Key Facts

Pharmacokinetics ('what the body does to the drug') is fundamental to rational prescribing. Understanding PK principles enables clinicians to select appropriate drugs, doses, routes, and intervals, and to adjust for organ impairment.

Absorption

• Oral: most common route; affected by gastric pH, motility, food, formulation
• Bioavailability (F): IV = 1.0 (100%); oral varies — e.g. atenolol ~50%, morphine ~30%, glyceryl trinitrate ~1%
• First-pass effect: gut wall and hepatic metabolism before systemic circulation
• Alternative routes bypass first-pass: sublingual, buccal, transdermal, rectal (partially), IV, IM, SC, inhaled

Distribution

• Volume of distribution (Vd): theoretical volume needed to contain total drug at plasma concentration
  • Low Vd (~5–10 L): drug remains in plasma — e.g. warfarin (highly protein-bound)
  • High Vd (>40 L): extensive tissue distribution — e.g. digoxin (~500 L), amiodarone
• Protein binding: albumin (acidic drugs), alpha-1-acid glycoprotein (basic drugs) — only free (unbound) drug is pharmacologically active
• Blood-brain barrier: lipid-soluble, non-ionised drugs cross more readily

Metabolism

• Phase I: oxidation, reduction, hydrolysis — mainly CYP450 enzymes in liver (CYP3A4, CYP2D6, CYP2C9 most important)
• Phase II: conjugation (glucuronidation, sulfation, acetylation, methylation) — produces water-soluble metabolites for excretion
• Pro-drugs: inactive form converted to active metabolite — e.g. codeine → morphine (CYP2D6), clopidogrel → active thiol (CYP2C19)

Excretion

• Renal: most common route — glomerular filtration, tubular secretion, tubular reabsorption
• Hepatobiliary: some drugs excreted in bile → enterohepatic circulation (e.g. rifampicin, oestrogen)
• Other: pulmonary (volatile anaesthetics), breast milk, sweat

Pathophysiology of Altered PK

• Renal impairment: reduced clearance of renally excreted drugs → accumulation → toxicity
• Hepatic impairment: reduced metabolism and protein synthesis → increased free drug, reduced clearance
• Heart failure: reduced hepatic blood flow → reduced first-pass metabolism → increased bioavailability
• Obesity: increased Vd for lipophilic drugs
• Extremes of age: neonates (immature metabolism); elderly (reduced renal/hepatic function)

Clinical Relevance

• Loading dose = Vd × target concentration / F — achieves therapeutic levels rapidly (e.g. digoxin, amiodarone)
• Maintenance dose = CL × target concentration / F — maintains steady state
• Steady state: achieved after ~5 half-lives; drug input = drug elimination
• Therapeutic drug monitoring (TDM): required for drugs with narrow therapeutic index — e.g. gentamicin, vancomycin, digoxin, phenytoin, lithium, ciclosporin

Signs of PK-Related Problems

• Drug toxicity with standard doses → suspect reduced clearance (renal/hepatic impairment)
• Subtherapeutic levels → suspect poor absorption, enhanced metabolism (enzyme induction), non-compliance
• Unexpected drug interactions → altered metabolism (enzyme inhibition/induction)

Red Flags

• Narrow therapeutic index drugs in renal/hepatic impairment — high risk of toxicity
• Zero-order kinetics drugs (phenytoin): small dose increase → large concentration rise → toxicity
• Pro-drug in CYP2D6 poor metabolisers: codeine → no morphine = no analgesia
• CYP2D6 ultra-rapid metaboliser: codeine → excessive morphine = respiratory depression

Therapeutic Drug Monitoring (TDM)

• Gentamicin: trough <1 mg/L (once daily: level at 6–14 hours, use Hartford nomogram)
• Vancomycin: trough 10–15 mg/L (or 15–20 for serious infections); AUC/MIC guided dosing
• Digoxin: 1.0–2.0 nmol/L (sample ≥6 hours post-dose)
• Phenytoin: 10–20 mg/L (total); corrected for albumin: corrected level = measured / (0.2 × albumin + 0.1)
• Lithium: 0.4–0.8 mmol/L (maintenance); 0.8–1.0 for acute mania; sample 12 hours post-dose
• Ciclosporin: trough levels — varies by indication
• Theophylline: 10–20 mg/L

Renal Function Assessment

• eGFR (CKD-EPI): estimates renal clearance — guide dose adjustments
• Cockcroft-Gault: estimates creatinine clearance — used by BNF for dose adjustments

Hepatic Function

• LFTs, albumin, INR: markers of synthetic function
• Child-Pugh score: classifies severity of liver disease — guides dose adjustment

Special Tests

• Pharmacogenomic testing: CYP2D6, CYP2C19, HLA-B*5701, TPMT — guide drug selection and dosing

Dose Adjustment Principles

• Renal impairment: reduce dose or extend interval for renally cleared drugs; use Cockcroft-Gault or eGFR; consult BNF renal appendix
• Hepatic impairment: reduce dose for hepatically metabolised drugs; use Child-Pugh score; avoid hepatotoxic drugs
• Elderly: 'start low, go slow'; reduced renal function, altered body composition, polypharmacy
• Obesity: dose some drugs on adjusted body weight (e.g. LMWH, aminoglycosides)

Loading Doses

• Used when rapid onset needed and drug has long half-life/large Vd
• Examples: digoxin 500 mcg, amiodarone 300 mg IV, phenytoin 15–20 mg/kg IV
• Loading dose independent of renal/hepatic function (depends on Vd)

TDM-Guided Prescribing

• Sample at appropriate time (trough for most; specific times for aminoglycosides)
• Adjust dose based on measured level and clinical response
• Repeat levels after dose change (wait ~5 half-lives for new steady state)

Pharmacological

• Not directly applicable — PK principles guide ALL drug prescribing

Referral Criteria

• Clinical pharmacology: complex dosing, TDM interpretation, pharmacogenomic queries
• Renal team: drug dosing in severe renal impairment/dialysis
• Hepatology: drug dosing in severe hepatic impairment

• Understanding PK reduces prescribing errors, drug toxicity, and treatment failure
• Narrow therapeutic index drugs require careful monitoring — toxicity can be life-threatening (aminoglycosides → nephro/ototoxicity, lithium → toxicity, digoxin → arrhythmia)
• Pharmacogenomic testing improves outcomes: HLA-B*5701 prevents abacavir hypersensitivity, TPMT testing prevents azathioprine toxicity
• Prescribing errors related to PK (wrong dose in renal failure, drug interactions) are common and preventable

Key PK Parameters

Zero-Order vs First-Order Kinetics