Makindo Medical Notes

💊 Pharmacokinetics is the study of how drugs move through the body over time — often summarised as ADME: Absorption, Distribution, Metabolism, and Excretion. It answers the question: “What does the body do to the drug?” — complementing pharmacodynamics (“What the drug does to the body”). Understanding pharmacokinetics is vital for designing safe, effective, and individualized dosing regimens.

🧩 Key Concepts

• Absorption: The process by which a drug moves from its site of administration into the bloodstream.
  • Influenced by formulation, route, pH, blood flow, and presence of food.
  • Bioavailability (F): the fraction of the administered dose reaching systemic circulation in its active form (e.g., IV = 100%).
  • Example: Oral morphine undergoes extensive first-pass metabolism, reducing bioavailability to about 25%.
• Distribution: Describes how a drug spreads through body compartments after entering the circulation.
  • Affected by lipid solubility, protein binding, tissue perfusion, and membrane barriers.
  • Volume of Distribution (V_d): a theoretical volume describing how widely a drug disperses; high V_d implies extensive tissue binding.
  • Example: Digoxin (V_d ≈ 7 L/kg) accumulates in cardiac tissue.
• Metabolism: The biochemical modification of drugs — primarily by hepatic enzymes — to facilitate excretion.
  • Involves Phase I (oxidation/reduction/hydrolysis) and Phase II (conjugation) reactions.
  • Key enzymes: CYP450 family (notably CYP3A4, CYP2D6).
  • Example: Codeine is metabolised to morphine via CYP2D6 — a polymorphism explaining variable analgesic response.
• Excretion: The process of eliminating parent drug and metabolites from the body.
  • Major route: renal excretion via glomerular filtration, secretion, and reabsorption.
  • Also occurs via biliary/faecal, pulmonary, sweat, and salivary routes.
  • Half-life (t_½): the time taken for plasma concentration to fall by half — determines dosing intervals and steady-state.
  • Example: Diazepam’s long half-life (~30 hours) explains prolonged sedation in elderly patients.

🔬 Detailed Processes

1️⃣ Absorption

• Oral absorption:
  • Dependent on gastric emptying, intestinal motility, pH, and first-pass metabolism.
  • Fat-soluble drugs (e.g., diazepam) cross membranes easily; polar drugs require transporters.
  • Enteric-coated and sustained-release formulations modify absorption rate and duration.
• Parenteral absorption:
  • Includes IV (immediate), IM, and SC routes — bypass the GI tract and first-pass metabolism.
  • IM absorption depends on muscle perfusion; may be delayed in shock or peripheral vasoconstriction.
• Transdermal and mucosal absorption:
  • Transdermal patches provide slow, sustained delivery (e.g., fentanyl, GTN).
  • Buccal and nasal routes (e.g., glyceryl trinitrate, desmopressin) allow rapid systemic absorption via mucosal capillaries.

2️⃣ Distribution

• Plasma protein binding: Drugs may bind reversibly to albumin (acidic drugs) or α₁-acid glycoprotein (basic drugs). Only the unbound fraction is pharmacologically active. Hypoalbuminaemia (e.g., in liver disease) increases free drug levels and toxicity risk.
• Tissue distribution: Some drugs accumulate in specific tissues:
  • Tetracyclines → bone and teeth.
  • Amiodarone → fat and lungs (explains long half-life).
• Blood–brain barrier (BBB): Highly selective — lipophilic drugs (e.g., benzodiazepines) cross easily, hydrophilic ones (e.g., gentamicin) do not. Inflammation (e.g., meningitis) increases permeability.

3️⃣ Metabolism (Biotransformation)

• Phase I reactions:
  • Introduce or expose functional groups via oxidation, reduction, or hydrolysis.
  • Carried out by CYP450 enzymes — subject to induction (e.g., rifampicin) or inhibition (e.g., erythromycin).
• Phase II reactions:
  • Conjugation with glucuronic acid, sulphate, acetate, or amino acids — making drugs more water-soluble.
  • Example: Paracetamol undergoes glucuronidation and sulphation; in overdose, conjugation saturates and hepatotoxic metabolites accumulate.
• First-pass metabolism: Orally administered drugs may be extensively metabolised in the gut wall and liver before reaching systemic circulation. This reduces bioavailability (e.g., propranolol, morphine) and necessitates higher oral doses.

4️⃣ Excretion

• Renal excretion:
  • Glomerular filtration: filters unbound drug from plasma.
  • Tubular secretion: active transport of drugs into urine (e.g., penicillin, furosemide).
  • Tubular reabsorption: lipid-soluble drugs may be passively reabsorbed — urine pH can alter this.
• Biliary excretion and enterohepatic recycling:
  • Drugs excreted into bile may be reabsorbed from the intestine, prolonging action (e.g., oestrogens, morphine).
  • Antibiotics can interrupt this process by reducing gut flora, lowering reabsorption.
• Other routes: Lungs (volatile anaesthetics), sweat, saliva, breast milk — clinically relevant in toxicology and pregnancy counselling.

⚖️ Clinical Relevance

• Dosing regimens: Knowledge of half-life and clearance informs dose frequency and maintenance levels. E.g., Gentamicin dosing uses peak/trough levels to balance efficacy and toxicity.
• Drug interactions: Understanding metabolism helps predict enzyme induction (reduces efficacy) or inhibition (increases toxicity). E.g., warfarin–erythromycin → increased INR and bleeding risk.
• Individual variability: Age (reduced renal clearance in elderly), genetics (CYP2D6 polymorphism), and organ disease alter drug handling. Paediatrics and frailty demand adjusted dosing and monitoring.
• Toxicology: Kinetic principles underpin antidote use (e.g., activated charcoal in early overdose, haemodialysis for lithium, N-acetylcysteine for paracetamol toxicity).

🧮 Key Pharmacokinetic Parameters

• Clearance (Cl): Volume of plasma cleared of drug per unit time (mL/min). Cl = (Rate of elimination) ÷ (Plasma concentration).
• Half-life (t_½): Related to volume of distribution and clearance: t_½ = (0.693 × V_d) / Cl.
• Steady state: Achieved after ~4–5 half-lives of repeated dosing.
• Loading dose: = (Target concentration × V_d) ÷ Bioavailability.
• Maintenance dose: = (Target concentration × Cl × dosing interval) ÷ Bioavailability.

🧠 Summary

Pharmacokinetics integrates the science of drug movement — from entry (absorption) to exit (excretion). It underpins rational prescribing, explaining why doses vary between routes, between patients, and across diseases. Mastery of these principles allows clinicians to predict plasma levels, optimise therapy, prevent toxicity, and adjust for renal or hepatic dysfunction. In short: it is the art of matching the right dose, for the right drug, to the right patient — at the right time. ⏱️💊