Slide - lecture N1

Routes of drug administration.

Notion about pharmacokinetics.
Absorption, distribution; biological barriers,
chemical transformations (biotransformation,
metabolism) of drugs
 Pharmacology
isthe science that deals with drugs.
It consists of detailed study of drugs,
particularly their action on living
organisms. The actions may be
beneficial or harmful.
 Drug and medicine
Drug is any substance that is or intended to
be used to modify or explore physiological
systems or pathological states for the benefit
of the recipent.
MEDICINE is any drug which has a definite
form, dose level and is therapeutically used for
the treatment of disease in living subject.
 Sources of drugs
Animal source: e.g., insulin, thyroid hormones
Plant source: e.g., morphine, reserpine, digoxin
Micro-organisms: e.g. liquid paraffin, kaolin
Synthetic: e.g. aspirin, sulfonamides
Drugs produced by genetic engineering (DNA
recombinant technology): e.g. human insulin, human
growth hormone
 Routes of drug administration
Intranasal
Inhalational
Sublingual
Per os (oral)
Transdermal
Parenteral:
Intravenous I.V.
Intramuscular I.M.
Subcutaneous S.C.
Intradermal, Intraarterial
Intrathecal, Intraperitoneal
Intraarticular, Intracardiac
Topical (application of drugs to skin
and mucous membrane for local
effects
Rectal
 Release from the drug form
Rate (speed)
Solution
Suspension
Capsule
Tablet
Tablet oating

Controlled - Release
tablet
 Enteric coated tablets
These tablets are coated with materials
that resist the action of gastric acid juice
and disintegrate only in alkaline pH of the
small intestine. They are coated with
cellulose acetate-phthalate, gluten and
anionic copolymers of methacrylic acid
and its esters
 Sustained (Controlled) Release drug forms

ADVANTAGES
Decrease freguency rate and increase
convenience for the patient
High stability of drug concentration in
plasma
High stability of the pharmacodynamic
processes
 Controlled Release drug forms
Types
ral forms (capsule, tablets)
Transdermal (cutaneous) drug delivery system
nitroglycerin, clonidine, fentanyl patches,
ointments, plaster
Parenteral forms (salts, ethers, suspensions,
pellet implantation) the SC and IM injection of
drugs in insoluble form (procaine penicillin,
lente insulin) or as oily solution
 Pharmacokinetics (PK) deals with
what the body does to the drug

Basic pharmacokinetic processes:

Release from drug form
Absorption
Distribution
Metabolism
Excretion
 ABSORPTION
is the movement of drug from its site of administration
into the systemic circulation.
Mechanisms
I. Passive transport
Passive diffusion e.g. aspirin, alcohol
Facilitated diffusion glucose, vitamin B12
II. Specialized transport
Active transport e.g. L-dopa, a-methyldopa in GIT;
penicillin in renal tubules (hydrophilic polar)
Filtration through pores
Pinocytosis, e.g. proteins and other macromolecules,
iron
 Mechanisms of absorption
Passive diffusion
Most common (without energy)

More easily lipophilic non-polar drugs

Small intestine (predominantly)

Large intestine and rectum (in addition)
 Factors affecting drug absorption
in the GIT
I. Factors related to drugs
Molecular size, shape, solubility at the site of its
absorption, degree of ionization
Rate of tablet disintegration
Dissolution rate
Presence of admixtures in the composition of
tablet or coating shell
Metabolism of drug by intestinal microflora
 Factors affecting drug absorption
in the GIT

II. Factors related to patient

in stomach and intestine
Time of stomach emptying
Time of food passage through gut
GIT surface area
GIT diseases
Blood circulation in gut
 Factors affecting drug absorption
in the GIT

III. Presence in GIT other substances

medicines
ions
food
Drugs that absorption is worsened on
change in stomach

Salicylates Codeine
Phenylbutazone Quinidine
Sulfonamides Rifampicin
Barbiturates Erythromycin
Drugs that are taken during meal

Hydrochlorothiazide
Griseofulvine
Propranolol
Metoprolol
Cefuroxim
Drugs that are taken 1 hour before meal

Destroyed in Combine with food

Ampicillin Tetracycline
Erythromycin
Erythromycin
Fusidic acid
Sulfonamides
Captopril
Fe preparations
 Drugs that are taken after meal

NSAIDs (course intake)

Glucocorticosteroids
Reserpine
Theophilline, Aminophilline
Potassium preparations
 DISTRIBUTION OF DRUGS

Stage 1
Depends on blood flow:
Entrance to highly vascularized organs (heart, liver, muscles)
Stage 2
Depends on protein binding.
Basic connected proteins:
- plasma albumin (for acidic drugs), e.g. SAs
- alpha 1 - acid glycoprotein (basic drugs), e.g. lidocaine
 Factors affecting distribution
I. Body properties (barriers)
- blood-brain
- blood ophthalmological (blood-aqueous)
- capsule of prostate
- cell membranes
II. Drug properties
- lipid solubility
III. Drug dose
Distribution of fluoroquinolones
Ciprofloxacin, floxacin
High concentrations in majority organs,
tissues and media
Norfloxacin
High concentrations in GIT, urine, prostate
 Reservoirs of drugs in the body
Cells Macrolides
Adipose tissues Amiodarone,
diazepam, thiopentone
Bones Tetracyclines, lead
Transcellular
reservoirs (GIT, liquor)
Rate of drugs protein binding
Drug % bounded drug
Warfarin 99,5
Diazepam 99
Phenytoin 96
Quinidine 71
Lidocaine 51
Digoxin 25
Gentamycin 3
Atenolol 0
 Metabolism
Mtabolism is the process of chemical
alteration of drugs in the body.
hase I reactions (non-synthetic):
- xidation
- reduction
- hydrolysis
- combination of processes
 Metabolism
Phase II reactions (synthetic, conjugation
with:)
- Glucuronic acid
- cetic acid
- Sulphuric acid
- Glycine
- Glutathione
 BIOTRANSFORMATION of drugs

Drug Some drugs

avoid phase 1
phase 1
xidation, Inactive
reduction drugs
and (or) hydrolysis

Phase 2
Products of
conjugation

Drug inactivated
or, rarely, activated
Individual variation of metabolism

- Genetic factors
- Age (newborns, elderly)
- Concomitant diseases (liver!)
- Influence of other drugs
- Saturation of metabolizing enzymes (alcohol)
 Presystemic metabolism
(first-passmetabolism)
Drug metabolism in small intestine wall and liver
after absorption from GIT before reaching systemic
circulation

It allows to access the intensity of drug metabolism

in the gut wall, liver and select its dose depending
on liver function
Sublingual, rectal, IV and transdermal routes avoid
first pass metabolism in liver
 First-pass metabolism
Liver
Passage
through liver
metabolism

Direct
Absorption hit into
in small intestine systemic
circulation
Drug intake
per os

Organs and tissues

 Drugs having therapeutically active
metabolites

Drug Metabolite
________________________________
Aspirin* ---------------> acetylsalicylic acid
mitriptyline Nortriptyline
Codeine Morphine
Phenacetin* ------------> Paracetamol
Prednisone*-------------> Prednisolone
Cefotaxime Desacetylcefotaxime
___________________________________________

*Prodrugs - preparations, that are initially non-active, but in

the body they form active metabolites.
 EXCRETION
is the process by which a drug or metabolite is
eliminated (removed) from the body without
change of chemical structure.
Kidneys
Liver/bile Enterohepatic
Intestine circulation
Saliva (theophylline, phenytoin, rifampin,
iodides,metronidazole)
Skin
Tears (rifampin, minocycline)
Breast milk (erythromycin, penicillin, morphine, pethidine,
TCADs, oral anticoagulants, chloramphenicol, tetracycline,
opiates, chlorpromazine, SAs, antithyroid drugs)
Exhaled air
Drugs which excretion is increased if
urine change

Acidic Basic
Aminoglycosides Barbiturates
Codeine Salicylates
Morphine Phenylbutazone
Rifampicin Penicillins
Quinidine Sulfonamides
Chloroquine Tetracyclines
 Processes involved in drug excretion
through the kidneys
1. Glomerular filtration: e.g, all drugs except
macromolecular substances like heparin and dextran or
highly protein bound drugs, e.g., phenylbutazone. Lipid
soluble are reabsorbed from the tubules after filtration
2. Active carrier mediated tubular secretion (the most
rapid mechanism) e.g. penicillin, cephalosporin
3. Passive diffusion (pH dependent) e.g. aspirin,
barbiturates, amphetamine. Changing the pH to alkaline
side with sodium bicarbonate, excretion of weak acids like
aspirin, phenobarbitone is increased and similarly by
changing the pH to acidic side by ammonium chloride or
ascorbic acid, excretion of weak bases like amphetamine is
increased
 First-order kinetics
Process by which a constant percentage of
substrate is metabolized per unit time (after
administration of drug by any route, except IV).
Ex.: 10% of a certain drug (concentration 100
mg/dL) is eliminated every 2 hours; 2 hours
later the concentration will be 90 mg/dL; in 4
hours it will be 81 mg/dL and so on.
 Zero-order kinetics
Process by which a constant amount of drug
is metabolized per unit of time regardless of
the drug concentration (after IV
administration).
Ex.: if a drug concentration is 100 mg/dL and
the body can remove 5 mg/dL every hour,
then 1 hour later the concentration will be 95
mg/dL; 2 hours later it will be 90 mg/dL and
so on.