Clinical pharmacology and prescribing: Principles of clinical pharmacology

🩺 Principles of clinical pharmacology. Every prescribing decision rests on two questions: what will the body do to this drug (pharmacokinetics) and what will this drug do to the body (pharmacodynamics)? Understanding these explains why we use loading doses, why some drugs need levels checked, why kidney failure and liver disease change dosing, and why interactions happen. System-specific drugs are covered in the Anatomy, Physiology and Pharmacology chapter for each specialty.
Your four questions for every drug: How does it work (mechanism)? How does it get in, around and out of the body? How quickly will it reach a steady effect -and does it need a loading dose? What could change its levels or effects in this patient (kidneys, liver, age, genes, other drugs)?

---

What the Body Does to a Drug

• Pharmacokinetics -the movement of a drug through the body -ADME:
  • Absorption -getting into the blood.
  • Distribution -spreading into tissues.
  • Metabolism -chemical change (mostly in the liver).
  • Excretion -removal (mostly by the kidneys and bile).
• Why it matters -determines the dose, dosing interval, route, time to effect, need for loading doses and monitoring, and dose changes in organ failure.
• Key measurements:
  • Bioavailability (F) -fraction of a dose reaching the circulation unchanged.
  • Volume of distribution (Vd) -how widely the drug spreads.
  • Clearance (CL) -volume of plasma cleared of drug per unit time.
  • Half-life (t½) -time for the plasma level to fall by half.
• Simple relationships:
  • Loading dose = target concentration × Vd ÷ F.
  • Maintenance dose rate = target concentration × CL ÷ F.
  • Half-life = 0.693 × Vd ÷ CL -a bigger Vd or lower clearance means a longer half-life.

Absorption and Bioavailability

• Absorption depends on -route, drug formulation, lipid solubility, ionisation (pH), gut motility and blood flow, food, and interactions.
• Bioavailability -100% for IV drugs; lower for oral drugs because of incomplete absorption and first-pass metabolism (gut wall and liver metabolise the drug before it reaches the systemic circulation).
• High first-pass metabolism -glyceryl trinitrate (given sublingually or as a patch), morphine (oral dose about 2–3 times the IV or SC dose), propranolol, lidocaine (not given orally), levodopa, verapamil, many statins.
• Avoiding first pass -sublingual, buccal, transdermal, rectal (partly), inhaled, IV, IM, SC routes.
• Food effects:
  • Take on an empty stomach -bisphosphonates (30 minutes before food, with water, upright), levothyroxine (30–60 minutes before breakfast), flucloxacillin, rifampicin, PPIs (before meals).
  • Take with food -NSAIDs, metformin, prednisolone (reduce GI upset), rivaroxaban 15/20 mg (better absorption).
• Interactions affecting absorption -calcium, iron, antacids and magnesium chelate tetracyclines, quinolones, bisphosphonates and levothyroxine -separate doses by 2–4 hours; colestyramine binds many drugs.
• Modified-release preparations -slower absorption, fewer peaks and troughs; must not be crushed; brands may differ (prescribe by brand for some -e.g. nifedipine MR, theophylline, lithium, diltiazem, tacrolimus, antiepileptics in some cases).
• Gut problems -vomiting, short bowel, high-output stoma (enteric-coated and MR tablets may pass unabsorbed), gastroparesis.

Distribution

• Volume of distribution (Vd) -the theoretical volume the drug would occupy if spread evenly at the plasma concentration.
  • Low Vd (stays in blood) -large, water-soluble or highly protein-bound drugs -warfarin, heparin, gentamicin, aspirin.
  • High Vd (enters tissues) -lipid-soluble drugs -digoxin, amiodarone (huge Vd -very long half-life -weeks), tricyclics, chloroquine.
• Why Vd matters:
  • Drugs with a large Vd need a loading dose to reach effective levels quickly (amiodarone, digoxin).
  • Haemodialysis removes drugs with a small Vd, low protein binding and low molecular weight (lithium, salicylate, methanol, ethylene glycol, metformin, theophylline) -but not those with a large Vd (digoxin, tricyclics).
• Protein binding:
  • Acidic drugs bind albumin (warfarin, phenytoin, NSAIDs); basic drugs bind alpha-1 acid glycoprotein.
  • Only free (unbound) drug is active.
  • Low albumin (liver disease, nephrotic syndrome, malnutrition, critical illness) increases the free fraction -important for phenytoin (measured total levels may look normal or low while free levels are toxic -use corrected or free levels).
• Barriers -the blood–brain barrier (lipid-soluble drugs cross; inflamed meninges let more antibiotic through), the placenta (most drugs cross -see page 4), breast milk.
• Body composition -older people (more fat, less water) and obese people need thought about weight-based dosing (actual vs ideal vs adjusted body weight).

Metabolism and the Liver

• Aim -make drugs more water-soluble so they can be excreted.
• Phase 1 -oxidation, reduction, hydrolysis -mainly by cytochrome P450 enzymes (CYP3A4 -about half of drugs; CYP2D6, CYP2C9, CYP2C19, CYP1A2); may produce active or toxic metabolites.
• Phase 2 -conjugation (glucuronidation, sulfation, acetylation, glutathione) -usually inactivates and makes the drug water-soluble.
• Prodrugs -inactive until metabolised:
  • Codeine → morphine (CYP2D6).
  • Clopidogrel → active metabolite (CYP2C19).
  • Enalapril, ramipril → enalaprilat, ramiprilat.
  • Levodopa → dopamine; azathioprine → 6-mercaptopurine; cyclophosphamide; valaciclovir → aciclovir.
• Toxic metabolites -paracetamol → NAPQI (normally neutralised by glutathione; overdose exhausts glutathione → liver damage); methanol → formic acid; ethylene glycol → oxalate.
• Enzyme induction and inhibition -the commonest mechanism of serious interactions (see page 3):
  • Inducers (speed up metabolism -reduce levels of other drugs; effect builds over 1–2 weeks) -e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort, chronic alcohol, smoking (CYP1A2).
  • Inhibitors (slow metabolism -increase levels; effect is quick) -e.g. clarithromycin, erythromycin, azole antifungals (fluconazole, itraconazole), HIV protease inhibitors (ritonavir), grapefruit juice, amiodarone, diltiazem, verapamil, ciprofloxacin, sodium valproate, omeprazole (CYP2C19), fluoxetine and paroxetine (CYP2D6).
• Liver disease reduces metabolism of many drugs -but liver function tests don't predict this well (see page 4).

Excretion and Clearance

• Kidneys -the main route for water-soluble drugs and metabolites: glomerular filtration, tubular secretion and reabsorption.
• Renally cleared drugs that accumulate in kidney impairment -gentamicin and vancomycin, lithium, digoxin, metformin, DOACs (dabigatran most), LMWH, morphine metabolites, gabapentin and pregabalin, aciclovir, allopurinol, methotrexate, penicillins and cephalosporins (seizures in high doses), sotalol, nitrofurantoin (ineffective and toxic).
• Estimating kidney function:
  • eGFR (CKD-EPI) -normalised to body surface area 1.73 m²; used for most dosing in the BNF.
  • Creatinine clearance (Cockcroft–Gault) -preferred for drugs with a narrow therapeutic index, DOACs, and in older people or extremes of body weight.
  • AKI -eGFR is unreliable when creatinine is changing; assume function is worse than it looks.
• Biliary excretion -some drugs are excreted in bile and reabsorbed (enterohepatic circulation) -e.g. oestrogens, rifampicin; activated charcoal can interrupt this in some poisonings.
• Other routes -lungs (volatile anaesthetics, alcohol), breast milk, sweat, saliva.
• Urine pH -alkalinising the urine increases excretion of weak acids (salicylate, phenobarbital) -"ion trapping" (see page 6).
• Clearance -determines the maintenance dose; halving clearance doubles steady-state levels (if the dose stays the same).

Half-life, Steady State and Loading Doses

• Half-life (t½) -the time for the plasma concentration to fall by 50%.
• After about 4–5 half-lives:
  • A drug is almost completely eliminated after stopping (about 94–97%).
  • A drug given regularly reaches steady state (intake equals elimination).
• Examples:

  Drug	Approximate half-life	Practical point
  Adenosine	Under 10 seconds	Rapid IV bolus with a flush
  Glyceryl trinitrate (IV)	Minutes	Continuous infusion; effects stop quickly
  Unfractionated heparin	About 1–2 hours	Infusion; quickly reversible
  Paracetamol	About 2–3 hours	4–6 hourly dosing
  Apixaban	About 12 hours	Twice daily
  Warfarin	About 36–42 hours	Days to reach steady effect; INR takes days to change
  Digoxin	About 36 hours (longer in CKD)	Loading dose for rapid effect
  Levothyroxine	About 7 days	Check TFTs 6–8 weeks after a change
  Amiodarone	Weeks to months	Loading regimen; effects persist long after stopping
  Fluoxetine (with metabolite)	Days to weeks	Less withdrawal; long washout before MAOIs

• Loading dose -a larger first dose to reach the target level quickly, when waiting 4–5 half-lives would be too slow: digoxin, amiodarone, phenytoin (and levetiracetam in status), vancomycin, teicoplanin, aminophylline, warfarin (in some regimens), clopidogrel (300–600 mg in ACS), ticagrelor.
• Loading doses depend on Vd (not kidney function) -don't usually reduce a loading dose in kidney failure; reduce the maintenance dose instead.
• Monitoring timing -check levels at steady state (after 4–5 half-lives) unless toxicity is suspected (e.g. digoxin at least 6 hours post-dose; lithium 12 hours post-dose).

First-order and Zero-order Kinetics

• First-order kinetics (most drugs) -a constant fraction of drug is eliminated per unit time; the rate of elimination is proportional to the concentration; half-life is constant; doubling the dose doubles the level.
• Zero-order (saturable) kinetics -the elimination system is saturated, so a constant amount is eliminated per unit time; small dose increases cause large, unpredictable rises in levels; half-life gets longer at higher concentrations.
• Drugs showing zero-order kinetics at therapeutic or toxic doses:
  • Phenytoin -the classic example -increase doses in small steps and monitor levels.
  • Alcohol (ethanol) -eliminated at about 1 unit per hour.
  • Salicylate (aspirin) in overdose.
  • Theophylline (at higher levels), heparin (partly).
• Memory aid -"PAST" -Phenytoin, Alcohol, Salicylate, Theophylline.

What a Drug Does to the Body

• Pharmacodynamics -the effects of a drug and how they're produced.
• Main drug targets:
  • Receptors -e.g. beta-adrenoceptors (beta-blockers), opioid receptors (morphine), GABA-A receptors (benzodiazepines).
  • Enzymes -e.g. ACE (ACE inhibitors), cyclo-oxygenase (NSAIDs, aspirin), HMG-CoA reductase (statins), xanthine oxidase (allopurinol), acetylcholinesterase (donepezil).
  • Ion channels -e.g. sodium channels (lidocaine, carbamazepine), calcium channels (amlodipine), potassium channels (sulphonylureas, amiodarone).
  • Transporters -e.g. the proton pump (PPIs), SGLT2 (dapagliflozin), Na-K-2Cl co-transporter (furosemide), serotonin reuptake transporter (SSRIs), Na-K ATPase (digoxin).
  • Other -DNA and cell division (chemotherapy), bacterial targets (antibiotics), physical effects (osmotic laxatives, antacids), antibodies (biologics).
• Selectivity -few drugs act on only one target; side effects often come from actions elsewhere (e.g. beta-blockers in the lungs; anticholinergic effects of tricyclics).

Receptors, Agonists and Antagonists

• Agonist -binds and activates a receptor (e.g. salbutamol at beta-2, morphine at mu-opioid).
• Partial agonist -activates the receptor but produces a smaller maximum effect; can block full agonists -e.g. buprenorphine (opioid -can precipitate withdrawal in people using heroin or methadone; ceiling effect on respiratory depression), varenicline (nicotinic), pindolol.
• Antagonist -binds without activating, blocking agonists:
  • Competitive (reversible) -can be overcome by more agonist -e.g. naloxone (opioids), flumazenil (benzodiazepines), atropine (muscarinic), beta-blockers.
  • Non-competitive / irreversible -can't be overcome -e.g. aspirin (irreversible COX inhibition -effect lasts the platelet's lifespan, 7–10 days), clopidogrel (irreversible P2Y12), phenoxybenzamine (alpha), omeprazole (proton pump).
• Inverse agonist -produces the opposite effect to the agonist (some antihistamines).
• Short duration of antagonists -naloxone wears off (30–90 minutes) before long-acting opioids (methadone, MR morphine) -re-sedation can occur -monitor and repeat or infuse.
• Receptor changes with chronic use:
  • Down-regulation (fewer receptors) with chronic agonist use → tolerance (e.g. salbutamol, opioids).
  • Up-regulation with chronic antagonist use → rebound on stopping (e.g. beta-blocker withdrawal -angina, tachycardia; clonidine -rebound hypertension).

Dose–Response, Potency and Efficacy

• Dose–response curve -the effect rises with dose then plateaus at a maximum effect (Emax).
• Potency -the dose needed to produce a given effect (EC50) -a more potent drug works at a lower dose (e.g. fentanyl is more potent than morphine, bumetanide more potent than furosemide -1 mg bumetanide ≈ 40 mg furosemide).
• Efficacy -the maximum effect a drug can produce, regardless of dose (e.g. loop diuretics have greater efficacy than thiazides; full agonists more than partial agonists).
• Potency ≠ efficacy -a more potent drug is not necessarily more effective.
• Ceiling effect -above a certain dose, no extra benefit but more side effects (e.g. codeine, buprenorphine for respiratory depression, NSAIDs for pain, loop diuretics -though higher doses are needed in CKD).
• Clinical implications -titrate to effect; know the usual maximum doses; adding a drug with a different mechanism is often better than pushing one drug to its maximum (e.g. BP control).

Therapeutic Index and Variability

• Therapeutic index -the ratio between the toxic dose and the effective dose; a narrow therapeutic index means small changes in level can cause toxicity or loss of effect.
• Narrow therapeutic index drugs (often need monitoring) -digoxin, lithium, phenytoin, theophylline, aminoglycosides (gentamicin), vancomycin, warfarin, ciclosporin and tacrolimus, carbamazepine, methotrexate, insulin, levothyroxine (in some), antiarrhythmics.
• Therapeutic drug monitoring (TDM) is useful when:
  • There is a narrow therapeutic index.
  • Levels correlate with effect and toxicity.
  • Pharmacokinetics vary a lot between people.
  • Toxicity is suspected, adherence is in doubt, or there's an interacting drug or organ dysfunction.
  (See page 5.)
• Sources of variability between patients -age, weight, sex, pregnancy, kidney and liver function, heart failure (gut and liver blood flow), genetics, interactions, adherence, disease (thyroid, albumin), smoking and diet.
• Brand switching -for some narrow therapeutic index drugs, keep patients on the same brand (e.g. ciclosporin, tacrolimus, lithium, some antiepileptics -carbamazepine, phenytoin, phenobarbital -MHRA categories).

Tolerance, Dependence and Withdrawal

• Tolerance -reduced effect with repeated doses, needing higher doses for the same effect -e.g. opioids, benzodiazepines, alcohol, nitrates (prevented by a nitrate-free period -asymmetric dosing of isosorbide mononitrate, patch off overnight).
• Tachyphylaxis -rapid tolerance after a few doses (e.g. nasal decongestants -rebound congestion).
• Physical dependence -the body adapts, so stopping causes a withdrawal syndrome:
  • Opioids -yawning, sweating, rhinorrhoea, dilated pupils, abdominal cramps, diarrhoea, anxiety (unpleasant but rarely dangerous in adults).
  • Benzodiazepines and alcohol -anxiety, tremor, insomnia, seizures, delirium -can be life-threatening -taper slowly.
  • SSRIs and SNRIs (discontinuation symptoms) -dizziness, "electric shocks", irritability, flu-like symptoms -worse with short half-life drugs (paroxetine, venlafaxine).
  • Beta-blockers -rebound tachycardia and angina; clonidine -rebound hypertension.
  • Steroids -adrenal crisis after long-term use; flare of underlying disease.
  • Antiepileptics -seizures; Parkinson's drugs -neuroleptic malignant-like syndrome; baclofen -seizures, hallucinations.
  • Gabapentinoids -anxiety, insomnia, seizures.
• Addiction -compulsive use despite harm, craving and loss of control -different from physical dependence (see the Psychiatry chapter on Alcohol, Drugs and Addiction).

Pharmacogenomics

• Genetic variation changes how people handle or respond to drugs -growing use of genetic testing in UK practice.
• Important examples:

  Gene	Drug	Effect
  TPMT (and NUDT15)	Azathioprine, mercaptopurine	Low activity → severe bone marrow suppression -test before starting
  DPYD	5-fluorouracil, capecitabine	Deficiency → severe, potentially fatal toxicity -test before starting (UK standard)
  HLA-B*57:01	Abacavir (HIV)	Hypersensitivity reaction -test before starting
  HLA-B*15:02	Carbamazepine (and phenytoin)	SJS/TEN -test in people of Han Chinese, Thai and some other Asian ancestry
  HLA-B*58:01	Allopurinol	Severe cutaneous reactions -higher risk in Han Chinese, Thai, Korean ancestry
  CYP2D6	Codeine, tramadol	Ultra-rapid metabolisers make too much morphine (toxicity -deaths in breastfed infants and children); poor metabolisers get little effect
  CYP2C19	Clopidogrel	Poor metabolisers → less active drug → more stent thrombosis and strokes (UK testing now used after stroke/TIA)
  G6PD deficiency	Primaquine, dapsone, nitrofurantoin, sulfonamides, rasburicase, quinolones	Haemolysis
  Acetylator status (NAT2)	Isoniazid, hydralazine, procainamide	Slow acetylators -neuropathy (isoniazid), drug-induced lupus
  Pseudocholinesterase deficiency	Suxamethonium	Prolonged paralysis ("scoline apnoea")
  Ryanodine receptor (RYR1)	Volatile anaesthetics, suxamethonium	Malignant hyperthermia -dantrolene
  MT-RNR1 (mitochondrial)	Aminoglycosides	Permanent deafness -rapid genetic test in neonates needing gentamicin

Choosing a Route

Route	Advantages	Disadvantages and points
Oral	Simple, cheap, patient-controlled	Variable absorption, first-pass, needs swallowing and working gut
Intravenous	100% bioavailability, fast, titratable	Infection, phlebitis, extravasation, errors, needs access; switch to oral when possible (IV-to-oral switch)
Intramuscular	Depot preparations (antipsychotics), vaccines, emergencies (adrenaline, glucagon)	Painful; avoid with anticoagulation or low platelets; unreliable in shock
Subcutaneous	Insulin, LMWH, palliative syringe drivers, some biologics	Limited volume; poor absorption in shock or oedema
Sublingual / buccal	Avoids first pass, fast (GTN, buprenorphine, midazolam in seizures)	Limited drugs
Transdermal	Steady levels, avoids first pass (fentanyl, buprenorphine, rotigotine, HRT, nicotine)	Slow onset and offset; heat increases absorption; not for acute pain
Inhaled	Direct to lungs, fewer systemic effects (asthma, COPD)	Technique matters; spacers help
Rectal	Vomiting, seizures (diazepam), local disease	Variable absorption; acceptability
Intrathecal	Spinal anaesthesia, some chemotherapy	Specialist only -never give vincristine intrathecally (fatal -"never event")

Key Drug Mechanisms to Know

Drug group	Mechanism	Key adverse effects
ACE inhibitors	Block angiotensin I → II conversion; reduce bradykinin breakdown	Dry cough, hyperkalaemia, AKI, angioedema, first-dose hypotension
Beta-blockers	Block beta-1 (± beta-2) adrenoceptors	Bradycardia, bronchospasm (asthma), fatigue, cold peripheries, masked hypoglycaemia
Calcium channel blockers	Dihydropyridines (amlodipine) -vessels; rate-limiting (verapamil, diltiazem) -heart	Ankle oedema, flushing; bradycardia and heart failure (verapamil)
Loop diuretics	Block Na-K-2Cl in the loop of Henle	Hypokalaemia, hyponatraemia, dehydration, AKI, gout, ototoxicity
Thiazides	Block Na-Cl in the distal tubule	Hyponatraemia, hypokalaemia, gout, hyperglycaemia
Statins	Inhibit HMG-CoA reductase	Myalgia, myopathy, raised ALT
PPIs	Irreversibly block the H+/K+ ATPase	C. difficile, low magnesium, low sodium, fractures
NSAIDs	Inhibit COX-1 and COX-2 (fewer prostaglandins)	GI bleeding, AKI, fluid retention, asthma, CV risk
Opioids	Mu-opioid agonists	Constipation, nausea, drowsiness, respiratory depression, dependence
SSRIs	Block serotonin reuptake	Hyponatraemia, GI upset, bleeding, sexual dysfunction, serotonin syndrome
Metformin	Reduces hepatic glucose output; improves insulin sensitivity	GI upset, lactic acidosis (rare), B12 deficiency
Warfarin	Blocks vitamin K epoxide reductase (factors II, VII, IX, X)	Bleeding, many interactions, teratogenic
DOACs	Direct factor Xa (apixaban, rivaroxaban, edoxaban) or thrombin (dabigatran) inhibition	Bleeding; kidney dosing
Penicillins	Inhibit bacterial cell wall synthesis	Allergy, diarrhoea, C. difficile; cholestasis (co-amoxiclav, flucloxacillin)

Pharmacology Terms at a Glance

Term	Meaning and example
Bioavailability	Fraction reaching circulation; IV = 100%; oral morphine about 30–50%
First-pass metabolism	Gut and liver metabolism before circulation -GTN given sublingually
Volume of distribution	Large Vd (amiodarone, digoxin) -needs loading dose; not dialysable
Clearance	Determines maintenance dose
Half-life	Steady state and elimination take 4–5 half-lives
Loading dose	Depends on Vd; not reduced in kidney failure
Zero-order kinetics	Phenytoin, alcohol, salicylate, theophylline
Prodrug	Codeine, clopidogrel, enalapril, levodopa, azathioprine
Enzyme inducers	Rifampicin, carbamazepine, phenytoin, St John's wort -lower other drugs' levels
Enzyme inhibitors	Clarithromycin, azoles, ritonavir, grapefruit, amiodarone -raise levels
Partial agonist	Buprenorphine, varenicline
Competitive antagonist	Naloxone, flumazenil, atropine
Irreversible inhibitor	Aspirin, clopidogrel, PPIs
Narrow therapeutic index	Digoxin, lithium, phenytoin, theophylline, gentamicin, warfarin, ciclosporin
Tolerance	Nitrates (need nitrate-free period), opioids, benzodiazepines

Spot the Concept

Clue	Concept
Oral morphine dose is about twice the subcutaneous dose	First-pass metabolism (bioavailability)
GTN is useless if swallowed	Extensive first-pass metabolism
Amiodarone side effects persist for months after stopping	Very large Vd, very long half-life
Phenytoin level jumps from 12 to 30 mg/L after a small dose increase	Zero-order (saturable) kinetics
Phenytoin toxicity with a "normal" total level and albumin 20 g/L	Increased free fraction -correct for albumin
Codeine gives no pain relief in one patient and drowsiness in another	CYP2D6 poor vs ultra-rapid metaboliser
Clopidogrel works less well in some patients	CYP2C19 poor metabolisers (prodrug)
Combined pill fails in a woman on rifampicin	Enzyme induction
Rhabdomyolysis in a man on simvastatin given clarithromycin	CYP3A4 inhibition
Ciprofloxacin ineffective when taken with calcium supplements	Chelation reducing absorption
Withdrawal symptoms when buprenorphine is given to a heroin user	Partial agonist displacing full agonist
Patient re-sedated 1 hour after naloxone for a methadone overdose	Antagonist shorter-acting than agonist
Angina worsens on continuous high-dose nitrates	Nitrate tolerance -need nitrate-free period
Chest pain after stopping propranolol suddenly	Beta-blocker withdrawal (receptor up-regulation)
Aspirin's antiplatelet effect lasts 7–10 days after stopping	Irreversible COX inhibition
Bone marrow failure on azathioprine in a patient with low TPMT	Pharmacogenetic toxicity
Haemolysis after primaquine	G6PD deficiency
Prolonged paralysis after suxamethonium	Pseudocholinesterase deficiency

Exam-style Scenarios

1. A 72-year-old man with new fast AF and heart failure is started on oral digoxin 125 micrograms daily. Three days later his heart rate is still 130.
Answer: Digoxin without a loading dose -not yet at steady state.

• Digoxin has a long half-life (about 36 hours, longer in CKD) and a large Vd -steady state takes about a week without loading.
• A loading dose (e.g. total 0.75–1.5 mg in divided doses over 24 hours, per BNF) gives a faster effect; the loading dose isn't reduced in CKD, but the maintenance dose is.
• Check potassium (hypokalaemia increases toxicity) and kidney function; monitor levels if toxicity is suspected (at least 6 hours post-dose).

2. A 34-year-old woman on the combined oral contraceptive pill is started on rifampicin for TB. She asks if there is anything she should know.
Answer: Enzyme induction reduces contraceptive effectiveness.

• Rifampicin strongly induces CYP3A4, lowering oestrogen and progestogen levels -risk of pregnancy.
• Advise a method unaffected by enzyme inducers -copper IUD, levonorgestrel IUS or progestogen injection -during treatment and for 28 days after stopping.
• Also warn that rifampicin turns urine, tears and contact lenses orange, and check for other interactions (warfarin, DOACs, antiretrovirals, steroids).

3. A 50-year-old man with epilepsy on phenytoin has his dose increased from 300 mg to 350 mg daily for breakthrough seizures. Two weeks later he is ataxic with nystagmus and slurred speech.
Answer: Phenytoin toxicity due to zero-order kinetics.

• Phenytoin metabolism is saturable -a small dose increase can cause a disproportionate rise in levels.
• Check a phenytoin level (and albumin -adjust for low albumin); withhold doses until symptoms settle, then restart at a lower dose.
• Look for interacting drugs (enzyme inhibitors -e.g. clarithromycin, fluconazole, amiodarone).

4. A 28-year-old woman is breastfeeding her 10-day-old baby. She was prescribed co-codamol after a caesarean section. The baby is now very sleepy and feeding poorly.
Answer: Possible opioid toxicity in the infant -maternal CYP2D6 ultra-rapid metabolism of codeine.

• Stop codeine; urgent paediatric assessment of the baby (respiratory depression; naloxone if needed).
• Codeine is contraindicated in breastfeeding (MHRA) and in children under 12 (and under 18 after tonsillectomy for sleep apnoea).
• Use paracetamol and ibuprofen; if a stronger opioid is needed, short-term low-dose morphine with monitoring of the baby.

5. A 62-year-old man with a heroin overdose wakes after IV naloxone 400 micrograms and wants to leave. He used long-acting methadone as well.
Answer: Risk of re-sedation after naloxone wears off.

• Naloxone acts for 30–90 minutes; methadone lasts much longer -respiratory depression can return.
• Observe (often 6 hours or more after the last naloxone dose for long-acting opioids); consider a naloxone infusion.
• Assess capacity if he wants to leave; explain the risk; harm reduction -take-home naloxone, drug services.

Key Points

• Pharmacokinetics -absorption, distribution, metabolism, excretion; pharmacodynamics -what the drug does.
• Bioavailability is 100% IV; first-pass metabolism lowers oral bioavailability (GTN, morphine, propranolol).
• Large Vd drugs (digoxin, amiodarone) need loading doses and aren't removed by dialysis.
• Low albumin increases free phenytoin and warfarin.
• Steady state and elimination take about 4–5 half-lives.
• Loading doses depend on Vd; maintenance doses depend on clearance -reduce maintenance doses in kidney failure.
• Zero-order kinetics -phenytoin, alcohol, salicylate, theophylline.
• Prodrugs -codeine, clopidogrel, ACE inhibitors, levodopa, azathioprine.
• Enzyme inducers lower other drugs' levels (rifampicin, carbamazepine, phenytoin, St John's wort); inhibitors raise them (clarithromycin, azoles, ritonavir, grapefruit, amiodarone).
• Partial agonists (buprenorphine) can precipitate withdrawal; naloxone is shorter-acting than many opioids.
• Potency is the dose needed; efficacy is the maximum effect.
• Narrow therapeutic index drugs need careful dosing and often monitoring.
• Taper benzodiazepines, beta-blockers, steroids, antiepileptics, SSRIs and opioids -don't stop abruptly.
• Pharmacogenomic tests before azathioprine (TPMT), fluorouracil (DPYD), abacavir (HLA-B*57:01) and carbamazepine in some ancestries (HLA-B*15:02).
• Codeine is contraindicated in breastfeeding and young children (CYP2D6 ultra-rapid metabolisers).

Guidelines and Further Reading

• British National Formulary (BNF) -guidance on prescribing; interactions; appendices
• British Pharmacological Society: Prescribing Safety Assessment (PSA) resources
• Ritter JM et al.: Rang and Dale's Pharmacology; Ritter's A Textbook of Clinical Pharmacology and Therapeutics
• MHRA Drug Safety Updates: Codeine in children and breastfeeding; Antiepileptic drug brand switching
• NHS England Genomic Medicine Service: Pharmacogenomic testing (DPYD, TPMT, CYP2C19)
• Specialist Pharmacy Service (SPS): Medicines advice
• BNF -for current doses