Makindo Medical Notes

🧠 Pharmacokinetics describes what the body does to a drug — encompassing absorption, distribution, metabolism, and excretion (ADME). Understanding these processes is fundamental to safe prescribing, as they determine how quickly and effectively a drug reaches its target, how long it acts, and how it is eliminated.

💉 Plasma Protein Binding

• Many drugs circulate in plasma either bound to proteins or unbound (free form).
• Acidic drugs (e.g. warfarin, phenytoin, furosemide) bind mainly to albumin.
• Basic drugs (e.g. propranolol, lidocaine, imipramine) bind primarily to α₁-acid glycoprotein.
• Only the free (unbound) fraction is pharmacologically active, diffusible across membranes, and subject to metabolism or excretion.
• ⚠️ Changes in binding (e.g. hypoalbuminaemia, uraemia, pregnancy, burns) can increase free drug levels and toxicity — notably for drugs with narrow therapeutic indices such as warfarin or phenytoin.
• Conversely, displacement interactions (e.g. valproate displacing phenytoin) transiently increase free drug concentration until equilibrium is restored by redistribution or metabolism.

📈 Linear vs Non-linear (Saturable) Kinetics

• Linear (first-order) kinetics: The rate of elimination is directly proportional to drug concentration. A constant fraction of drug is eliminated per unit time (e.g. most drugs such as penicillin, paracetamol).
• Non-linear (zero-order) kinetics: Enzyme systems become saturated; a constant amount is eliminated per unit time, regardless of concentration. Small dose increases → disproportionate rises in plasma level → toxicity risk.
• 📌 Classic examples: phenytoin, ethanol, salicylates.
• Clinically important: In phenytoin, doubling the dose may cause several-fold increase in concentration due to saturation of hepatic CYP2C9/19 enzymes.
• Mixed kinetics occur when elimination is first-order at therapeutic levels but becomes zero-order at higher concentrations.

🚪 Drug Elimination Pathways

• Hepatic metabolism: Lipid-soluble drugs are converted into more water-soluble metabolites to facilitate renal clearance. Two main phases:
  • Phase I (functionalisation): oxidation, reduction, or hydrolysis — mainly via CYP450 enzymes (e.g. codeine → morphine).
  • Phase II (conjugation): addition of polar groups (glucuronidation, acetylation, sulphation) to increase solubility (e.g. morphine → morphine-6-glucuronide).
• Renal excretion: Glomerular filtration, active tubular secretion, and reabsorption determine urinary drug loss. Weak acids (e.g. aspirin) are excreted more in alkaline urine, whereas weak bases (e.g. amphetamines) are excreted more in acidic urine.
• Drugs with high renal clearance include gentamicin and digoxin; those with high hepatic clearance include propranolol and lignocaine.

🔥 Potent Enzyme Inducers (CYP Induction)

• Inducers increase synthesis or activity of metabolic enzymes, accelerating drug metabolism. This reduces plasma concentration and half-life of the parent drug and co-administered agents — possibly causing treatment failure.
• Enzyme induction often requires several days to develop and persists after stopping the inducer due to sustained enzyme synthesis.
• 💊 Common enzyme inducers:
  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Rifampicin
  • St John’s Wort (herbal CYP3A4 inducer)
  • Smoking (induces CYP1A2 → ↑ clearance of theophylline, caffeine)
  • Ethanol (chronic use induces CYP2E1 → ↑ paracetamol toxicity)
• 💡 Clinical impact: Induction reduces efficacy of oral contraceptives, warfarin, corticosteroids, ciclosporin, and many antiretrovirals.

🧊 Enzyme Inhibitors (CYP Inhibition)

• Inhibitors reduce CYP450 activity, leading to higher plasma concentrations and potential toxicity of co-administered drugs.
• Onset of inhibition is rapid (within hours) and resolves after the inhibitor is withdrawn.
• 💊 Common enzyme inhibitors:
  • Grapefruit juice — inhibits CYP3A4 → ↑ levels of midazolam, simvastatin, amlodipine.
  • Macrolides — erythromycin, clarithromycin (CYP3A4 inhibitors).
  • Azole antifungals — ketoconazole, itraconazole (CYP3A4 inhibitors).
  • Ritonavir — potent CYP3A and CYP2D6 inhibitor; used to “boost” protease inhibitors.
  • Ciprofloxacin — inhibits CYP1A2 → ↑ theophylline levels.
  • Amiodarone, cimetidine, fluoxetine — inhibit multiple CYPs.
• ⚠️ Clinical relevance: Combining inhibitors with narrow-therapeutic-index drugs (warfarin, digoxin, ciclosporin, lithium) increases toxicity risk.

🧬 Pharmacogenetics and Acetylation Status

• Genetic polymorphisms affect drug metabolism, explaining inter-individual variability in drug response.
• Acetylation: Drugs such as isoniazid, hydralazine, procainamide, and sulphonamides undergo N-acetylation by hepatic N-acetyltransferase-2 (NAT2).
• Individuals are classified as:
  • Slow acetylators (~50% in Caucasians) → prolonged drug half-life, increased toxicity (e.g. lupus-like reaction with hydralazine).
  • Fast acetylators (~50% in Asians and Africans) → reduced efficacy due to rapid clearance.
• Other pharmacogenetic examples:
  • CYP2D6 poor metabolisers: reduced activation of codeine to morphine → reduced analgesia.
  • CYP2C9 variants: increased warfarin sensitivity.
  • Thiopurine methyltransferase (TPMT) deficiency: azathioprine toxicity.
  • G6PD deficiency: haemolysis with sulphonamides, primaquine, or dapsone.

🧠 Clinical Integration

• When prescribing, always consider the “three Ps”: Protein binding, P450 status, and Physiology (renal/hepatic function).
• ⚖️ Adjust dose in renal or hepatic impairment — reduced clearance leads to accumulation.
• Use therapeutic drug monitoring (TDM) for drugs with narrow therapeutic windows (phenytoin, lithium, digoxin, aminoglycosides).
• Remember that age, disease, and comorbidities modify pharmacokinetics profoundly:
  • Neonates: immature hepatic and renal systems → lower metabolism.
  • Elderly: reduced GFR, lower albumin, higher body fat → prolonged half-life of lipophilic drugs.

📚 References

• BNF: Pharmacokinetics and Drug Metabolism
• Katzung BG. Basic and Clinical Pharmacology, 15th ed.
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.
• NICE: Medicines Optimisation in Polypharmacy (NG5, 2022)