PHARMACOLOGY with DRUG TESTING

PHARMACODYNAMICS
Actions/effects of the drug on the body
Determines the group in which the drug is classified and plays a major role in deciding whether
a group is appropriate therapy for particular symptom or disease

RECEPTORS
Specific molecules in a biologic system with which drugs interact to produce changes in the
function of the system
Determine the quantitative relations between dose or concentration of drug and
pharmacologic effects
Selective in choosing a drug molecule to bind to avoid constant activation by promiscuous
binding of many different molecules
Changes its function upon binding in such a way that the function of the biologic system is
altered in order to have pharmacologic effect
Selective in ligand-binding characteristics (respond to proper chemical signals and not to
meaningless ones)
Mediates the actions of both pharmacologic agonists and antagonists
Majority are proteins which provide the necessary diversity and specificity of shape and
electrical charge
Receptor site/ recognition site
o Specific binding region of the macromolecule
o High and selective affinity to the drug molecule
Interaction between the drug and the receptor is the fundamental event that initiates the
action of the drug

Classification of Receptors

1. Regulatory Protein
Best characterized drug receptors
Mediates the action of endogenous chemical signals like neurotransmitters, autacoids
and hormones
Mediates the effects of the most useful therapeutic agents

2. Enzymes
Inhibited (or less commonly, activated) by binding a drug
E.g. dihydrofolate reductase, the receptor for methotrexate

3. Transport Proteins
E.g. Na+/ K+ ATPase, the membrane receptor for digitalis

4. Structural Proteins
E.g. tubulin, the receptor for colchicines, an anti-inflammatory drug

EFFECTORS
Molecules that translate the drug-receptor interaction into a change in cellular activity
E.g. adenyl cyclase
Some receptors are also effectors
A single molecule may incorporate both the drug binding site and the effector mechanism

DRUG CONCENTRATION AND RESPONSE

Graded Dose-Responsive Curve

Response of a particular receptor-effector system is measured against increasing concentration
of a drug
Graph of the response versus the drug dose

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 Sigmoid curve
Efficacy (Emax) and potency (EC50) are derived from this curve
The smaller the EC50 , the greater the potency of the drug

Emax
Maximal response that can be produced by a drug
All receptors are occupied
No response even if the dose is increased

EC50
Concentration of drug that produces 50% of maximal effect
Smaller EC50 more potent

Bmax
Total number of receptor sites
All receptors have been occupied

KD
Equilibrium dissociation constant
Concentration of drug required to bind 50% of the receptors
Measure of the affinity of a drug for its binding site on the receptor
Smaller KD greater affinity of drug to receptor

COUPLING
Transduction process between the occupancy of receptors and production of specific
effect
Highly efficient coupling can be elicited by a full agonist and spare receptors

SPARE RECEPTORS
Maximal drug response is obtained at less than maximal occupation of the receptors
Not qualitatively different from non-spare receptors, not hidden or unavailable
Temporal in character, when occupied, they can be coupled to respond, there is still effect
Drugs with low binding affinity for receptors will be able to produce full responsive even at low
concentration
Compare concentration for 50% of maximal effect (EC50) with concentration for 50% maximal
binding (KD)
KD > EC50 with spare receptors
Effect of the drug-receptor interaction may persists for a longer time than the interaction
itself
Actual number of receptors may exceed the number of effectors available

INERT BINDING SITES

Non-regulatory molecules of the body
Binding with these molecules will result to no detectable change in the function of the
biologic system
Buffers the concentration of the drug
Bound drugs do not contribute directly to the concentration gradient that drives diffusion
E.g. Albumin

AGONIST
Binds to the receptor and directly or indirectly bring about an effect
Full activation of the effector system

PARTIAL AGONIST
Produces less than the full effect, even when it has saturated the receptors
Acts as an inhibitor in the presence of a full agonist

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ANTAGONIST
Binds but do not activate the receptors
Blocks or competes with agonist

COMPETITIVE ANTAGONIST
Competes with agonist receptor
Binds to the receptor reversibly without activating the effector system
Antagonist increases the agonist concentration needed for a given degree of response
Concentration-effect curve is shifted to higher doses (ie, horizontally to the right of the dose
axis)
Same maximal effect is reached
Effects are overcomed by adding more agonist
Increases the median effective dose (ED50)

COMPETITIVE ANTAGONIST: 2 THERAPEUTIC IMPLICATIONS

1. Degree of inhibition produced by the competitive antagonist depends on the
concentration of antagonist (e.g. propranolol)
2. Clinical response to a competitive antagonist depends on the concentration of
agonist that is competing for binding to the receptor

IRREVERSIBLE ANTAGONIST
Binds with the receptor via covalent bonds
Antagonists affinity to the receptor maybe so high
Receptor is not available to bind the agonist
Concentration-effect curve moves downward
No shift of the curve in the dose axis
Emax is not reached
No increase in median effective dose (ED50) unless there are spare receptors
Duration of action is relatively independent of its own rate of elimination
More dependent on the rate of turnover of receptors
E.g. phenoxybenzamine binding with alpha receptors

CHEMICAL ANTAGONISM
Does not depend on interaction with the agonists receptor
Drug that interacts directly with the drug being antagonized to remove it or to prevent it
from reaching its target
E.g. protamine used to counteract the effect of heparin making it unavailable for interaction
with proteins involved in the formation of blood

PHYSIOLOGIC ANTAGONISM
Makes use of the regulatory pathway
Effects that are less specific and less easy to control
Binds to a different receptor producing an effect opposite to that produced by the drug it is
antagonizing
Examples:
o Glucocorticoids catabolic effects of increase in sugar is physiologically opposed by
insulin
o Histamine causes bronchoconstriction in asthmatic patients, opposed by
bronchodilators like salbutamol and epinephrine

SIGNALING MECHANISMS

5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS

1. Lipid soluble drug crossing the plasma membrane and acts on intracellular receptor
(e.g. steroids)
2. Transmembrane receptor protein intracellular enzymatic activity is regulated by a
ligand that binds to the proteins extracellular domain

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 3. Transmembrane receptor that binds and stimulates a protein tyrosine kinase (e.g.
insulin)
4. Ligand-gated transmembrane ion channel which regulates the opening of the ion
channel (e.g. GABA, excitatory acetylcholine)
5. Transmembrane receptor is coupled with an effector enzyme by G protein which
modulates production of an intracellular second messenger [e.g. cathecolamine
(epinephrine)]

INTRACELLULAR SECONDARY MESSENGERS

A. cAMP
Mediates hormonal responses
o Mobilization of stored energy (breakdown of carbohydrates in the liver
stimulated by cathecolamines)
o Conservation of water by the kidneys mediated by vasopressin
o Calcium homeostasis by parathyroid hormone
oHeart rate and contraction by beta-adrenomimetic cathecolamines
B. Calcium and Phosphoinositides
Bind to receptors linked to G proteins while others bind to receptor tyrosine kinases
Crucial step is the stimulation of membrane enzyme phospholipase C

C. cGMP
Few signaling roles in a few cell types like the intestinal mucosa and vascular
smooth muscle cells
Causes relaxation of vascular smooth muscle by a kinase-mediated mechanism

RECEPTOR DESENSITIZATION
Response gradually diminishes even if the drug is still there (after reaching an initial high
level of response)
Reason is not known

STRUCTURE ACTIVITY RELATIONSHIP

Cells use more than one signaling mechanism to respond to the drug

QUANTAL DOSE-RESPONSE CURVE

Graph of the fraction of a population that shows a specified response to increasing
doses of a drug
Minimum dose required to produce a specific response is determined in each member of the
population
Sigmoid curve

ED50
Median effective dose
50% of the individuals manifested the desired therapeutic effect

TD50
Median toxic dose
50% of the individuals manifested the toxic effects

LD50 : Median lethal dose

THERAPEUTIC INDEX
Ration of the TD50 (or LD50) to the ED50 determined from the quantal dose-response curves
Increased therapeutic index-wide margin of safety
Represents an estimate of the safety of the drug
A very safe drug might be expected to have a very large toxic dose and a much smaller
effective dose
E.g. ED50 of 3 mg and the LD50 is 150 mg. Therapeutic index is 50 (150/3)

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THERAPEUTIC WINDOW
Dosage range between the minimum effective therapeutic concentration or dose (MEC) and the
minimum toxic concentration or dose (MTC)
More clinically relevant index of safety
E.g. theophylline
o MEC = 7-10 mg/L (average of 8 mg/L)
o MTC = 15-20 mg/L (average of 18 mg/L)
o Therapeutic window = 8-18 mg/L

MAXIMAL EFFICACY
Maximal efficacy (Emax) an agonist can produce if the dose is taken to very high levels
Determined mainly by the nature of receptors and its associated effectors
Measured with a graded dose-response curve but not with quantal dose-response curve

POTENCY
A. Amount of drug needed to produce a given effect
B. In the graded dose-response curve, the effect chosen is the 50% of the maximal effect and
the dose is (EC50)
C. In the quantal dose-response curve, ED50, and LD50 are variables in 50% of the population

VARIATION OF RESPONSES IN INDIVIDUALS

1. IDIOSYNCRATIC RESPONSE
Caused by differences in metabolism (genetic) or immunologic mechanisms
Response to the drug is unknown or unusual

2. HYPOREACTIVE RESPONSE
Intensity of the drug is decreased
Large dose of the drug is needed to have an effect

3. HYPEREACTIVE RESPONSE
Intensity of the drug is increased or exaggerated

4. TOLERANCE
Decreased sensitivity acquired as a result of exposure to the drug

5. TACHYPHYLAXIS
Tolerance develops after a few doses

VARIATIONS IN DRUG RESPONSIVENESS

1. Alteration on the concentration of the drug that reaches the receptor due to absorption,
distribution and elimination differences
2. Variation in the concentration of the endogenous ligands (chemicals produced by the
body that binds to receptors, e.g. cathecolamines)
3. Alterations in number/function of receptors
Down regulation: decrease in # of receptors
Up regulation: increase in the # of receptors

Overshoot Phenomenon; Rebound Hypertension

Drug has been taken for a long time, then abruptly discontinued
E.g. propranolol (beta-blocker)
Gradual decrease of taking the drug by decreasing/ tapering the dose.

4. Changes in 2nd messengers

5. Clinical selectively
give the drug that really acts on the disease
no drug causes a single specific effect delay, they are selective never specific

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 beneficial and toxic effects may be mediated by the same receptor-effector mechanism

D + R <=> DR -> X (beneficial / toxic

WHAT TO DO TO AVOID/CIRCUMVENT TOXIC EFFECTS

Give low doses
Carefully monitors the patient
Employ ancilliary procedures
Use a safer drug if possible
Beneficial and toxic effects are mediated by identical receptors but in different ways

D + R DR -> X (beneficial)
Y ( toxic)

HEPARIN
Low doses for prevention of blood clots
Very high doses causing internal bleeding
Monitor PT, PTT and bleeding parameters

STEROIDS
Give lowest dose possible
Give adjunctive drugs
Anatomic selectivity (lungs-by inhalation)

ANTI-HISTAMINE
H1 receptors H1 blocker D + R1 -> DR1 -> X (beneficial)
D + R2 -> DR2 -> Y (toxic)
H2 receptors H2 blocker
PHARMACOKINETICS
Dose-concentration relationship
Effects of the biologic system on drugs
Deals with the processes of absorption, distribution and elimination of drugs
Makes possible the calculation of loading and maintenance doses

EFFECTIVE DRUG CONCENTRATION

Concentration of a drug at the receptor site (in contrast to drug concentrations that are more
rapidly measured, e.g. blood)

PLASMA CONCENTRATION
Rate of input of the drug (by absorption) into the plasma
Rate of distribution to peripheral tissues (including the target organ)
Rate of elimination, or loss, from the body

2 BASIC PARAMETERS
Unique for a particular drug in particular patient
Average values in large populations that can be used to predict concentrations
o VOLUME OF DISTRIBUTION (Vd)
Measure of apparent space in the body available to contain the drug
Amount of drug in the body to the plasma/serum concentration
Intracellular and extracellular compartments
When a drug is avidly bound in peripheral tissues, its concentration in plasma
may drop to very low values even if the total amount in the body is large
High volume of distribution
When a drug is completely retained in the plasma compartment
Volume of distribution is equal to the plasma volume
o CLEARANCE (CL)
Rate of elimination compared to plasma concentration
Depends on the drug and the organs of elimination in the patient
Drugs eliminated with first-order kinetics
Clearance is a constant
Elimination rate is equal to clearance time plasma concentration
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 Elimination will be rapid at first and slow as the concentration
decreases

HALF LIFE
o T1/2
o Time it takes for the amount or concentration of a drug to fall to 50% of an earlier
measurement
o Drugs eliminated by first-order kinetics
Constant regardless of concentration
o Drugs eliminated by zero-order kinetics
Particularly useful
Not a constant
o Derived parameter from the volume of distribution and clearance
o Determines the rate at which blood concentration rises during a constant infusion and
falls after administration is stopped
o T1/2 = 0.693 x Vd / CL
STEADY STATE CONCENTRATION
Rate of drug administration is equal to rate of elimination
Dose in = dose out

BIOAVAILABILITY
Fraction of the administered dose of the drug that reaches the systemic circulation
Equal to the amount absorbed over the amount administered
Intravenous administration
o Unity or 100%
Administration by other routes
o Reduced by incomplete absorption
o 1st pass metabolism
o distribution into other tissues before the drug enters the systemic circulation
Dependent on
o Extent of absorption
o 1st pass effect
o rate of absorption
o site of administration [e.g. topical drugs (ointments) which have very slow rate of
absorption]
Drugs are more absorbed in the small intestines because it has a larger surface area

TIME COURSE OF DRUG EFFECTS

1. IMMEDIATE EFFECT
Directly related to concentration
E.g. anticoagulants

2. DELAYED EFFECT
due to distributional delay
delayed expression of the physiologic substance needed for the effect

3. CUMULATIVE EFFECTS
Constant infusion
Aminoglycosides causes renal toxicity if given constantly
Intermittent dosing only

EXTRACTION
Fraction of the drug removed from the perfusing blood during passage to the organ
Measure of the elimination of the drug by that organ
Drugs with high hepatic extraction ration have large 1st pass effect

TARGET CONCENTRATION
Desired therapeutic effects are produced

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DOSAGE REGIMENS
Plan for drug administration over a period of time
Achievement of therapeutic levels of the drug in the body without exceeding the minimum toxic
concentration

MAINTENANCE DOSE
Dose needed to maintain a steady state of concentration
Maintain plasma concentration within a specified range over long periods of therapy
Enough drugs to replace eliminated drugs
Clearance is the most important parameter in defining rational drug dosage

LOADING DOSE
For drugs with long half-lives and longer time to reach a steady state
Given to promptly raise the concentration of the drug to the target concentration
If the therapeutic concentration must be achieved rapidly and the volume of distribution is
large, a large loading dose maybe needed at the onset of therapy
Volume of distribution (Vd) is important

THERAPEUTIC DRUG MONITORING

A. PHARMACOKINETIC VARIABLES
1. ABSORPTION
Compliance of patient is important
Variation in bioavailability are usually due to variation in metabolism during absorption

2. CLEARANCE
Most important parameter is designing dosage regimen
Creatinine clearance

3. VOLUME OF DISTRIBUTION
1. - Vd binding to plasma proteins
2. - Vd binding to tissues
3. - vd drug distributed to body waters, extracellular accumulation of body fluids

4. HALF LIFE
Clearance and volume of distribution

B. PHARMACODYNAMIC VARIABKES
1. MAXIMUM EFFECT
Emax
No more increase in effect end if the concentration is increasing

2. SENSITIVITY
Increased, exaggerated response to small doses

PLASMA BINDING PROTEINS

More highly protein bound drug will displace the less than protein bound drug
Inert
E.g. A 50% protein bound
B 50% protein bound
* A will displace b
More inbound drug to act on the receptor site
Acidic drugs bind to albumin
Basic drugs bind alpha 1 acid glycoprotein

Most appropriate time to measure drug concentration:

2 absorption is complete
2 hours after the dose

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STEADY STATE CONCENTRATION
average total amount of drug in the body does not change over multiple dosing intervals
Rate of drug input equals the rate of elimination
Condition in 3 to 4 t1/2 must elapse before checking drug blood concentration
THERAPEUTIC WINDOW
Safe opening between the MEC and the MTC of the drug
Use to determine the range of plasma levels that is acceptable when designing a dosage
regimen
Theophylline
MEC = 7-10 mg/L
MTC = 15-20 mg/l
Therapeutic window = 8 17mg/L
PEAK AND TROUGH CONCENTRATION
MEC determines the desired trough levels of a drug given intermittently
MTC determines the permissible peak plasma concentration
Maximum and minimum drug concentration in plasma or blood measured during cycles of
repeated dosing
Drugs given intermittently are in steady state of concentration

DRUG METABOLISM
Most drugs are lipid soluble and remain unionized or only partially ionized at physiologic pH
readily reabsorbed from the glomerular filtrate
Drugs bound to plasma protein: will not be filtered at the glomerulus, therefore these drugs
would have prolonged duration of action if termination of their action depends solely on renal
excretion.
Why is there a need for biotransformation?
o To terminate the action of drugs (the body transforms a drug to a less lipid-soluble,
less readily reabsorbed form
If not removed through renal excretion, an alternative process of inactivation called
METABOLISM

Sites of Drug Metabolism

1. Liver principal organ
2. GIT
3. Lungs
4. Skin
5. Kidneys

First pass effect greatly limits the bioavailability of orally administered drugs

TYPES OF METABOLIC REACTIONS

1. PHASE I
Non-synthetic reactions
Includes oxidation, reduction, deamination, hydrolysis
Converts the parent drud to a more polar (water soluble) metabolite by unmasking or
inserting a polar functional group such as OH, -SH, or NH2
Although they may be polar, however, they are not readily excreted and undergoes
subsequent reactions to form a highly polar conjugate

LIVER
Most important organ for drug metabolism
Smooth endoplasmic reticulum (SER) contains high concentration of PHASE 1 enzymes
Mixed function oxidases
Activity of these enzymes require
o NADPH (reducing agent)
o Molecular form of oxygen
o P450 reductase

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 Co-administration of certain agents may stimulate or inhibit the metabolism of many drugs.
Mechanisms include:
A. Enzyme induction
Induction usually results from increased synthesis of cytochrome P450-
dependent drug-oxidizing enzymes in the liver
Inductions results in an acceleration of substrate metabolism and usually in a
decrease in a pharmacologic action of the inducers and also of co-administered
drugs
In the case of drugs metabolically transformed to reactive metabolites, enzyme
induction may exacerbate metabolite-mediated toxicity
Many isozymes of P450 family exists [Table 4-2] and inducers increase
subgroups of isozymes. Common inducers of isozymes and drugs whose
metabolism is increased
Several days are usually required to reach maximum induction and similar
amount of time is required to regress after withdrawing the inducers

B. Enzyme inhibition
Inhibition of cytochrome P450 enzyme activity by certain drugs.
Suicide inhibitors are drugs that are metabolized to products which irreversibly
inhibit the metabolizing organ
Metabolism may be also decreased by reduction in blood flow to the
metabolizing organ

2. PHASE II
Synthetic reactions
Reactions that increase water solubility by conjugation of the drug molecule with a
polar moiety such as glucoronate or sulfate
Endogenous substrate is conjugated to the parent drug to make it more polar
TYPES of Metabolic Reactions
1. Glucoronidation - glucoronic acid
2. Acetylation acetyl CoA
3. Sulfation
4. Methylation
5. Glycine conjugation glycine
6. Glutathione conjugation
7. H2O conjugation

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PHASE I PHASE II (most drugs)
PHASE II PHASE I (other drugs)
Isoniazid
o Acetylation hydrolysis
OTHER DRUGS METABOLIZED
Gastric acid
o Penicillin must be given 2 hours before meals id given through the oral route
Gastric and digestive enzymes
o Insulin
Intestinal wall enzymes
o Epinephrine

TOXIC METABOLISM
Drug metabolism is not synonymous with drug inactivation because some drugs are
converted to active products by metabolism
Mechanism by which the body terminates the action of some drugs
In some cases, it serves to activate prodrugs
1. Active inactive (readily excreted by the kidneys)
2. Active active metabolites
3. Inactive active (Prodrug)

Ac-glucoronide Ac Ac-sulfate

Determinants of Biotransformation Rate

Dose and frequency of administration required to achieve effective therapeutic blood and tissue
levels vary because of individual differences in drug distribution and rates of drug metabolism
and elimination
A. Nature of the drug itself
B. Genetic Factors
1. Hydrolysis of Esters
Succinylcholine is an ester metabolized by cholinesterase
(pseudocholinesterase or butyrycholinesterase)
Normal:
muscle paralysis
rapid metabolism
short duration of action (5 mins)

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 Abnormal:
abnormal enzymes form
slow metabolism
muscle paralysis may last many hours

2. Acetylation of Amines
e.g. Isoniazid, Procainamide, Warfarin inactivated by N-acetylation
Abnormal:
Individuals deficient in acetylation capacity (slow acetylators) may have
prolonged or toxic responses to normal doses of these drugs
Autosomal recessive gene

3. Oxidation
Dextrometorphan, metoprolol and some tricyclic antidepressants
Oxidation by P450 isoenzymes are genetically predetermined

C. Individual Differences
1. Diet and environmental factors
Charcoal-broiled food inhibits the effect of the drug
Grapefruit juice increases the amount of drug in the body
Cigarette smoking
Pesticides
2. Age and sex
Very young and very old: increased toxicity of drugs
o Differences in absorption, distribution, elimination
o Reduced availability of essential endogenous co-factors
Male > Females

D. Diseases affecting drug metabolism

1. Acute or chronic liver disease
Impair hepatic drug metabolizing enzymes (microsomal oxidases)
Reduce drug elimination, high effects of drug delivery to the liver for metabolism
2. Pulmonary disease
Impaired hydrolysis
3. Hypothyroidism
Decreased metabolism, high half-life
4. Hyperthyroidism
Increased metabolism, decreased half-life

E. Drug-Drug Interaction during Metabolism

1. Lipophilic drugs are retained
2. Enzyme induction
Increase rate of synthesis of the enzyme
Drug may induce enzymes resulting to enhanced metabolism of co-
administered drugs (warfarin if taking with barbiturates)
Reduce the rate of degradation of the enzyme
Inhibitors inactive enzymes and result in impairment of their own
metabolism and other co-substrates
A common metabolizing enzyme is irreversibly inhibited by
simulataneously administered drug
Enzyme inducers
Phenobarbital
Carbamazepine + drug = decreased effects
Phenytoin
Rifampicin

3. Enzyme inhibition
Inhibit Cytochrome P450
Metabolism of the drug is diminished
Increase effect of the drug
Enzyme inhibitors
Amiodarone
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 Cimetidine
Ketoconazole + drug = increased effect
Ritonavir
Furanocoumarin

4. Altered absorption
Cholestyramine inhibits the effect of digoxin when combined with it
5. Altered metabolism
Affects drug action
6. Altered plasma binding protein
7. Altered excretion
Probenecid inhibits the secretion of acids
Penicillin inhibits the excretion of probenecid

F. Interaction between drugs and endogenous compounds

1. Different drugs may compete for the same endogenous substrates (for conjugation) and
the faster-reacting drug may deplete the endogenous substrates levels and impair the
slow-reacting drug metabolism (if the slow-reacting has a narrow margin of safety,
pronouncement of its effects and toxic results, may result)

DRUG INTERACTION
1. ADDITIVE
1+1=2
Response elicited by combined drugs is equal to the combined response of the
individual drugs
Sedative + ethanol
2. SYNERGISTIC
1+1=3
Response elicited by combined drugs is greater than the combined responses of
each individual
Penicillin G removes the cell wall
Gentamicin inhibits production of protein
3. POTENTIATION
0+1=2
Drug which has no effect enhances the effect of the second drug
Cimetidine + anticoagulant (enhances the anticoagulation)
4. ANTAGONISM
1+1=0
Drug inhibits the effect of another drug
Heparin + protamine

DRUG DISCOVERY
New drug candidates are identified through:
1. Chemical modification of a known molecule Thiazide
2. Random screening for biologic activity of large numbers of natural products, banks of
previously discovered chemical entities or large libraries of peptides, nucleic acids or other
organic molecules Illiosone
3. Rational drug design based on an understanding of biologic mechanisms and chemical
structures Histamine receptors
4. Biotechnology and cloning using genes to produce larger peptides and proteins insertion
into yeasts, bacteria, insulin, hormones, vaccines
5. Identification or clarification of a new drug target
6. Combination of known drug to obtain new therapeutic use

DRUG SCREENING
Involves a sequence of iteration, experimentation and characterization
A variety of biologic assays at the molecular, cellular, organ and whole animal levels are used
to define the activity and selectivity of a drug
Why screen drugs?
1. To attain the pharmacologic goal antibiotics tested against microorganisms
2. To establish selectivity of a drug binding affinity of drugs to receptors; 2nd messengers

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 3. To determine pharmacologic activity and selectivity of new compounds (drugs) in
comparison with reference compounds
4. To demonstrate suspected toxic effects
5. To disclose previously unsuspected therapeutic action

Examples:
Anti-HPN drugs can lower BP, other effect of the drug
Duration of action and efficacy comparing different routes of drug absorption
Possible adverse effects on other major organs
Tolerance, physical dependence, abuse potential

DRUG EVALUATION DEFINITIONS

1. No-effect dose
The maximum dose at which a specified toxic effect is not seen
2. Minimum lethal dose
The dose that is observed to kill any experimental animal
3. Median lethal dose
The dose that kills approximately 50% of the experimental animals
4. Placebo
A dummy medication made up of inert material with exactly the same physical
appearance, odor, consistency, etc. as the active dosage form
5. Positive Control
A known standard therapy used to evaluate the safety and efficacy of a drug in relation
to others available, used along with a placebo
6. Teratogenic
Having an effect on the prenatal development of an organism resulting in abnormal
structure and function; not generally inheritable
7. Mutagenic
Having an effect on the inheritable characteristics of all organism
8. Carcinogenic
Having an effect of inducing malignant characteristic
9. Orphan drugs
Drugs for rare disease
Can be difficult to research, develop and market
Basic research in pathophysiology and mechanism of rare diseases receives very little
funding in both academic and industrial settings, so recognize rational targets for drug
action maybe few
Target population is relatively small
10. Single Blind Study
a clinical trial in which investigators know which subject are receiving active drug and
which are receiving placebo
11. Double Blind Study
A clinical trial in which neither subjects are receiving placebo; the code to a third party
12. Pharmacologic Profile
A description of all the pharmacologic effects of a drug (e.g. effect on BP, GI activity,
respiration, renal function, endocrine functions, CNS)

LIMITATIONS of PRE CLINICAL TESTING

1. Toxicity testing is time consuming and expensive (2 to 6 years to collect and analyze data
on toxicity)
2. Large numbers of animals are used to obtain pre-clinical data
3. Extrapolation of toxicity data from animals to humans is not completely reliable
4. For statistical reasons, rare adverse effects are unlikely to be detected

CONFOUNDING FACTORS IN CLINICAL TRIALS

The variable natural history of most diseases
1. Disease tend to wax and wane in severity, some disappear spontaneously
Take into account the natural history of disease therefore evaluate as large population and
a sufficient period of time
To protect against disease fluctuations use a Crossover Design (alternate periods of
administration of test drug placebo preparation and standard treatment)

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 2. The presence of other disease and risk factor
Known and unknown disease and risk factors may influence the results of a clinical study
Obtain accurate medical and pharmacological history
3. Subject and Observer Bias
Placebo response positive response of patients involving physiological changes and
changes in subjective complaints

ANIMAL TESTING
Required before human studies begin
Amount of testing depends on proposed use and urgency of the application of drugs
Occasional non-systemic use less extensive testing
Chronic systemic disease more extensive testing
Anti-cancer and AIDS because of urgency requires less evidence of safety than those
used in less threatening diseases
Includes: general screening tests for pharmacologic effects, hepatic and renal function
monitoring, blood and vine test of reproduction effects, carcinogenicity

PRECLINICAL SAFETY AND TESTING

The amount of animal testing required before human studies begin is a function of the
proposed use and urgency of the application
All drugs are toxic at some dose
No chemical/drug can be certified as completely safe
Candidates drugs that survive the initial screening and profiling producers must be evaluated
for potential risks before and during testing

GOALS OF PRE-CLINICAL TOXICITY STUDIES

1. Identifying potential human toxicities
2. Designates to further define the toxic mechanisms
3. Predicts the specific and the most relevant toxicities to be motivated in clinical trials

SAFETY TEST
1. ACUTE TOXICITY
Required for all drugs
Acute dose that is lethal in approximately 50% of animals and maximum tolerated dose
Involves two species, two routes, single dose
2. SUBACUTE
Drugs intended for chronic use
3 doses, 2 species, 2-4 weeks
3. CHRONIC TOXICITY
2 and 3 tests are conducted for at least the length of time proposed for human
2 species, 6-24 months
4. REPRODUCTIVE TOXICITY
The study of the fertility effects of he candidate drug and its teratogenic and mutagenic
effects
Effects on animal mating behavior, reproduction, parturition, birth defects, post natal
development
5. MUTAGENIC POTENTIAL
Effects on genetic stability
Ames test uses a special strain of salmonella bacteria medium, loss of this
dependence during exposure to the test signals mutation
Dominant lethal test carried out on male mice before mating. Abnormalities in the
male germ cells results to loss of embryos, deformed fetuses
6. CARCINOGENIC POTENTIAL
Drugs intended for prolonged periods of use
2 years, 2 species
7. INVESTIGATIVE TOXICITY
Determines sequence and mechanism of toxic action
Develop new methods for assessing toxicity

PHARMACOLOGY NOTES ALEE ABAD EMT 2011

CLINICAL TRIALS
A. PHASE I
Consist of careful evaluation of the dose-response relationship in a small number of healthy
human volunteers (25-50)
Non-blind or open trials
Measurement of absorption, half-life and metabolism are done
B. PHASE II
Evaluation of a drug in a moderate number of patients (100-300) with the target disease to
determine its efficacy
Single-blind or double-blind study
Includes a placebo drug, positive control drug and investigational agent
Carefully controlled conditions and very closely monitored
C. PHASE III
Large design involving many patients (1000 5000) or more in many centers and many
clinicians who are using the drug in the manner proposed for its general use
Placebo, double-blind crossover design
Uses information from phase 1-2
Explore the spectrum of beneficial actions of the new drug, compare with older therapies
Discover toxicities and immune responses
Difficult to execute design and expensive
Permission to market approval
D. PHASE IV
Represents post-marketing surveillance phase of evaluation after approval
Toxicities that occur very infrequently will be detected and reported early enough to
prevent a major therapeutic disasters
Complete reporting of toxicities
Not rigidly regulated by the Bureau of Food and Drugs (BFAD)

ADVERSE DRUG REACTION

Drugs can be remarkably beneficial, lengthens life and improves its quality by reducing
symptoms and improving well-being
However, all drugs have adverse effects and carry the potential of causing injury, even if used
properly
Incidence:
o 65% chart review, 45% computer review, 4% voluntary reporting
o 10 per 100 admission (true incidence)
o ADE are expensive to the health care system

DEFINITION OF TERMS
1. ADVERSE DRUG EVENT (ADE)
An injury resulting from medical intervention related to a drug
E.g. errors in giving the medication
2 types
o Preventable
o Non-preventable

2. ADVERSE DRUG REACTION (ADR)

WHO definition:
o an effect which is noxious and unintended, and which occurs at doses used in
man for prophylaxis, diagnosis or therapy
restrictive because it only considers incidents where use of the drug is appropriate,
excluding the many adverse events caused by errors that are by definition preventable
Serious or unexpected ADR should be reported to the drug manufacturer and to the
BFAD

3. MEDICAL ERROR
an error in ordering, transcribing, dispensing, or administering a medication regardless
of whether an injury occurred or whether the potential for injury was present Bates,
1995
4. POTENTIAL ADE
Medication errors that do not result in harm

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 5. PREVENTABLE ADE
Medication errors that resulted to injuries

RISK FACTORS FOR ADVERSE DRUG EVENTS

1. AGE
Neonates: enzymes for drug metabolism and elimination have not been functional and
clearance is less than adults
Elderly: changes in liver and kidney function may decrease drug elimination
2. GENDER
Female > Male (50% higher ADE)
Definite periods during a womans lifetime when there is alteration of the
pharmacokinetics of drugs:
o Menarche
o Pregnancy and delivery
o Lactation
o Menopause
3. Past History of Reactions to Medications
4. History of Allergic Diseases
Genetically predetermined propensity to form larger amount of IgE
5. Genetic Factors
Sex-linked G6PD
6. Route of administration

TYPES OF ADVERSE DRUG REACTIONS

1. TYPE A (Augmented)
Exaggerated extensions of the pharmacological activity of the primary drug or its
metabolites
Dose-dependent, predictable
Subtypes:
o Extension effect
reaction is extension of therapeutic effect
Remedy: dose adjustment
E.g. insulin hypoglycemia
o Adverse effect
Reaction is unrelated to the goal of the therapy
Remedy: change drug
E.g. gentamicin nephrotoxicity
E.g. complete heart block induced by a beta-blocker, fatal hepatic necrosis with
acetaminophen overdose
2. TYPE B (Bizarre)
Idiosyncratic reactions (usually immunologic or allergic reactions)
Reaction is unrelated to drugs known pharmacologic action
Refers to totally abnormal effect
Host-dependent
Independent of dose and route of administration
Difficult to predict or unpredictable
E.g. deficiency of G6PDase
3. TYPE C (Continuous)
Long term effects are related to dose and duration of treatment
E.g. ethambutamol optic neuropathy
4. TYPE D (Delayed)
E.g. carcinogenesis and teratogenesis
5. TYPE E (Ending of Use)
Adverse drug withdrawal events (ADWE)
A consequence of discontinuing the use of a drug
E.g. withdrawal symptoms after narcotic analgesia, sympathetic overactivity and
severe hypertension after clonidine therapy, adrenal insufficiency after corticosteroid
therapy, delirium, confusion, agitation, seizures after CNS depressants
6. TYPE F (Failure of Efficacy)
E.g. counterfeit medicines, drug interaction

PHARMACOLOGY NOTES ALEE ABAD EMT 2011

DRUG ALLERGIES (Hypersensitivity)
Extremely varied in their presentation
Can be life-threatening
Recognized as non-self and induce an immune response
Pathophysiology
o The drug or its metabolites are chemically active or activated into reactive status in
the body by biotransformation
o The active drug binds to an endogenous carrier (conjugate)
o The drug-conjugate (hapten) becomes an immunogen and elicits an antibody or
cellular response resulting to tissue injury

TYPES OF HYPERSENSITIVITY REACTIONS

1. Type I Hypersensitivity Reactions
Immediate type, anaphylactic, or IgE-mediated
Result from release of pharmacologically active substances such as histamine,
leukotrienes, prostaglandins, platelet-activating factor and eosinophilic chemotactic
factor from sensitized basophils and mast cells after contact with specific antigen
Clinical examples include systemic anaphylaxis, reactions to stinging insects, allergic
extrinsic asthma, seasonal allergic rhinitis, urticaria, reactions to foods and drugs
2. Type II hypersensitivity reactions
Cytotoxic hypersensitivity, antibody-dependent cytotoxicity, cytolytic complement-
dependent cytotoxicity
Clinical examples include Coombs-positive hemolytic anemia, antibody-induced
thrombocytopenia, leukopenia, pemphigus, pemphigoid, Goodpastures syndrome,
pernicious anemia
3. Type III Hypersensitivity reactions
Immune complex deposition in vessels or tissues
Clinical conditions include Arthus reaction, serum sickness due to serum, drugs or viral
hepatitis antigen, SLE, rheumatoid arthritis, polyarteritis, chronic MPGN
4. Type IV Hypersensitivity reactions
Cell-mediated, delayed or tuberculin type hypersensitivity reaction
Caused by sensitized lymphocytes (T cells) after contact with antigen
Clinical example include contact dermatitis, allograft rejection, drug sensitivity and
thyroiditis

Penicillin allergy
Occurs in 2% of the population
Reactions could be immediate (with few minutes), accelerated (within hours) or late
(days after intake)
Pathogenesis is antibody production

Radiographic Contrast Media

1. Release of histamine and serotonin and activation of a cascade of systems including
complement, fibrolysin, and kinins
2. Increased in patients with history of allergies

SELECTED ADVERSE EFFECTS ON SELECTED ORGAN SYSTEMS

1. Dermatologic toxicity
Photosensitivity, exfoliative dermatitis, Stevens-Johnson syndrome, cutaneous
necrotizing vasculitis, redness, scaling, thickening of the skin
Penicillin, Sulfonamide, Phenothiazines, Tetracycline, Bisacodyl, Phenolphtalein

2. Ototoxicity
Dizziness, tinnitus, hearing loss
Aminoglycosides (Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin,
Tobramycin)
Macrolide (Vancomycin, Erythromycin)
Salicylates
Quinidine, Quinine, Chloroquine
Cisplatin

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 3. Ocular toxicity
Photophobia, snowy vision, blurred vision, disturbance of color vision, scotomata,
degeneration of the retina, cornea, sclera, lens, optic nerve, extraocular muscles
Digitalis glycosides
Phenothiazines
Chloroquine, Hydrochloroquine, Quinine
Scopolamine
Hydrochlorothiazide
Tricyclic Antidepressants

4. Nephrotoxicity
Decrease urine output, weight gain, increase BUN and creatinine, hyperkalemia, acute
intestinal nephritis, acute renal failure
NSAIDs, Penicillin, Cephalosporin, Aminoglycoside, Amphotericin B, Vancomycin,
Cisplatin, Cyclosporine, Radiocontact dye, Methotrexate, Sulfonamide, Acyclovir,
Allopurinol, Acetazolamide

5. Hematologic toxicity
Decrease platelet aggregation, bone marrow suppression, aplastic anemia,
thrombocytopenia, agranulocytosis
Chloramphenicol, Phenylbutazone, Sulfonamide, Gold, Inhaled solvents (benzene),
Organic chemicals, Insecticides, Heparin

6. Cardiotoxicity
ECG changes, dysarhythmia, myocarditis, transient cardiac dysfunction, congestive
heart failure
Anthracycline, Doxorubricin, Cyclophosphamide, Phenothiazine, Tricyclic
antidepressants, Lithium

7. Hepatotoxicity
Abnormal liver function, cholestasis, cirrhosis, hepatoma
Inorganic iron, Acetaminophen, Dietary supplements, Botanicals

8. Pulmonary toxicity
Asthma, Pulmonary infiltrates, Pulmonary fibrosis
Ampicillin, Carbamazepine, Cromolyn, Isoniazid, Penicillin, Phenytoin, Sulfonamides,
Oral contraceptives

PHARMACOLOGY NOTES ALEE ABAD EMT 2011