation antihistaminics (SGAs) may be defined as those H1 receptor
blockers marketed after 1980. Their principal indications are:
a. Allergic rhinitis and conjunctivitis, hay fever, pollinosis-rontrol sneezing, runny
but not blocked nose, and red, watering, itchy eyes.
b. Urticaria, dermographism, atopic eczema.
c. Acute allergic reactions to drugs and foods. They have poor antipruritic,
antiemetic and antitussive actions.
List of drugs:
a. Fexofenadine
b. Loratadine
c. Desloratadine
d. Cetirizine
e. Levocetirizine
f. Azelastine
g. Mizolastine
h. Ebastine
i. Rupatadine
Uses
i.
ii.
iii.
iv.
v.
vi.
vii.
Allergic disorders, Pruritides

Common cold
Motion sickness, Vertigo
Preanaesthetic medication, Cough
Parkinsonism
Acufe muscle dystonia
As sedative, hypnotic, anxiolytic
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(ii)

Migraine
It is a mysterious disorder characterized bypulsating headache, usually restricted to one
side, which comes in attacks lasting 4-48 hours and is often associated with nausea,
vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other
symptorns.
Two major types of migraine are:
a. Migraine with aura (Classical migraine)
b. Migraine without aura (Common migraine)
Drug therapy of migraine has to be individualized depending on severity and frequency of
attacks and response of individual patients to drugs.
A. Mild: Simple analgesics/NSAIDs or their combinations ( + antiemetic)
B. Moderate: NSAIDs combinations/ergot alkaloids/sumatriptan ( + antiemetic)
C. Severe: Ergot alkaloids/sumatriptan/rizatriptan ( + antiemetic) + Prophylaxis
Propranolol/other Beta blockers
Amitriptyline/other tricyclic antidepressants
Flunarizine/other Calcium channel blockers
Valproate/topiramate
Methysergide/cyproheptadine
Prophylaxis of Migraine
Regular medication to reduce the frequency and/ or severity of attacks is recommended
for moderate-to-severe migraine when 2-3 or more attacks occur per month. Diverse
classes of drugs are used but none is effective in all cases, and none abolishes the attacks
totally. It may be prudent to discontinue prophylaxis every 6 months to check whether its
continuation is needed or not. It is important to avoid the precipitating factors.
Drugs used for Prophylaxis of Migraine
i.
Beta Adrenergic blockers (Propranolol)
ii.
Tricyclic antideprassants (Amitriptyline/Nortriptyline)
iii.
CCBs (Verapamil)
iv.
Anticonvulsant (Valporic Acid/Gabapentin)
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(iii)
Prostaglandins
Prostaglandins
Prostaglandins (PCs) and Leukotrienes (LTs) are biologically active derivatives of 20
carbon atom polyunsaturated essential fatty acids that are reseased from cell membrane
phospholipids. They are the major lipid derived autacoids. Chemically PGs may be
considered to be derivatives of prostanoic acid, though prostanoic acid does not naturally
occur in the body.
Actions of Prostaglandins
1. CVS: PCE2 and PGF2 cause vasodilatation in most but not all vascular beds. In
isolated preparations, they are more potent vasodilators than ACh or histamine.
2. Platelets: TXA2, which can be produced locally by platelets, is a potent inducer of
aggregation and release reaction.
3. Uterus: PGE2 and PGF2 uniformly contract human uterus, pregnant as well as
nonpregnant in vivo.
4. Bronchial muscle: PCF2 - PGD2 and TXA2, are potent bronchoconstrictors while
PGE2, is a powerful bronchodilator.
5. GIT: In isolated preparations, the longitudinal muscle of gut is contracted by PGE 2
and PGF2 while the circular muscle is either contracted or relaxed.
6. Kidney: PGE2 and PGI2 increase water, Na+ and K+ excretion and have a diuretic
effect.
7. CNS: PGs injected i.v. penetrates brain poorly and central effects are not prominent.
8. ANS: Depending on the PG, species and both inhibition as well as augmentation of
NA release from adrenergic nerve endings has been observed.
9. Peripheral nerves: PGs sensitize afferent nerve endings to pain including chemical
and mechanical stimuli.
10. Eye: PGF2induces ocular inflammation and lowers i.o.t by enhancing uveoscleral
outflow.
11. Endocrine system: PGE2 facilitates the release of anterior pituitary hormones-growth
hormone, prolactin, ACTH, FSH and LH as well as that of insulin and adrenal
steroids. It has a TSH like effect on thyroid.
12. Metabolism: PGEs are antilipolytic, exert insulin like effect on carbohydrate
metabolism and mobilize Calcium from bone: may mediate hypercalcaemia due to
bony metastasis.
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(iv)
NSAIDS
NSAIDS (Non Steroidal Anti-Inflammatory Drugs)

These are the group of chemically dissimilar agents that differ in their analgesics,
antipyretic and anti-inflammatory properties. E.g. Aspirin, Ibuprofen, Paracetamol,
Phenylbutazone, Indomethacin, Mephanamic acid, Piroxicam, Diclofenac, Piroxicam,
Nimesulide, Ketorolac etc.
Figure: 10.4.1- Non Steroidal Anti-Inflammatory Drugs (NSAIDs)
W
Figure: 10.4.2- Non Steroidal Anti-Inflammatory Drugs and Classification
Beneficial action due to PG synthesis inhibition

Analgesic (CNS and peripheral effect) may involve non-PG related effects.
Prevention of pain nerve ending sensation, Antipyretic (CNS effect)
Anti-inflammatory (except acetaminophen) mainly due to PG inhibition.
Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of
lysosomal enzymes, Antithrombotic
Closure of ductus arteriosus
Common Adverse Effects of NSAIDs due to inhibition of PG synthesis
Platelet Dysfunction: bleeding
Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)
Acute Renal Failure in susceptible individuals
Sodium+ water retention and edema
Analgesic nephropathy
Prolongation of gestation and inhibition of labor.
Asthma and anaphylactoid reactions in susceptible individuals
W
Aspirin
It is an Acetyl salicylic acid
It is rapidly converted in the body into salicylic acid
Analgesic, Antipyretic, Anti-inflammatory actions
It is weak organic acid.
Mechanism of Action
Blocks PG synthesis at thermoregulatory centres in hypothalamus and at peripheral
target sites.
Inhibits the sensitization of pain receptors to both mechanical and chemical stimuli.
Actions of Aspirin
i.
Anti-inflammatory action: Aspirin inhibits the Cycloxygenase thus decreases
synthesis of PGs. Acetaminophen has very weak anti-inflammatory action.
ii.
Analgesic action: PGE2 sensitize the nerve endings to bradykinin, histamine and other
chemicals mediators causing pain. Aspirin dec. the PGE2 synthesis thus suppress pain.
iii.
Antipyretic action: Fever occurs due to elevated set-point of thermoregulatory centre
which may be due to PGE2 synthesis. Aspirin decreases PGE2 synthesis, sets the
thermoregulatory set-point to normal and also causes peripheral vasodilation. Aspirin
has no effect on normal body temperature.
iv.
Respiratory actions: Salicylates increases CO2 which increase alveolar ventilation. So
at higher dose it leads to hyperventilation and respiratory alkalosis and usually
compensated by kidney. At toxic dose it paralyses the respiratory centre and causes
respiratory acidosis.
v.
Gastrointestinal effect: Normally prostacyclin inhibits gastric acid secretion and PGE2
and PGF2induces production of protective mucus in stomach and intestine. Thus
Aspirin causes increased gastric acid secretion and diminished production of mucus
leading to epigastric distress, ulceration, heamorrhage.
vi.
Actions on kidney: PGE2 and PGI2 are responsible for maintaining renal blood flow
particularly in presence of circulating vasoconstriction. Thus decrease production of
PGs can cause sodium and water retention leading to edema and hyperkalemia.
vii.
Effect on platelets: TXA2 enhances platelet aggregation whereas PGI2 decreases it.
Low dose (60-80mg/day) inhibits TXA2 production in platelets but TXA2 production
from endothelial cells of blood vessels very less affected. Thus low dose aspirin has
anticoagulant effect.
Pharmacokinetics
Absorbed from stomach and small intestine
Rapidly deacetylated in gut wall, liver, plasma, other tissues to release salicylic acid
Mostly plasma protein bound
Slowly enters brain
Freely crosses placenta
Excretion by glomerular filtration and tubular secretion.
W

Nausea, Vomiting
Epigastric distress
Increased occult blood loss in stools
Gastric mucosal damage
Peptic ulceration
Hypersensitivity and idiosyncracy
5H\HVV\QGURPH$VSLULQZKHQJLYHQWRFKLOGUHQGXULQJYLUDOLQIHFWLRQFDQFDXVH
fulminating hepatitis with cerebral edema.
Aspirin Toxicity: Salicylism
Headache - tinnitus - dizziness hearing impairment diminished vision
Confusion and drowziness
Sweating and hyperventilation
Nausea, vomiting
Marked acid-base disturbances
Hyperpyrexia
Dehydration
Cardiovascular and respiratory collapse, coma convulsions and death.
Uses
Analgesic: Headache, backache, myalgia, joint pain, toothache, neuralgia,
dysmenorrhoea
Antipyretic
Rheumatic fever
Osteoarthritis
Post myocardial infarction and post stroke patients (low dose - 80mg/day).
Dose: 300-600mg TDS.
Contraindication
Peptic ulcer
Bleeding disorder
Hypersensitivity to NSAIDs
Under <12 yrs children
Liver diseases
Pregnancy and lactation
Chickenpox or influenza infection
W
Figure: 10.4.3 Drug Interection of Aspirin

Paracetamol (Acetoaminophen): Analgesic and antipyretic.
It inhibits the PG synthesis in the brain which accounts for its antipyretic and analgesic
properties. It has less effect on cycloxygenase in peripheral tissues- so less antiinflammatory activity.
Pharmacokinetics
Well distributed in the body
Conjugated with glucoronic acid and sulphate
Excreted rapidly in urine
ADR: Nausea, rashes, leucopenia, renal tubular necrosis and hypoglycaemic coma.
Uses: Fever, headache, musculoskeletal pain, dysmenorrhoea.
Dose: Adult: 500-1000mg TDS/QID and Child: 10mg/kg QID/TDS; orally after meal.
Contraindication: Liver disease (Jaundice).
Phenylbutazone
It has powerful anti-inflammatory effect, weak analgesic and antipyretic. Complete oral
absorption, Mostly plasma protein bound and metabolized in liver.
ADR: Nausea, Vomiting, Diarrhoea, epigastric discomfort, Agranulocytosis, applastic
anemia, Skin rashes, insomnia, vertigo, Edema, fluid and electrolyte retention.
W
Uses: Rheumatoid arthritis, ankylosing spondylitis, rheumatoid fever, acute gout.

Dose: 100-200mg BD/TDS after meal.
Drug interaction: It displaces sulfonamides, tolbutamide, warfarin, imipramine and
methotrexate from plamsa protein binding sites. It induces microsomal enzymes.
Indomethacin
It is more potent than Aspirin as anti-inflammatory agent and highly potent inhibitor of
PG synthesis and suppresses neutrophil motility.
ADR: Nausea, Vomiting, Diarrhoea, headache, abdominal pain, ulceration, perforation,
haemorrhage, hypersensitivity rxn (rashes, urticaria).
Dose: 25-50mg OD/BD orally after meal.
Contraindication: epilepsy, pregnant women, kidney damage, children.
Diclofenac sodium
It is a newer analgesic, antipyretic and anti-inflammatory drug. It achieves high synovial
concentration. Well absorbed orally, 99% plasma protein bound, metabolized and
excreted both in urine and bile. ADR is same as aspirin.
Uses: rheumatoid arthritis, osteoarthritis, bursitis, ankylosing spondylitis, dysmenorrhoea,
post traumatic and post operative conditions.
Dose:
Oral: 50mg BD or TDS after food
I/M: 75 mg deep intramuscular OD/BD for maximum 2 days.
Contraindication: peptic ulcer, children under 7 years, kidney and liver disease.
Ibuprofen
It inhibits PG synthesis and inhibits platelet aggregation. ADR is same as aspirin.
Uses: Rheumatoid arthritis, arthritis, headache, Toothache, musculoskeletal pain, after
minor surgery.
Dose: Adult: 400-800mg TDS and Child: 20mg/kg/day in divided dose orally.
Contraindication: peptic ulcer, pregnancy, lactating mother, hypersensitivity, unknown
bleeding, children under 7 years.
W
Piroxicam
It is long acting potent NSAID with anit-inflammatory action same as Indomethacin and
good analgesic-antipyretic action. It is reversible inhibitor of COX, lowers PG conc in
synovial fluid and inhibits platelet aggregation. It also decreases production of IgM
rheumatoid factor. Chemotaxis of leukocytes and ratio if T helper to T suppressor
lymphocytes is reduced.
Pharmacokinetics
Rapidly and completely absorbed
Largely metabolized in liver
Excretion in urine and bile
Enterohepatic cycling occurs
ADR: Nausea, anorexia, heart burn, edema, azotemia.
Uses: Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis, acute gout,
musculoskeletal injury, Episiotomy, Dysmenorrhoea.
Dose: 20- 40mg daily in single or divided dose orally.
Ketorolac
It is a potent analgesic and moderate anti-inflammatory activity. In post operative pain, it
has equal efficacy as morphine but does not interact with opioid receptors and is free of
respiratory depressant, dependence producing, hypotensive and constipating side effects.
It inhibits PG synthesis and rapid absorption after oral and IM administration. It is highly
plasma protein bound and mostly excreted unchanged in urine.
ADR: Nausea, diarrhoea, abdominal pain, ulceration, headache, drowsiness, dizziness,
pruritus and pain at injection site, rise in serum transaminase, fluid retention.
Uses: Post operative pain, renal colic, pain due to bony metastasis, acute musculoskeletal
pain, migraine.
Dose: 10-20 mg QID max. 5 days orally.
Mephanamic acid
It has analgesic (peripheral and central action), antipyretic and anti-inflammatory.
ADR: Diarrhea, epigastric distress, skin rash, dizziness, peptic ulcer, hemolytic anemia.
Uses: Muscular, dental, traumatic pain, Headache, menorrhagia, dysmenorrhoea,
osteoarthritis, rheumatoid arthritis.
W
Dose: 250-500mg TDS.

Nimesulide: Newer NSAID, selective COX-2 inhibitor, weak PG synthesis inhibitor. It
reduces generation of superoxide by neutrophils, inhibition of PAF synthesis & TNF-D
release, free radical scavanging, inhibition of metalloproteinase activity in cartilage. No
cross reaction aspirin and other NSAID which cause bronchospasm in asthmatic patient.
So it can be used in asthmatic patient.
Dose: 100 mg BD orally.
Celecoxib: Newer NSAID, selective COX-2 inhibitor, potent analgesic, antiinflammatory and analgesic actions. It has less chance of peptic ulcer.
ADR: Abdominal pain, dyspepsia, mild diarrhoea.
Uses: Osteoarthritis and rheumatoid arthritis.
Dose: 100-200mg BD.
Acute Paracetamol Poisoning
Common in children (low glucoronide conjugation in liver)
Toxic dose:
Children: >150mg/kg
Adult: >10gram
Fatal dose: >250mg/kg
Features of toxicity:
Early features: Nausea, vomiting, abdominal pain and tender liver
After 12-18hrs: Centrilobular hepatic necrosis, renal tubular necrosis,
hypoglycema and finally coma. Jaundice starts after 2 days.
Mechanism of toxicity:
N-acetyl-benzoquinone-imine is a highly reactive aryl metabolite of paracetamol
and this is detoxified by conjugation with glutathione.
When large dose paracetamol taken , conjugation capacity is saturated and more
reactive metabolites are formed which damages liver cell and renal tubules
causing necrosis.
Treatment:
Vomiting, gastric lavage, activated charcoal
Specific: N-acetylcysteine 150mg/kg infusion over 15min, followed by same dose
I/V over next 20 hrs. OR, 75mg/kg orally every 4-6hrs for 2-3 days.
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(v)
Anti-Rheumatoid Drugs
Anti-Rheumatoid Drugs
It is an autoimmune disease in which there is joint inflammation, synovial proliferation
and destruction of articular cartilage.
Classification
1. Disease modifying drugs (DMDs)
Gold salts
D-Penicillamine
Chloroquine or Hydroxychloroquine
Sulfasalazine
Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine,
Cyclophosphamide, Chlorambucil
2. Adjuvant drugs: Corticosteroids
Gold salts
It is considered to be the most effective agent for arresting the rheumatoid process and
preventing involvement of additional joints. It is believed that Gold salts are taken by
macrophages and suppress phagocytosis and lysozomal enzyme activity but exact
mechanism unknown.
Pharmacokinetics
Gold sodium thiomalate and aurothioglucose are water soluble salts and given I/M
Auranofini is taken by mouth
High concentration in synovial fluid and macrophages in a number of tissues
including liver, kidney, spleen and adrenal cortex.
Excretion through urine and feces.
Vasodilation
Dermatitis
Albuminuria
Eosinophilia
Hepatitis, peripheral neuritis, encephalopathy
Uses: Rheumatoid arthritis that does not respond to salicylates and other NSAIDs.
Contraindication: Kidney, liver and skin disease, Pregnancy, Lactation, Bone marrow
toxic drugs.
W
D- Penicillamine
It is an analogue of amino acid cysteine. It slows the progress of bone destruction and
rheumatoid arthritis. Mechanism of action is unknown, rheumatoid factor, levels falls
with administration and also conc. of immune complexes in plasma and synovial fluid.
Pharmacokinetics
Incompletely but adequately absorbed orally
Metabolism in liver
Excretion in urine and feces
Rash
Kidney damage, proteinuria
Bone marow depression
Anorexia, nausea, loss of taste sensation
Uses
Chelating agent in treatment of poisoning by heavy metals
To treat cystinuria
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(vi)
Anti-Gouts Drugs
Anti-Gouts Drugs
Gout
It is a metabolic disorder characterized by hyperuricaemia (normal plasma urate:
1-4mg/dl).
Gouty Arthritis results from the deposition of monosodium urate monohydrate
crystals in synovial membranes of small (proximal) joints
Components of Gouty arthritis:
Hyperuricemia (normal = 360 mol/l)
Formation of Na urate crystals
Interaction between crystals and inflammatory systems in the synovial
membrane.
Drugs for Gout
A. For acute gout:
NSAIDS
Colchicine
Corticosteroids
B. For chronic gout:
Uricosurics:
Sufinpyrazone
Probenecid
Uric acid synthesis inhibitor
Allopurinol
NSAIDs
Phenylbutazone
Indomethacin
Naproxen
Piroxicam
Colchicine
It is an alkaloid obtained from colchicum autumnale
Used for treatment of acute attack of gout
It is not a uricosuric nor analgesic but relieves pain in acute attack of gout.
W
Mechanism of Action
It binds to tubulin and depolymerizes microtubules.
Interferes with cell motility.
Prevents neutrophil migration into the joint.
Prevents formation and release of inflammatory mediators.
Pharmacokinetics
Administered orally
Rapid absorption
Recycled in bile
Excreted, unchanged in faeces or urine
Nausea, Vomiting, Diarrhoea, abdominal pain, GIT haemorrhage
Myopathy, Alopecia
Agranulocytosis, aplastic anemia
Kidney damage, peripheral neuropathy
Contraindicated in Pregnancy.
Dose: orally given 1mg initially followed by 0.5mg every 2-3 hrs untill pain is relieved or
vomiting occurs. The course should not be repeated within 3 days.
Allopurinol
It is a hypoxanthine analogue used in chronic gout. It reduces the production of uric acid
by competitively inhibiting last two steps in uric acid synthesis, which are catalyzed by
xanthine oxidase.
Pharmacokinetics
Oral absorption is good
Primary metabolite is alloxanthine which is also xanthine oxidase inhibitor
Drugs and its metabolites are excreted in feces and urine.
Hypersensitivity rxn- skin rashes
Nausea, diarrhoea, gastric irritation
Dizziness
Uses: Chronic gout, secondary hyperuricaemia, kala-azar.
Contraindication: Pregnancy, Lactation, Hypersensitive patients. Precautions should be
taken for elderly, children, kidney or liver damage.
W
Probenecid
It is a uricosuric drug used in chronic gout. It competitively inhibits the active transport of
organic anions across the kidney tubule thus prevents the reabsorption of uric acid from
tubular fluid and increases its excretion in urine.
Pharmacokinetics
Completely absorbed orally
Partly conjugated in liver
Excreted by kidney
Adverse Drug Reaction: Dyspepsia, rashes, convulsion, respiratory failure.
Uses
Chronic gout
Secondary hyperuricaemia
To prolong penicillin or ampicillin action
Sulfinpyrazone
It is uricosuric drug. It inhibits tubular reabsorption of uric acid same as probenecid.
Pharmacokinetics
Rapid excretion through secretion in proximal tubule
Gastric irritation
Rashes
Uses: Chronic gout
Contraindication: Peptic ulcer
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(vii)
Insulin
Insulin
Insulin was discovered in 1921 by Banting and best who demonstrated the hypoglycaemic
action of an extract of pancreas prepared after degeneration of the exocrine part due to
ligation of pancreatic duct. It was first obtained in pure crystalline form in 7926 and, the
chemical structure was fully worked out in 1956 by Sanger. Insulin is a two chain
polypeptide having 51 amino acids and MW about 6000. The A-chain has 21 while Bchain has 30 amino acids.
Regulation of insulin secretion
Under basal condition -1U insulin is secreted per hour by human pancreas. Much larger
quantity is secreted after every meal. Secretion of insulin from B cells is regulated by
chemical, hormonal and neural mechanisms.
Actions of insulin
The overall effects of insulin are to favour storage of fuel. The actions of insulin and the
results and deficiency can be summarized as:
i.
Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat
are highly sensitive.
ii.
The first step in intracellular utilization of glucose is its phosphorylation to form
glucose-6-phosphate. This is enhanced by insulin through inceased production of
glucokinase.
iii.
Insulin inhibits gluconeogenesis in liver by gene mediated decreased synthesis of
phosphoenol pyruvate carboxykinsae.
iv.
Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis. In
diabetes increased amount of fat is broken down due to unchecked action of
lipolytic hormones
increased FFA and glycerol in blood
taken up by
liver to produce acetyl-CoA.
v.
Insulin enhances transcription of vascular endothelial lipoprotein lipase ind thus
increases clearance of VLDL and chylomicrons.
vi.
Insulin facilitates AA entry and their slmthesis into proteins, as well as inhibits
protein breakdown in muscle and most other cells.
Conventional preparations of insulin
The conventional commercial preparations are aroduced from beef and pork pancreas.
They contain ~1% (10,000 ppm) of other proteins which are potentially antigenic.
i.
Regular (soluble) insulin
ii.
Lente insulin (Insulin-zinc suspension)
iii.
lsophane (Neutral Protamine Hagedorn or NPH)
iv.
Protamine zinc insulin (PZI)
W
Highty purified insulin preparations

In the 1970s inproved purification techniques were applied to produce highly purified and
practically nonantigenic insulins.
Human insulins
In the 1980s, the human insulins were produced by recombinant DNA technology in
Escherichica coli proinsulin recombinant bacterial (prb) and in precursor yeast
recombinant (pyr) or enzyrnatic modification of porcine insulin (emp).
Insulin analogues: insulin lispro, insulin aspart, insulin glulisine, insulin glargine.
Reactions to insulin
Hypoglycaemia
Local reactions: swelling, erythema, stinging sometimes occurs.
Allergy: urticaria, angioedema and anaphylaxis are the manifestations.
Edema
Drug interactions
Beta adrenergic blockers prolong hypoglycemia by inhibiting compensatory
mechanisms of operating through beta2 receptors.
Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tent
to raise blood sugar and reduce effectiveness of insulin.
Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic
glycogen.
Salicylates, lithium and theophylline may also accentuate hypoglycaemia by
enhancing secretion and peripheral glucose utilizatior.
Uses
Diabetes mellitus
Diabetic ketoacidosis/DKA (Diabetic coma)
Hyperosmolar (nonketonic hyperglycemic) coma
Inslulin resistance
When insulin requirement is increased, insulin resistance is said to have developed. It
may be acute and chronic.
Newer insulin delivery devices
i.
Insulin syringes
ii.
Pen devices - fountain pen like
iii.
Inhaled lnsulin
iv.
Insulin pumps
v.
Implantable pumps
vi.
External artificial pancreas
vii.
Other routes of insulin delivery: Intraperitoneal, oral and rectal routes are being tried.
These have the advantage of providing higher concentrations in the portal circulation,
which is more physiological.
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(viii) Oral Hypoglycemic Drugs
Oral Hypoglycemic Drugs

1) Sulfonylureas:
A. First generation
Chlorpropamide
Tolbutamide
Tolazamide
B. Second generation
Glimepiride
Glipizide
Glipizide (extended release)
Glyburide
Meglitinide
Repaglinide
2) Biguanides: Metformin, phenformin
3) D-glucosidase inhibitors: Acarbose, miglitol
4) Meglitinide analogues: Repaglinide, Nateglinide
5) Thiazolidinediones: Rosiglitazone, Pioglitazone
Sulfonylureas
Mechanism of Action
Stimulation of insulin release from the beta cells of pancreas
Reduction of serum glucagon level
Increase binding of insulin to target tissues and receptors
Pharmacokineics
Oral, bind to serum protein
Metabolized by the liver and excreated by the liver or kidney-contraindicated in
hepatic and renal insufficiency.
Drug interactions
Displace from protein binding site-aspirin, sulfonamides etc.
Inhibit metabolism/excretion-cimetidine etc, warfarin and chloramphenicol.
Cross placenta; deplete insulin from fetal pancrease-use insulin in pregnant mother.
Synergise with or prolong pharmacodynamic action-asa, propanolol.
Decrease action-induce metabolism-phenobarbitone
W

Hypoglycemia
Nonspecific: nausea, vomiting, diarrhoea, flatulence, headache, paresthesias and
weight gain.
Hypersensitivity, rash, photosensitivity, purpura, transient leukopenia, rarely
agranulocytosis.
Chlorpropamide
Longest acting
Can cause prolonged hypoglycemia so avoided in elderly
Potentiates adh action-hyponatremia
Cholestatic jaundice
Disulfiram reaction with alcohol
Tolbutamide
Shorter acting, safe in those prone to hypoglycemia
In renal dysfunction
Glyburide
Potent but slow acting
Active metabolites decrease dose in renal failure
Excreated in urine mainly and bile also
Glipizide
Decrease dose in hepatic dysfunction
Fast acting
Insulinemic action persists even after prolonged use
Gliclazide
It has antiplatelet action, reduces free radicals, may delay diabetic retinopathy, less
weight gain.
Biguanides
Mechanism of Action
Decrease hepatic glucose output largely inhibiting gluconeogenesis
Enhance insulin medeated glucose disposal in musal and fat
Inhibit intestinal absorption of glucose
Promote peripheral glucose utilization
Increase HDL and decrease LDL, VLDL
Weight reduction
W
Pharmacokinetics
Oral, not bound to serum protein and not metabolized
Excretion is via the urine
No hypoglycemia
GI-Abdominal pain, anorexia, nausea, metallic taste, mild diarrhoea
Lactic acidosis-phenformin
Vit B12 deficiency in long term use
Meglitinide analogues: Repaglinide, Nateglinide
Mechanism of Action
Acts like sulfonylurea
It binds to sulfonylurea receptor /ATP sensitive potassium channel of B-Cell-Insulin
release. It is used as niddm with metformin.
Pharmacokinetics
Well absorbe orally.
Metabolized to inactive form by the liver and excreted by bile-avoid in liver diseases.
Incidence of hypoglycemia less than sulfonylureas.
Taken before major meal to control pp hyperglycemia-rapid onset.
Lower risk of hypoglycemia
Mild headache, dyspepsia, arthralgia, weight gain
Should be avoid in liver diseases
Thiazolidinediones: Rosiglitazone, Pioglitazone
Mechanism of Action
Bind to nuclear peroxisome proliferator activators (PPARS) involved in transcription
of insulin-responsive genes.
Sensitization of tissues to insulin-increase insulin receptor numbers- stimulating gult4
expression and translocation.
Supressed hepatic gluconeogenesis.
Decrease TG and increase HDL.
It is used in type II, with other OHD.
Pharmacokinetics
Rosiglitazone CYP2C8, Pioglitazone CYP2C8, CYP3A4-failure of OCP.
Monitoring of liver function.
W

Well tolerated, less hypoglycemia than sulfonylureas
Plasma volume expansion-edema, weignt gain
Hepatotoxicity of troglitazone-led to withdrawal
Headache, myalgia, mild anemia
Contraindicated in liver diseases and CHF
-glucosidase inhibitors: Acarbose, miglitol
It is complex oligosaccharide which reversibly inhibits alpha glucosidases in brush
borders of small intestine decrease formation of absorbable carbohydrate-decrease
phospholipid-decrease insulin. It is used in type II with or without other OHD, OBESE.
Pharmacokinetics
Orally taken
It is taken before each major meal
It absorbed minimally
GI discomfort
Flatulence
Diarrhoea
Potential hepatotoxicity-recent concern
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(ix)
Corticosteroids
Corticosteroids
Prednisone used most often orally
Methylprednisolone used parenterally
Numerous available preparations
Corticosteroid Actions
Inhibition of IL-1 and TNF gene expression and synthesis
Decreased activation of T lymphocytes by decreasing IL-1 release
Decreased neutrophil functions espcieally chemotaxis
Decreased antibody production (high doses)
Decreased release of kinins and proinflammatory eicosanoids (prostaglandins and
leukotrienes).
Corticosteroid Immunosuppression
Decreased cell-mediated immune reactions that mediate rejection of organ transplants
Decreased activation of T lymphocytes by inhibition of IL-1 synthesis by
macrophages
Decreased lymphocyte mobilization out of lymphoid organs (lymphopenia)
Corticosteroid Adverse Reactions
All commonly occur because high doses used for immunosuppression
Suppression of hypothalmic-pituitary adrenal axis (HPA) function
Osteoporosis, Hypertension, Weight gain
Hyperglycemia, Euphoric personality changes, Cataracts
Clinical Concerns with Corticosteroids
Growth inhibition in pediatric transplants
Cataracts (10% incidence)
Bone disease (inhibition of osteoblastic activity, decreased calcium absorption,
increased urinary calcium excretion)
Diabetes (insulin-resistance, gluconeogenesis)
Hyperlipidemia (40-60% posttransplant accelerated atherogenesis, increased
incidence if combined with calcineurin inhibitors and sirolimus)
Hypertension (60-80% in transplant patients)
Increased cardiovascular risk factors
Predisposition to infection (decrease PMN, T cell activity).
W
&+$37(5$87$&2,'6+25021(6 0,6&(//$1(286'58*6
(x)
Immunosuppressant
Immunosuppressant
These are the drug which inhibits cellular / humoral immunity
Have major use in organ transplantation, auto immune diseases
Immunosuppressant Drugs
1. Specific T- cell Inhibitors: Cyclosporine, Tacrolimus.
2. Cytotoxic drugs (Anti- Proliferative): Azathioprine, Cyclophosphaide,
Methotrexate, Chlorambucil, Mycopheolate mofetil.
3. Glucocorticoids: Prednisolone and others.
4. Antibodies: Muromonab CD3, Antithymocyte globulin (ATG), Rho (D)
Immunoglobulin.
Mechanism of Action
Glucocorticoids inhibit MHC expression and IL-1, IL-2, IL-6 production so that
helper T-cells is not activated.
Cytotoxic drugs block proliferation and differentiation of T and B lymphocytes.
Cyclosporine and tacrolimus inhibit antigen stimulated activation and proliferation of
helper T cells as well as expression of IL-2 and other cytokines by them.
Antibodies like muromonab CD3, antithymocyte globulin specifically bind to helper
T cells, prevent their response and deplete them.
Cyclosporine
Specific T-cells inhibitors
Highly selective immuno-suppressants which has markedly increased the success of
the organ transplantation
Cyclosporin binds to cyclophilin and this complex inhibits Ca-calmodulin activated
Calcineurin. Normally Calcineurin activates cytokine gene which responsible for
production of IL-2 and other cytokines. Syclosporin inhibits this pathway.
Free of the toxic effect on bone marrow and RE system.
Nephrotoxic major limitation
Impairs liver function
Rise in BP, Precipitation of the diabetes, anorexia, lethargy, hyperkalemia and viral
infections, gum hyperplasia
Hirsutism, tremor and seizures
W
Uses
Prevention and treatment of graft rejection reaction
Routinely used in renal, hepatic and bone marrow transplantation.
Second line drug in auto immune diseases like
Serum rheumatoid arthritis
Bronchial asthma
Inflammatory bowel diseases
Psoriasis
Aplastic anemia
Drug interaction
Enhances nephrotoxicity when used along with other nephrotoxic drugs ilke:
Aminoglycosides, vancomycin, amphotericin B.
Drugs decreasing cyclosporin level in blood: Phenytoin, phenobarbitone, rifampin,
other enzyme inducers.
Erythromycin, ketoconazole inhibits its metabolism.
When given with potassium sparing diuretics or potassium supplements can cause
marked hyperkalemia.
Azathioprine
It is Purine antimetabolite
6- Mercaptopurine is its active metabolite
More marked immnosuppressants than antitumor action
It has prominent effect on T cells and cell mediated immunity
Depresses cell mediated immunity
It inhibits the differentiation and activation of T cells and also inhibits CTL.
Uses
Prevention of renal and other graft rejection but less effective than cyclosporine
Progressive rheumatoid arthritis and some other autoimmune diseases.
Cyclophosphamide
It is a cytotoxic drug. It has marked effect on B Cells and humoral immunity.
Uses
Bone marrow transplantation
Other transplantation reserved drug
Rheumatoid arthritis (used as third line drug)
Low doses are used in maintenance therapy of
Pemphigus
Systemic lupus erythematosus
Idiopathic thrombocytopenic purpura
W
Methotrexate
It is folate antagonist. It has prominent immuno suppressants. It decreases cytokine
production and cellular immunity. It has anti-inflammatory property.
Uses
First line drug
Rapidly progressing rheumatoid arthritis
Pemphigus
Myasthenia gravis
Uveitis
Chronic active hepatitis
Chlorambucil: Weak immunosuppressant
Uses
Auto immune diseases
Transplant maintenance regimen
Glucocorticoids
It is potent immunosuppressants and anti- inflammatory action. It mainly inhibits MHC
expression and proliferation of T cells.
Uses
Companion drug to cyclosporine in various organ transplants
All cases of severe autoimmune diseases especially during exacerbation.
Anti-D immunoglobulin: human IgG against Rh-D antigen
Uses
Prevention of postportum/post abortion formation of antibodies in Rh-D negative
women who have delivered/aborted Rh-D positive baby.
Should be given within 72 hours of delivery/abortion. Also given at 28 th week of
gestation.
Immunostimulators: Levamisole
It synthesizes originally as an antihelmintics but appears to restore depressed immune
function. It is indicated in sdjuvant treatment with fluorouracil after surgical resections in
SDWLHQWVZLWK'XNHVVWDJH&FRORQFDQFHU Adverse effect includes agranulocytosis
(Fatal), Bacillus Calmette Guerin (BCG).
Uses
Treatment and Prophylaxis of carcinoma in situ of the urinary bladder.
Prophylaxis of primary and recurrent stage of papillary tumors.
W
$%%5(9,$7,216

AB
Antibody
ACh
Acetylecholine
AD
$O]KHLPHUVGLVHDVH
ADH
Antidiuretic Hormone
ADP
Adinosine Diphosphate
ATP
Adinosine Triphosphate
ADR
Adr
Adrenaline
AF
Atrial Fibrilation
AG
Antigen
AIDS
Acute Immune Deficiency Syndrome
AMB
Amphotericin B
Amp
Ampule
AP
Action Potential
ANS
Autonomic Nervous System
PNS
Peripheral Nervous System
CNS
Central Nervous System
A-V
Atroventricular
AZT
Zidovudine
BP
Blood Pressure
BMD
Bone Mineral Density
BPN
Bisphosphonate
BZD
Benzodiazepine
CA
Catecholamine
CAD
Coronary Artery Disease

W
CBG
Cortisol binding Globulin
CCB
Calcium Channel Blocker
ARB
Angiotensin Receptor Blocker
CH
Cholesterol
CHF
Congestive Heart Failure
CMV
Cytomegalovirus
COX
Cyclooxygenase
CL
Clearence
CLcr
Creatinine Clearence
CVP
Central Venous Pressure
CSF
Cerebrospinal Fluid
CVS
Cardiovascular System
DDT
Dichloro Diphenyl Trichloroethane
DI
Diabetes Insipidus
DM
Diabetes Mellitus
DNA
Deoxyribose Nucleic Acid
RNA
Riboneucleic Acid
DT
Distal Tubule
ECG
Electrocardiogram
Ethambutol
EEG
Electroencephalogram
FA
Folic Acid
FEV1
Forced Expiratory Volume in 1 Second
FFA
Free Fatty Acid
FSH
Follicle Stimulating Hormone
GABA
Gamma Amino Butyric Acid
GFR
Glomerular Filtration Rate

W
GH
Growth Hormone
GIT
Gastro-Intestinal Tract
GnRH
Gonadotropin Reseasing Hormone
Bb
Haemoglobin
HBV
Hepatitis B Virus
Isoniazid
HDL
High Density Lipoprotin
HIV
Human Immunodeficiency Virus
HMG-CoA
Hydroxymethyl Glutaryl Coenzyme A
HR
Heart Rate
HRT
Hormone Replacement Therapy
IBD
Inflammatory Bowel Disease
IBS
Irritable Bowel Syndrome
IG
Immunoglobulin
IM
Intramuscular
IV
Intravenous
SC
Subcutanous
IU
International Unit
GA
General Anasthetic
LA
Local Anasthetic
LDL
Low Density Lipoprotein
LH
Luteinizing Hormone
LMW
Low Molecular Weight
LVF
Left Ventricular Failure
MDR
Multidrug Resistance
MW
Molecular Weight
NADP
Nicotinamide Adenine Dineucletide Phosphate

W
NADPH
Reduced Nicotinamide Adenine Dineucletide Phosphate
NR
Nicotinic Receptor
NSAID
Non Steroidal Anti-Inflammatory Drug
NRTI
Nucleoside Reverse Transcriptase Inhibitor
ORS
Oral Rehydration Solution
PABA
Paraamino Benzoic Acid
PD
3DUNLQVRQVGLVHDVH
PG
Prostaglandin
PI
Protease Inhibitor
PPH
Post Partum Haemorrhage
PPI
Proton Pump Inhibitor
Rifampin/Rifampicin
RMP
Resting Membrane Potential
Streptomycin
SA
Sinoauricular (Node)
SCID
Severe Combind Immunodeficiency Disease
T1/2
Half Life
TG
Triglyceride
VLDL
Very Low Density Lipoprotein
Vit
Vitamin
WBC
White Blood Cells
RBC
Red Blood Cells
VT
Ventricular Tachycardia
WPW
Wolff-Parkinson-White Syndrome
Volume of distribution
VF
Ventricular Fibrilation
Pyrazinamide
W
%,%/,2*5$3+<
Tripathi KD. Essentials of Medical Pharmacology - Sixth Edition. New Delhi: Jaypee
Brothers Medical Publishers (P) LTD, 2008.
Whalen Karen, Finkel Richard, Panavelil Thomas A. Lippincott Illustrated Reviews Sixth
Edition. Philadelphia: Wolters Kluwer, 2014.
Katzung Bertram G., Masters Sussan B., Trevor Anthony J. LANGE Basic & Clinical
Pharmacology 12th Edition. Burr Ridge: McGraw Hill Companies Inc., 2012.
Grag Gobind Rai, Gupta Sarash. Examination Review Series Pharmacology. New Delhi: GS
Publishers, 2014.
Sharma K. K., Sharma H. L. Principles of Pharmacology Second Edition. New Delhi: Paras
Medical Publishers, 2009.
Satoskar R. S., Bhandarkar S. D., Ainapure S. S. Pharmacology and Pharmacotherapeutics
23rd Edition. Mumbai: South Asia Books, 2013.
Corey Paul N., Pomeranz Bruce H., Lazarou Jason. Incidence of Adverse Drug Reactions in
Hospitalized Patients. JAMA. 1198; 279:1200-1205.
Protus B. M., Kupferberg N. Accuracy and Completeness of Drug Information in Wikipidia:
An assessment. J Med Libr Assoc 2011; 99:310-3.
Thomas J. Hwang, Florence T. Bourgeois, John D. Seeger. Drug Safety in the Digital Age.
The New England Journal of Medicine 370; 26 nejm.org June 26, 2014.
Bojita Marius, Farcas Andreea. Adverse Drug Reactions in Clinical Practice: a Causality
Assessment of a Case of Drug-Induced Pancreatitis. J Gastrointestin Liver Dis September
2009 Vol.18 No 3, 353-358.
I Ralph Edwards, Jeffrey K Aronson. Adverse drug reactions: definitions, diagnosis, and
management. Lancet 2000; 356: 125559.
W

Tmp66e2 TMP

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Tmp66e2 TMP

Uploaded by

Copyright:

Available Formats



   

4& )*5/ +)

Dr. Md Rezaul Karim

Dr. Md Rezaul Karim

CHAPTER 2: Anti-Microbial Drugs

CHAPTER 3: Respiratory Drugs

CHAPTER 4: Circulatory System Drugs

Anemia & Erythropoietin

CHAPTER 5: Cardiovascular Drugs

Drugs for Heart Failure

CHAPTER 6: Gastro-Intestinal drugs

CHAPTER 7: Urinary System drugs

CHAPTER 8: Anti-Cancer Drugs

CHAPTER 9: Nervous System Drugs

General Anesthetic Agents

Section B: Peripheral Nervous System (Somatic & ANS) Drugs

Local Anesthetic Agents

CHAPTER 10: Autacoids, Hormones & Miscellaneous Drugs

Histamines & Anti-Histamines

Pharmacology (Greek: Pharmacon-drugs; Logos-discourse in) is the science that deals

Pharmacodynamics (Greek: Dynamics-power) :KDWWKHGUXJGRHVWRWKHERG\It is

Inhibition of Na-K pump activity

Increase Na ions concentrations intra-cellularly

Greater Ca ions infuse into cell

Strong systolic concentration of Myocardium

Pharmacokinetics (Greek; Kinesis-movement) :KDWWKHERG\GRHVWRWKHGUXJ. It is

Drug (French-Drogue: a dry herb)

Drug nomenclature: A drug has 3 names:(i)

Dosage forms of drugs: The forms of the drug by which it is administered:(i)

Inorganic E.g. Li, Ca, Mg, K, etc.

Some important terminologies

Routes of Drug Administration and Dosages

Routes of Drug Administration

Site of desired action.

Rate and extent of absorption of drugs from different route.

Effect of digestive juice and first pass metabolism on the drug.

Rapidity with which the response is desired.

Accuracy of dosage required.

Condition of the patient.

Classification of routes of drug administration

Pharmacodynamics and Pharmacokinetics

Drugs acting on the metabolic processes with in the cell.

R A is more potent than B.

Figure: 1.3.1 - Potency and

Combined Effect of the drugs

Figure: 1.3.2- Dose - Response curves

Figure: 1.3.3 Bioavailability Graph

Factors affecting Bioavailability

Therapeutic Index (TI = MTC/MEC)

Maintenance dose: is the dose given to maintain the therapeutic window.

Factors Affecting Metabolism

Body surface area

Important processes in renal clearance

Factors that decrease clearance

Adverse Drug Reaction

Adverse drug reaction (ADR)

R Next six weeks or first trimester period Susceptible to the damage.

Figure: 2.1.1- Antibacterial Spectrum of Sulfonamides

Figure: 2.1.2- Mechanism of Action of Quinolones

Mechanism of action (MOA)

Figure: 2.1.3- Antibacterial Spectrum of Quinolones

Figure: 2.1.4- Mechanism of

4&)*5/ +)

Pharmacodynamics (Greek: Dynamics-power) :KDWWKHGUXJGRHVWRWKHERG\It is