Pharmacokinetics is “what the body does to the drug.” It governs how much drug reaches its target, how long it stays, and how often you must dose. Every concept reduces to four steps — Absorption, Distribution, Metabolism, Excretion — and one graph ties them together.
A — Absorption
The movement of drug from its site of administration into the bloodstream.
- Bioavailability (F): the fraction of a dose reaching systemic circulation. IV = 100% by definition; oral is usually lower.
- First-pass metabolism: orally absorbed drug passes through the gut wall and liver before reaching circulation. Heavily extracted drugs (propranolol, lignocaine, GTN, morphine) have low oral bioavailability — which is why GTN is given sublingually.
- Ionisation & pH (Henderson–Hasselbalch): only the un-ionised, lipid-soluble form crosses membranes. Weak acids (aspirin) are absorbed well from the acidic stomach; weak bases from the alkaline intestine.
- Other factors: surface area, gastric emptying, blood flow, formulation, and food.
D — Distribution
- Volume of distribution (Vd = dose / plasma concentration): an apparent volume. A high Vd (digoxin, ~7 L/kg) means extensive tissue binding; a low Vd (warfarin) means the drug stays in plasma.
- Plasma protein binding: only the free fraction is active and eliminated. Acidic drugs bind albumin; basic drugs bind α1-acid glycoprotein. Displacement (warfarin + sulfonamides) transiently raises free drug.
- Barriers & redistribution: the blood–brain barrier and placenta exclude polar drugs; highly lipophilic drugs (thiopentone) redistribute from brain to fat, ending their action.
M — Metabolism (biotransformation)
Mostly hepatic, converting lipophilic drugs into water-soluble metabolites for excretion.
- Phase I — oxidation, reduction, hydrolysis, largely by cytochrome P450 (CYP) enzymes. Often produces an active or reactive metabolite.
- Phase II — conjugation (glucuronidation, sulfation, acetylation) yielding inactive, water-soluble products.
- Enzyme inducers (rifampicin, carbamazepine, phenytoin, chronic alcohol, St John’s Wort) speed metabolism → reduced drug effect.
- Enzyme inhibitors (ketoconazole, erythromycin, cimetidine, grapefruit juice) slow it → raised levels and toxicity.
- Prodrugs (enalapril, codeine, levodopa) require metabolism to become active.
E — Excretion
- Renal is the main route: glomerular filtration + active tubular secretion − reabsorption. Urinary pH manipulation aids overdose management (alkalinise urine for aspirin/phenobarbitone).
- Other routes: bile (with enterohepatic recirculation), lungs (anaesthetic gases), sweat, milk.
- Half-life (t½): time for plasma concentration to halve — sets dosing interval.
- Clearance (CL): volume of plasma cleared per unit time — the key determinant of maintenance dose.
- Steady state is reached in ~4–5 half-lives; a loading dose reaches it faster.
First-order vs zero-order kinetics
- First-order: a constant fraction is eliminated per unit time; t½ is constant (most drugs).
- Zero-order: a constant amount is eliminated because the system is saturated — small dose changes cause large, unpredictable level rises.
Exam tip: For low oral bioavailability, think first-pass metabolism. For zero-order (saturation) kinetics remember PEA — Phenytoin, Ethanol, Aspirin (high dose).
Why it matters clinically
Loading dose depends on Vd; maintenance dose depends on clearance; dosing frequency depends on half-life; and drug interactions usually act through CYP enzymes. Master ADME and the rest of pharmacology — dosing, interactions, toxicity — becomes reasoning, not memorising.