1. By : Dr. Roshini Murugupillai
Pharmacokinetics - I
By :
Dr. Roshini Murugupillai

2. Pharmacokinetics
It is the quantitative study of drug movement into the body and subsequent alteration of the drug by the body
Includes :
Absorption
Distribution
Biotransformation
Excretion
(It is what the body does to the drug)

3. Absorption
Absorption is the movement of drug from the site of administration in to the circulation
Except when given intravenous route, drug has to cross biological membranes to get in to the circulation
Drugs are transported across the membranes by :
Passive diffusion
Filtration
Specialized transport

4. Factors affecting drug absorption
Aqueous solubility
Rate of dissolution governs the rate of absorption
A drug given as solution is absorbed faster than when the same is given in solid form
Concentration
Passive transport (simple diffusion)depends on the concentration gradient
Area of absorbing surface
Larger it is faster is the absorption
Vascularity of the absorbing surface
Blood circulation maintains the concentration gradient across the membrane
Increased blood flow hastens drug absorption

5. Route of administration
Oral – acidic pH, presence of food, digestive enzymes, luminal effect ( interaction of concurrently ingested drugs), first pass metabolism affects the absorption
S.C & I.M – drug is deposited directly in the vicinity of capillaries. Lipid soluble drugs pass readily across endothelium. Absorption from s.c is slower than i.m.
vasoconstrictors administered with the drug retard absorption
Topical – systemic absorption of topical application primarily depends on lipid solubility of drugs. Only few drugs significantly penetrate the intact skin

6. Bioavailability
It is the measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.
Refers to the rate of absorption of a drug from a dosage form determined by :
Concentration – time curve in blood
Excretion in urine
Bioavailability of drug injected i.v is 100%
It’s frequently lower after oral ingestion
Incomplete bioavailability after s.c/i.m may occur due to local binding of the drug

7. Distribution
Once the drug reaches the blood circulation, it is distributed to other tissues; concentration gradient in the direction of plasma to tissue
Movement of drugs proceeds until an equilibrium is reached between the unbound drug in the plasma & tissues.
Subsequently there is a parallel decline in both due to excretion

8. Apparent volume of distribution (V)
Blood
Total amount of drug in the body = 1000mg
Plasma drug concentration = 50 mg/L
Hence,
V = 1000/50
= 20 L
Drugs extensively bound to plasma proteins are largely restricted to the vascular compartment and have low values of V E.g. Warfarin (99% bound) V=0.1 L/kg
Drugs sequestered in other tissues may have V larger than total body water and their plasma concentration is low. E.g. Digoxin
In case of poisoning, drugs with large volume of distribution are not easily removed by haemodialysis

9. 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 congestive heart failure, uremia, cirrhosis

10. Redistribution
Highly lipid soluble drugs administered i.v/inhalation initially get distributed to organs with high blood flow
E.g. brain, heart, kidney
Later, less vascular but more bulky tissues take up the drug. E.g. muscle, fat
Greater the lipid solubility of the drug, faster is its redistribution
Therapeutic importance : if the site of action of a drug is one of high vascular area, the action of the drug will be terminated early at the site due to its redistribution
E.g. Thiopentone

11. Blood-brain barrier & therapeutics
Capillary endothelial cells in brain have tight junctions & an investment of neural tissues. Together they form the BBB
This barrier is lipoidal and limit the entry of non-lipid soluble drugs e.g. Streptomycin
Only lipid soluble drugs therefore are able to penetrate and have action on the CNS
Inflammation of meninges or brain increases permeability of these barriers
BBB is deficient at the CTZ in the medulla oblongata & few other sites