Pharmacokinetics — ADME, Half-Life, Dosing Formulas, Kinetics and CYP450

Pharmacokinetics describes how the body handles a drug over the whole period of exposure; pharmacodynamics is the reverse — what the drug does to the body. Pharmacokinetics is organised around four processes, remembered as ADME: Absorption, Distribution, Metabolism and Excretion.

• Absorption — movement from the site of administration (tablet, injection, patch) into the systemic circulation. Its end result is bioavailability.
• Distribution — spread from plasma into tissues, captured by the volume of distribution (Vd) and modified by protein binding.
• Metabolism — chemical change, mainly in the liver by phase I (CYP450) and phase II (conjugation) reactions, usually making the drug more water-soluble.
• Excretion — removal, mostly by the kidneys (filtration, tubular secretion, reabsorption), summarised by clearance.

Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation unchanged. An intravenous dose reaches the circulation completely and almost instantly, so IV bioavailability is 100% (F = 1) — the reference against which every other route is measured.

An oral drug must survive stomach acid, gut enzymes and the gut wall, then pass through the portal vein and liver before it reaches the systemic circulation. Metabolism along this route is the first-pass effect. It happens mainly in the liver but also in the gut wall, lungs and vasculature, and it varies between patients.

The volume of distribution (Vd) is the amount of drug in the body divided by its plasma concentration. It is an apparent volume — the fluid volume that would be needed to hold all the drug at the plasma concentration — not a real anatomical space.

• Large, charged or highly protein-bound molecules stay inside the vessels → low Vd.
• Small, lipophilic molecules enter cells and fat → very high Vd.
• At a constant clearance, a higher Vd means a longer half-life, because most of the drug sits outside the plasma where it cannot be cleared.
• Haemodialysis removes drugs with a small Vd and low protein binding (gentamicin, lithium) but not drugs with a large Vd (amiodarone, digoxin).
• Children have proportionately more body water, so water-soluble drugs need higher doses per kilogram.

Only the free (unbound) drug can act on receptors, cross into other compartments or be eliminated. The main drug-binding proteins are albumin and alpha-1 acid glycoprotein, whose levels change with age, nutrition, and liver or kidney disease.

• Displacement interactions — aspirin and warfarin compete for the same binding site, raising the free fraction and the bleeding risk.
• Hypoalbuminaemia (malnutrition, inflammation, cirrhosis) increases the free fraction — a highly bound drug such as warfarin can have an enhanced effect at a 'normal' total level.
• Uraemia reduces the binding of acidic drugs such as diazepam, so more free drug reaches the brain (risk of respiratory depression).
• Protein binding changes matter clinically mainly when a drug is more than 90% protein bound.
• A large bound reserve can act as a sustained-release depot, prolonging drug effect.

Clearance (CL) is the volume of plasma cleared of drug per unit time — formally, the rate of elimination divided by the plasma concentration. Half-life (t½) is the time for the plasma concentration to fall by 50%. In first-order kinetics the two are tied together by the volume of distribution.

StatPearls states that 94–97% of a drug is eliminated after 4–5 half-lives, at which point it is considered effectively gone. Its worked example: morphine with a half-life of about 120 minutes is negligible 8–10 hours after a dose. Renal failure lowers clearance and hepatic disease slows metabolism, so both prolong the half-life.

With regular dosing or a constant infusion, a drug accumulates until the rate in equals the rate out. This plateau is the steady state, reached after about 4–5 half-lives (the Loading Dose chapter of StatPearls quotes 5–7). The steady-state level depends on the dose, dosing interval and clearance — not on the loading dose.

• A loading dose gives the target concentration immediately instead of waiting 4–5 half-lives — useful for drugs with long half-lives or urgent situations.
• Examples in StatPearls: vancomycin in severe infection, levetiracetam in status epilepticus, amiodarone and digoxin (sometimes split over hours to days), phenytoin (given IV as a single loading dose), heparin for pulmonary embolism.
• A common error is continuing the loading dose after transfer between wards instead of switching to the maintenance dose.

Phenytoin is the classic exam drug. Below about 10 mg/L its elimination is first-order; above that the liver enzymes saturate and elimination becomes zero-order, so a small dose increase can push levels into the toxic range. Its usual half-life of about 22 hours becomes much longer in overdose. Toxicity follows the level: nystagmus first (about 10–30 mg/L), then ataxia and slurred speech (30–40 mg/L), lethargy and confusion (40–50 mg/L), and coma or seizures above 50 mg/L.

Salicylates follow first-order kinetics below about 1.4 mmol/L and become zero-order above it. Ethanol is metabolised by alcohol dehydrogenase, which saturates even at moderate blood levels, so it is removed at a constant rate. For methanol (zero-order at higher doses), the time since ingestion matters more than the dose when deciding on fomepizole or ethanol.

Lipophilic drugs are filtered by the kidney but then diffuse back across the tubule, so they must first be made more polar. The liver does this in two stages.

• Drugs that already carry a polar group can skip phase I and go straight to phase II.
• A prodrug needs metabolism to become active — codeine is converted to morphine by CYP2D6. Poor metabolisers get little pain relief; ultrarapid metabolisers can develop dangerous respiratory depression.
• Some texts add a phase III — transporters pumping conjugates out of cells.
• Metabolism slows with age, and genetic polymorphisms make people poor, intermediate, normal or ultrarapid metabolisers.

CYP enzymes handle an estimated 80–90% of enzymatic drug metabolism, and about six isoforms do most of the work: CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. An inducer speeds up metabolism of other drugs on that pathway (risk: treatment failure); an inhibitor slows it (risk: accumulation and toxicity). The direction reverses for prodrugs that need activation.

• Rifampin + imatinib → imatinib levels fall (CYP3A4 induction) and anticancer effect drops.
• Grapefruit juice inhibits intestinal CYP3A4 (naringin), raising levels of CYP3A4 substrates even in small amounts.
• Smokers metabolise caffeine and theophylline faster (nicotine/tobacco induces CYP1A2).

The kidney removes drugs by glomerular filtration and active tubular secretion (organic anion and cation transporters), opposed by passive tubular reabsorption of the un-ionised, lipid-soluble form. Some drugs are also excreted in bile, by the lungs or through the skin.

Changing urine pH changes how much of a weak acid or base is ionised in the tubule. The ionised form cannot diffuse back, so it is 'trapped' in the urine and excreted — ion trapping.

• Calculations — given Vd and target level, find the loading dose; given CL, find the maintenance dose; given Vd and CL, find t½.
• Time to steady state — 4–5 half-lives; unaffected by dose size.
• Zero-order drugs — phenytoin, ethanol, high-dose aspirin; 'constant amount eliminated per unit time'.
• Loading dose depends on → Vd; maintenance dose depends on → clearance.
• CYP450 interactions — rifampin lowering levels of CYP3A4 substrates such as imatinib, ketoconazole or clarithromycin with CYP3A4 substrates, smoking and theophylline.
• Prodrugs and polymorphism — codeine and CYP2D6.
• Ion trapping — alkalinise the urine for aspirin (weak acid) poisoning.

For past papers see the NEET PG pharmacology PYQs and INI-CET PYQs. Applied examples appear in anti-diabetic drugs, antipsychotics and corticosteroids.