Pharmacokinetics and half-life

Absorption

• Most drugs cross membranes by passive diffusion of the un-ionised, lipid-soluble form. Weak acids are un-ionised in acid, weak bases in alkali (Henderson–Hasselbalch), yet most absorption happens in the small intestine because of its huge surface area.
• Ion trapping: alkalinising urine with sodium bicarbonate ionises weak acids (aspirin, phenobarbital) so they cannot be reabsorbed and are excreted faster.
• Absorption is shaped by formulation, gastric emptying, food, gut wall enzymes and P-glycoprotein efflux pumps.
• Drugs can also block absorption of nutrients: ezetimibe inhibits the NPC1L1 cholesterol transporter on enterocytes, lowering LDL.
• Inhaled drugs: many patients use a pressurised metered-dose inhaler poorly; a spacer removes the need to coordinate pressing and breathing, so more drug reaches the lungs and less sticks in the mouth (rinse after inhaled steroids).

Bioavailability and first-pass metabolism

• Bioavailability (F) is the fraction of a dose that reaches the systemic circulation unchanged. Intravenous dosing gives 100% by definition; F = AUC oral / AUC IV. For the fastest, most complete effect, give IV.
• First-pass metabolism: a swallowed drug passes through gut wall and liver before reaching the circulation. Glyceryl trinitrate swallowed is almost entirely destroyed by first pass, so it is given sublingually, where it enters the systemic veins directly. Others with high first pass: lidocaine, propranolol, morphine, verapamil, testosterone.
• Routes avoiding first pass: sublingual, buccal, transdermal, inhaled, parenteral; rectal partly.
• Grapefruit juice irreversibly inhibits intestinal CYP3A4 in the gut wall, reducing first-pass metabolism and raising levels of simvastatin, ciclosporin, felodipine and some calcium channel blockers.
• Enterohepatic circulation: drugs conjugated in the liver are excreted in bile, deconjugated by gut bacteria and reabsorbed, prolonging their action (oestrogens, some opioids, mycophenolate). Broad-spectrum antibiotics kill these bacteria and can reduce reabsorption (classically of ethinylestradiol). Repeated activated charcoal works partly by interrupting this cycle.
• Some drugs are prodrugs needing metabolic activation: clopidogrel needs CYP2C19, so poor metabolisers make little active drug and stents thrombose. Codeine needs CYP2D6; ultra-rapid metabolisers make too much morphine.

Distribution

• Volume of distribution (Vd) = total amount of drug in the body ÷ plasma concentration. It is an apparent volume that shows where the drug goes.

• Drugs with large Vd are hardly removed by dialysis, because little is in the plasma.
• Protein binding: acidic drugs bind albumin (warfarin, phenytoin, sulphonamides); basic drugs bind alpha-1 acid glycoprotein (lidocaine, propranolol). Only free drug acts and is cleared. Low albumin raises free phenytoin; sulphonamides displace bilirubin in neonates, causing kernicterus.
• Obesity changes distribution: lipid-soluble drugs have a larger Vd; water-soluble drugs such as gentamicin distribute into lean mass, so they are dosed on adjusted body weight.
• Blood–brain barrier and placenta admit small, lipid-soluble, un-ionised drugs; heparin and insulin do not cross the placenta.

Elimination: first-order and zero-order

• With zero-order drugs a small dose increase causes a large rise in level and toxicity.

Clearance, half-life and steady state

• Clearance = rate of elimination ÷ plasma concentration: the volume of plasma cleared of drug per unit time. Total clearance = renal + hepatic + other.
• Renal clearance = filtration of free drug + tubular secretion − reabsorption. Inulin is filtered only, so its clearance equals GFR. A drug with clearance greater than inulin must be secreted by the tubules (penicillin, PAH); one with lower clearance is reabsorbed or protein-bound.
• Half-life depends on Vd and clearance: t½ = 0.693 × Vd ÷ CL. Bigger Vd or lower clearance lengthens it.
• Steady state is reached after about 4–5 half-lives, whatever the dose; the same time clears a drug after stopping.
• Hepatic clearance of high-extraction drugs (lidocaine, propranolol, morphine) depends on liver blood flow; low-extraction drugs (warfarin, phenytoin, theophylline) depend on enzyme activity.
• Pharmacokinetic interactions change absorption, distribution, metabolism or excretion: enzyme inhibitors such as ciprofloxacin and erythromycin reduce theophylline clearance; thiazides reduce lithium clearance (sodium depletion makes the proximal tubule reabsorb more lithium).

Dosing calculations

• Loading dose = target concentration × Vd ÷ F. For Vd 40 L, F = 1 and target 2 mg/L: 2 × 40 = 80 mg. Use a loading dose when half-life is long and effect is needed quickly (amiodarone, digoxin, phenytoin, teicoplanin). Renal function does not change it.
• Maintenance dose rate = target concentration × CL ÷ F. It must be reduced when clearance falls.

• Therapeutic drug monitoring for narrow-index drugs: digoxin, lithium, aminoglycosides, vancomycin, phenytoin, ciclosporin, tacrolimus, theophylline.

Special groups

• Elderly: lower GFR (creatinine may look normal because muscle mass is small), more fat, less albumin. For gentamicin, which is renally excreted, keep the dose that achieves an effective peak but extend the dosing interval guided by trough levels, since concentration-dependent killing needs the peak while toxicity follows a high trough.
• Renal impairment: reduce or space doses of aminoglycosides, vancomycin, digoxin, lithium, metformin, dabigatran, LMWH.
• Neonates: immature glucuronidation (grey baby syndrome with chloramphenicol); more body water.
• Pregnancy: larger Vd and higher GFR.

Remember Loading dose fills the volume; maintenance dose replaces what clearance removes.

Exam trap Steady state takes 4–5 half-lives regardless of the dose given.

Exam trap Phenytoin, ethanol and high-dose aspirin follow zero-order kinetics, so small dose rises cause toxicity.

How FCPS asks about this

• Why GTN is given sublingually: swallowed GTN is lost by first-pass metabolism.
• Route with 100% bioavailability: intravenous.
• Loading dose for Vd 40 L, target 2 mg/L, F = 1: 80 mg.
• Grapefruit juice: inhibits intestinal CYP3A4.
• Bile excretion, bacterial deconjugation and reabsorption: enterohepatic circulation; broad-spectrum antibiotics can reduce it.
• Clopidogrel failure in a poor CYP2C19 metaboliser: it is a prodrug needing activation.
• Gentamicin in an elderly man with reduced GFR: extend the dosing interval guided by levels; half-life depends on Vd and clearance.