Pharmacokinetics

Cell membrane
BASIC MECHANISMS OF MEMBRANE TRANSPORT

 Passive diffusion
 Facilitated diffusion
 Active transport. Active transport can be further
subdivided into:
- primary active transport
-secondary active transport
Factors affecting absorption of drugs
Dissolution and disintegration
Ionization
In the stomach, drugs that are weak acids (such
as aspirin) will be present mainly in their non-
ionic form, and weak bases will be in their ionic
form.
Since non-ionic species diffuse more readily
through cell membranes, weak acids will have a
higher absorption in the highly-acidic stomach.
Ionization …
However, the reverse is true in the basic environment
of the intestines-- weak bases (such as caffeine) will
diffuse more readily since they will be non-ionic.
Factors …
Vascularity of the absorpting surface
Surface area of the absorpting surface
Route of drug administration
Concentration of drug molecules
Aqueous solubility of drugs
 Bioavailability
It is defined as the fraction of unchanged
drug reaching the systemic circulation by
any route
 Volume of distribution
It the measure of the apparent space in the
body available to contain the drug
 Vd = amount of drug in the
body/concentration of the drug (l/kg)
 The volume of distribution, like
clearance, may be defined with respect to
blood, plasma, or water (unbound drug),
depending on the concentration used
 Factors governing volume of drug
distribution
Lipid:water partition coefficient of the drug
Pka value of the drug
Degree of plasma protein binding
Affinity for different tissues
fat:lean body mass ratio
Diseases like CHF, uraemia, cirrhosis
 Drugs bound to plasma protein
To albumin(mainly acidic drugs)
barbiturates, benzodiazepines, NSAIDs,
valporic acid, phenytoin, penicillins,
sulfonamides, tetracyclines,warfarin
To alpha 1 acid glycoprotein(mainly
basic drugs)
b- blockers, bupivacaine, lignocaine,
methadone, imipramine, prazocine,
verapamil
 Biotransformation (metabolism)

 chemical alteration of the drug in the body

The nonpolar (lipid soluble) drug becomes

polar(water soluble) so that they are not
reabsorbed in the renal tubules and are
excreted from the kidney
 Biotransformation may lead to the
following

Inactivation

Active metabolite from an active drug

Activation of inactive drug

 Sites of metabolism
Liver: many drugs
Lungs: prostanoids
Intestines: salbutamol, tyramines
Plasma: hydrolysis of suxamethonium by
plasma cholinesterase
 Types of metabolism
Phase one reactions:
 catabolic(oxidation, reduction, hydrolysis)
Products are chemically reactive,
sometimes more toxic and carcinogenic
than parent compound
Monoxygenase enzymes are
involved,eg.cytochrome P450
monoxygenase system
Occurs in endoplasmic reticulum
Phase 2 reactions
Mainly synthetic (anabolic) which involves
conjugation(glucoronidation), methylation,
sulfation etc

It results in inactive and easily excretable

products

Mainly occurs in cytosol

First pass (presystemic) metabolism
It is the metabolism of a drug during its
passage from the site of absorption into the
systemic circulation. Liver and intestines
are common sites of first pass metabolism
Examples: aspirin, glyceral trinitrate,
isosorbide dinitrate, levodopa, lidocaine,
morphine, propranolol, salbutamol,
verapamil
 Biological Half life(T1/2)
it is the time required to change the
amount of drug in the body by one half
during elimination(or during constant
infusion)
 T1/2 = 0.7+volume of
distribution/clearance
Elimination half-life (t1/2) is directly
proportional to Vd and inversely proportional
to CL

With repeated dosage or sustained delivery

of a drug, the plasma concentration
approaches a steady value within three to five
plasma half-lives
 Clearance
It is the measure of the ability of the body to
eliminate the drug

 Clearance=Rate of elimination/concentration

 Clearance may be defined with respect to

blood, plasma, or unbound in water, depending
on the concentration measured

 Clearance systemic=CL Renal + CL liver + CL

other
First order (exponential) kinetics
The rate of elimination is directly proportional
to drug concentration, clearance remains
constant; or a constant fraction of the drug
present in the body is eliminated in unit time
Zero order (linear) kinetics
The rate of elimination remains constant
irrespective of drug concentration , clearance
decreases with increase in concentration; or a
constant amount of the drug is eliminated in
unit times
Elimination of drugs by the kidney
 Most drugs, unless highly bound to plasma
protein, cross the glomerular filter freely.
Many drugs, especially weak acids and
weak bases, are actively secreted into the
renal tubule and thus more rapidly
excreted.
Lipid-soluble drugs are passively
reabsorbed by diffusion across the tubule,
so are not efficiently excreted in the urine.
 Elimination ….
Because of pH partition, weak acids are
more rapidly excreted in alkaline urine, and
vice versa

Several important drugs are removed

predominantly by renal excretion, and are
liable to cause toxicity in elderly persons
and patients with renal disease.
 Bioequivalence
Drug products are considered to be
pharmaceutical equivalents if:
 they contain the same active ingredients
 identical in strength or concentration,
dosage form, and route of administration.
Two pharmaceutically equivalent drug
products are considered to be bioequivalent
when:
The rates and extents of bioavailability of the
active ingredient in the two products are not
significantly different under suitable test
conditions