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

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)

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

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

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

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

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

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

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

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

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