Pharmacokinetics, adverse drug reactions, drug interactions, prescribing in special populations, and toxicology essentials.
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Pharmacokinetics
The study of drug absorption, distribution, metabolism, and excretion (ADME). Determines the time course of drug concentration in the body. Key concepts include bioavailability, volume of distribution, clearance, half-life, and steady state. Essential for rational prescribing, dose adjustment in organ impairment, and understanding drug interactions.
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Key Facts
ADME: Absorption, Distribution, Metabolism, Excretion - the four pharmacokinetic processes
Bioavailability (F): fraction of administered drug reaching systemic circulation unchanged; IV = 100% by definition
Volume of distribution (Vd): apparent volume into which drug distributes; high Vd = extensive tissue binding (e.g. amiodarone ~70 L/kg)
Half-life (t½): time for plasma concentration to fall by 50%; steady state reached at ~5 half-lives
Clearance (CL): volume of plasma cleared of drug per unit time; CL = Dose × F / AUC
Zero-order kinetics: constant rate of elimination regardless of concentration (ethanol, phenytoin at high doses, aspirin overdose)
First-order kinetics: rate of elimination proportional to drug concentration - most drugs follow this
Overview
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)
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)
The study of the biochemical and physiological effects of drugs on the body ('what the drug does to the body'). Encompasses receptor theory, dose-response relationships, agonism, antagonism, and signal transduction. Key concepts include efficacy, potency, therapeutic index, and receptor types. Underpins rational drug selection and understanding of drug effects and side effects.
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Key Facts
Pharmacodynamics: 'what the drug does to the body' - drug-receptor interactions and downstream effects
Agonist: binds receptor and activates it - full agonist (maximal response) vs partial agonist (submaximal, e.g. buprenorphine)
Antagonist: binds receptor without activating - competitive (reversible, surmountable, e.g. naloxone) or non-competitive (irreversible, e.g. phenoxybenzamine)
Potency: dose required to produce a given effect (ED50) - relates to receptor binding affinity
Efficacy: maximum effect achievable regardless of dose - relates to intrinsic activity
Therapeutic index: ratio of TD50/ED50 - narrow TI drugs require careful monitoring (digoxin, lithium, warfarin, aminoglycosides)
Four receptor superfamilies: ligand-gated ion channels, G-protein coupled receptors, tyrosine kinase receptors, nuclear/intracellular receptors
Dose-response curve: plots drug concentration vs response - sigmoidal shape; shifted right by competitive antagonist
Overview
Key Facts
Pharmacodynamics provides the theoretical framework for understanding how drugs produce their effects. Combined with pharmacokinetics, it enables rational prescribing and prediction of drug effects, side effects, and interactions.
Receptor Theory
Drugs produce effects by interacting with biological targets - mostly receptors, but also enzymes, ion channels, and transporters
Affinity: ability of drug to bind to receptor
Intrinsic activity (efficacy at receptor): ability of drug-receptor complex to produce a response
Agonist: has affinity AND intrinsic activity
Antagonist: has affinity but NO intrinsic activity
Dose-Response Relationships
Graded dose-response: increasing dose → increasing response in an individual
Quantal dose-response: percentage of population responding at each dose
ED50: dose producing 50% maximal effect
TD50: dose causing toxicity in 50% of population
LD50: dose causing death in 50% (animal studies)
Therapeutic index = TD50/ED50 (or LD50/ED50)
Signal Transduction
Four major receptor superfamilies:
Ligand-gated ion channels (ionotropic): fastest response (milliseconds) - e.g. nicotinic ACh receptor, GABA_A receptor
Drug metabolism occurs predominantly in the liver via Phase I (oxidation/reduction - mainly CYP450 enzymes) and Phase II (conjugation) reactions. The cytochrome P450 system is the most important drug-metabolising enzyme family. CYP3A4 metabolises ~50% of drugs. Enzyme induction and inhibition are the most common causes of pharmacokinetic drug interactions.
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Key Facts
Phase I (functionalisation): oxidation, reduction, hydrolysis - CYP450 enzymes; introduces/exposes functional group
Phase II (conjugation): glucuronidation, sulfation, acetylation, methylation - increases water solubility for excretion
CYP3A4: metabolises ~50% of all drugs; located in liver and gut wall; key interaction target
Induction: takes days–weeks (new enzyme synthesis); increases drug clearance → reduced effect of substrate drug
Inhibition: rapid onset (hours); decreases drug clearance → increased effect/toxicity of substrate drug
Overview
Key Facts
Drug metabolism is the body's primary mechanism for eliminating lipophilic drugs. The cytochrome P450 system is central to this process. Understanding enzyme induction and inhibition is essential for predicting and managing drug interactions.
Phase I Metabolism
Cytochrome P450 (CYP) enzymes: superfamily of haem-containing monooxygenases, predominantly in hepatic endoplasmic reticulum
Most important CYPs: CYP3A4 (~50% of drugs), CYP2D6 (~25%), CYP2C9, CYP2C19, CYP1A2, CYP2E1
Clinically significant modifications of drug effect caused by co-administration of another drug, food, or herbal product. Classified as pharmacokinetic (ADME) or pharmacodynamic (additive/synergistic/antagonistic effects at receptors). Drug interactions are a major cause of adverse drug events, particularly in elderly patients with polypharmacy. BNF interactions checker is the key UK prescribing resource.
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Key Facts
Pharmacokinetic interactions: affect absorption, distribution, metabolism (CYP450 induction/inhibition), or excretion
Pharmacodynamic interactions: additive, synergistic, or antagonistic effects at the same or related receptors/pathways
QT prolongation: multiple QT-prolonging drugs → risk of torsades de pointes - e.g. amiodarone + macrolides + ondansetron
BNF interactions checker: essential prescribing tool - classifies interactions as mild, moderate, or severe
Overview
Key Facts
Drug interactions are a leading cause of preventable adverse drug events. With increasing polypharmacy, the risk of interactions rises exponentially. Awareness of the most clinically important interactions is essential for safe prescribing.
Epidemiology
Drug interactions account for ~1% of hospital admissions and ~3–5% of in-hospital adverse drug events
Risk increases exponentially with number of drugs: 2 drugs = 6% risk; 5 drugs = 50% risk; 8+ drugs = nearly 100%
Elderly most affected: polypharmacy + altered PK/PD
The concurrent use of multiple medications, typically defined as ≥5 drugs. Affects ~30% of adults >65 years in the UK. Associated with increased risk of adverse drug reactions, drug interactions, falls, hospitalisation, and mortality. Structured medication review and deprescribing are the cornerstones of management. NICE NG5 provides guidance on medicines optimisation.
Structured medication review (SMR): NICE NG5 recommends at least annually for patients with polypharmacy
STOPP/START criteria: evidence-based screening tool for potentially inappropriate prescribing in older adults
Deprescribing: planned, supervised withdrawal of inappropriate medications - taper gradually
Anticholinergic burden: cumulative anticholinergic effect of multiple drugs → cognitive impairment, falls, constipation, urinary retention
Overview
Key Facts
Polypharmacy is a growing challenge driven by an ageing population and increasing multi-morbidity. While some polypharmacy is appropriate ('necessary polypharmacy'), much is problematic. Structured medication review and deprescribing can significantly reduce harm.
Epidemiology
UK: ~30% of adults >65 take ≥5 regular medications
~10% of adults >65 take ≥10 regular medications
Care home residents: average ~8 medications
ADRs cause ~6.5% of hospital admissions; >70% are predictable and preventable
NHS cost of ADR-related admissions: ~£500 million/year
Aetiology
Multi-morbidity: multiple conditions each requiring treatment
Clinical guidelines: guideline adherence for each condition individually → cumulative pill burden
Prescribing cascade: ADR misinterpreted as new disease → additional drug
Fragmented care: multiple prescribers without coordination
Patient expectations: perceived need for medication for every symptom
Failure to review: 'drug accumulation' - medications started but never stopped
Pathophysiology
Pharmacokinetic changes in elderly: reduced renal clearance, hepatic blood flow, lean body mass, increased body fat, reduced albumin
Pharmacodynamic changes: increased sensitivity to sedatives, anticoagulants, anticholinergics
Drug interactions: risk increases exponentially with number of medications
Anticholinergic burden: cumulative effect of drugs with anticholinergic properties → confusion, falls, constipation, urinary retention, dry mouth
Unwanted or harmful effects caused by medication at normal therapeutic doses. ADRs cause ~6.5% of UK hospital admissions and are the fourth leading cause of death in developed countries. Classified as Type A (dose-dependent, predictable) or Type B (idiosyncratic, unpredictable). MHRA Yellow Card scheme is the UK reporting system. NICE CG183 covers drug allergy management.
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Key Facts
~6.5% of hospital admissions in UK are caused by ADRs; >70% are preventable
Type A (augmented): dose-dependent, predictable, common (~80% of ADRs) - e.g. bleeding with warfarin, hypoglycaemia with insulin
Type B (bizarre): dose-independent, unpredictable, often immune-mediated, rare - e.g. anaphylaxis, SJS/TEN, DRESS
Type C (chronic): long-term use - e.g. osteoporosis with corticosteroids, nephropathy with NSAIDs
Type D (delayed): occurs after a delay - e.g. malignancy after immunosuppression
MHRA Yellow Card scheme: UK national ADR reporting system - report ALL suspected ADRs for new drugs (▼) and serious ADRs for established drugs
Naranjo scale: probability scale to assess causality of suspected ADR (definite, probable, possible, doubtful)
Common culprits: NSAIDs, anticoagulants, antibiotics, diuretics, opioids, chemotherapy
Overview
Key Facts
ADRs are a major cause of morbidity, mortality, and healthcare cost. The majority are preventable with careful prescribing, monitoring, and patient education. Recognition and reporting are essential for improving drug safety.
Epidemiology
~6.5% of hospital admissions attributable to ADRs in UK (Pirmohamed et al., BMJ 2004)
~2–5% of in-hospital patients experience ADRs
ADRs are the 4th leading cause of death in developed countries
~70% of ADR-related admissions are potentially preventable
Cost to NHS: ~£500 million–£1 billion/year
Classification (Rawlins-Thompson)
Type A (Augmented): dose-dependent, predictable from pharmacology; common; rarely fatal; manageable with dose reduction - e.g. hypotension with antihypertensives, bleeding with anticoagulants
Type B (Bizarre): dose-independent, unpredictable, often immune-mediated; uncommon but may be fatal - e.g. anaphylaxis, SJS/TEN, DRESS, hepatotoxicity
Type C (Chronic): related to cumulative dose/duration - e.g. osteoporosis (steroids), analgesic nephropathy
Type D (Delayed): delayed onset after exposure - e.g. secondary malignancy (cytotoxics), teratogenicity
Type E (End-of-use): withdrawal reactions - e.g. seizures (benzodiazepines), rebound hypertension (clonidine, beta-blockers)
Pathophysiology
Type A: extension of pharmacological action - dose-dependent; related to PK (altered absorption, metabolism, excretion) and PD (receptor sensitivity)
Type B: immune-mediated (Types I–IV hypersensitivity) or pharmacogenetic - e.g. HLA associations, enzyme deficiencies (G6PD, TPMT)
Risk factors: polypharmacy, extremes of age, renal/hepatic impairment, genetic polymorphisms, female sex, previous ADR history
An immune-mediated adverse drug reaction involving specific immunological mechanisms (Types I–IV hypersensitivity). Most commonly caused by penicillins, NSAIDs, and neuromuscular blocking agents. True allergy must be distinguished from non-allergic ADRs. NICE CG183 provides guidance on diagnosis, documentation, and management. Specialist allergy assessment can confirm or exclude allergy safely.
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Key Facts
Immune-mediated: Types I–IV hypersensitivity; distinct from non-immune ADRs (e.g. GI upset with antibiotics)
Penicillin allergy: most commonly reported drug allergy; ~90% of those labelled are NOT truly allergic on formal testing
Type I (IgE-mediated): urticaria, angioedema, anaphylaxis - minutes to hours after exposure
Type IV (T-cell mediated): maculopapular rash, SJS/TEN, DRESS - days to weeks after exposure
NICE CG183: drug allergy - diagnosis and management of drug allergy in adults, young people and children
Mast cell tryptase: elevated 1–6 hours after anaphylaxis; confirms diagnosis
Allergy testing: skin prick test, specific IgE, graded drug challenge - specialist allergy clinic
Delabelling: removing incorrect penicillin allergy labels - improves antibiotic stewardship; ~90% can be safely delabelled
Overview
Key Facts
Drug allergy is a specific immune-mediated adverse drug reaction. It is critically important because incorrect allergy labelling leads to suboptimal prescribing (broader-spectrum antibiotics, increased costs, resistance), while true allergy can be life-threatening.
Epidemiology
~10% of UK population labelled as 'penicillin allergic' - but ~90% are NOT truly allergic on formal testing
Anaphylaxis: ~1 in 5,000 anaesthetics; ~1 in 100,000 penicillin exposures
Drug allergy accounts for ~10% of all adverse drug reactions
Most common causative drugs: penicillins, cephalosporins, NSAIDs, neuromuscular blocking agents
Classification (Gell and Coombs)
Type I (IgE-mediated/immediate): minutes to hours; urticaria, angioedema, bronchospasm, anaphylaxis
Type II (cytotoxic): hours to days; drug-induced haemolytic anaemia, thrombocytopenia
Type III (immune complex): days to weeks; serum sickness, vasculitis
Type IV (T-cell mediated/delayed): days to weeks; maculopapular rash, contact dermatitis, SJS/TEN, DRESS
Pathophysiology
Type I: drug/metabolite acts as hapten
IgE production
mast cell/basophil degranulation on re-exposure
histamine, tryptase, prostaglandins
anaphylaxis
Type IV: drug-specific T-cells
cytokine release, direct cytotoxicity
tissue damage
Cross-reactivity: penicillin ↔ cephalosporin cross-reactivity ~2% (previously overestimated at 10%)
Renal impairment significantly affects drug pharmacokinetics, requiring dose adjustment for renally cleared drugs. Key considerations include reduced drug clearance, altered protein binding, and increased sensitivity to nephrotoxic drugs. The BNF renal appendix provides dose guidance based on eGFR or creatinine clearance. Essential drugs to adjust include metformin, DOACs, digoxin, gentamicin, and lithium.
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Key Facts
Reduced renal clearance: accumulation of renally excreted drugs → toxicity
eGFR (CKD-EPI) or creatinine clearance (Cockcroft-Gault): used to guide dose adjustment; BNF uses CrCl for most drugs
DOACs: dose reduction required in renal impairment; dabigatran particularly dependent on renal clearance (~80%)
Loading doses: usually NOT adjusted in renal impairment (depends on Vd, not clearance); maintenance doses need adjustment
Sick day rules: temporarily stop ACE-i/ARB, diuretics, metformin, NSAIDs during acute illness/dehydration
Overview
Key Facts
Prescribing in renal impairment is one of the most important aspects of safe drug therapy. Renal impairment affects all aspects of pharmacokinetics and increases sensitivity to many drugs. The BNF provides essential guidance on dose adjustment.
Epidemiology
CKD affects ~13% of UK population (stages 3–5)
ADRs more common in renal impairment - drug accumulation is a leading cause
AKI affects ~20% of emergency hospital admissions; often drug-related
Pharmacokinetic Changes in Renal Impairment
Absorption: may be altered by nausea, GI oedema; rarely significant
Distribution
reduced protein binding (uraemia + hypoalbuminaemia)
increased free drug
increased effect/toxicity (e.g. phenytoin)
Metabolism: generally preserved; some renal metabolism reduced (e.g. insulin degradation in kidneys)
Excretion: most important change - reduced GFR and tubular secretion → drug accumulation
Pharmacodynamic Changes
Increased sensitivity to sedatives, opioids, anticoagulants
Altered electrolyte handling → hyperkalaemia risk with ACE-i/ARBs/K-sparing diuretics
Impaired platelet function in uraemia → increased bleeding risk
Impaired immune function → increased infection risk
Pathophysiology
Reduced nephron mass
reduced GFR
decreased filtration/secretion of drugs
Accumulation of uraemic toxins → altered drug binding and receptor sensitivity
Fluid overload → altered volume of distribution for water-soluble drugs
Liver disease significantly alters drug pharmacokinetics through reduced metabolism (Phase I > Phase II), decreased protein synthesis (reduced albumin → increased free drug), altered volume of distribution (ascites), and portal-systemic shunting. The Child-Pugh score guides prescribing. Hepatotoxic drugs must be avoided or used with extreme caution. No single liver test reliably predicts drug-metabolising capacity.
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Key Facts
Phase I metabolism reduced first: CYP450 activity declines with liver disease; Phase II (conjugation) relatively preserved until severe disease
Child-Pugh score: classifies severity (A, B, C) - guides drug dose adjustments; no direct correlation with drug-metabolising capacity
Hepatotoxic drugs to avoid: methotrexate, paracetamol (reduce max dose), isoniazid, valproate, statins (monitor LFTs)
Coagulopathy: reduced clotting factor synthesis → increased sensitivity to anticoagulants
Hepatic encephalopathy risk: sedatives (benzodiazepines, opioids) may precipitate or worsen encephalopathy
No reliable predictive test: LFTs do not directly correlate with drug metabolism - clinical judgement essential
Overview
Key Facts
Prescribing in hepatic impairment is more complex than renal impairment because there is no single test equivalent to eGFR to quantify hepatic drug-handling capacity. Clinical assessment, Child-Pugh score, and cautious prescribing are essential.
Pharmacokinetic Changes
Absorption
portal-systemic shunting
drugs bypass first-pass metabolism
increased oral bioavailability (e.g. morphine bioavailability increases from ~30% to ~80%)
Distribution
reduced albumin
increased free drug fraction; ascites
increased Vd for water-soluble drugs
Metabolism: Phase I (CYP450) reduced first; Phase II (glucuronidation, etc.) relatively preserved until advanced disease
Excretion: biliary excretion may be impaired (cholestasis); renal function often impaired too (hepatorenal syndrome)
Pharmacodynamic Changes
Increased CNS sensitivity: to benzodiazepines, opioids - risk of precipitating hepatic encephalopathy
Coagulopathy: reduced synthesis of clotting factors → increased sensitivity to warfarin and other anticoagulants
Hypoalbuminaemia: altered drug binding → increased effect of protein-bound drugs
Portal hypertension: may increase susceptibility to GI bleeding with NSAIDs/anticoagulants
Pathophysiology
Progressive hepatocyte loss → reduced CYP450 content and enzyme activity
Drug prescribing in pregnancy requires balancing the risk of teratogenicity and fetal harm against the risk of untreated maternal disease. Most drugs cross the placenta. Key teratogens include valproate, methotrexate, ACE inhibitors, warfarin, retinoids, and lithium. The BNF and UK Teratology Information Service (UKTIS) provide guidance. Folate supplementation (400 mcg–5 mg daily) reduces neural tube defect risk.
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Key Facts
Most drugs cross the placenta by passive diffusion - lipophilic, non-ionised, low molecular weight drugs cross most readily
Critical period for teratogenesis: weeks 3–8 post-conception (organogenesis); first trimester is highest risk
Sodium valproate: most teratogenic commonly prescribed drug - NTDs (~7%), cardiac defects, developmental delay; MHRA Pregnancy Prevention Programme
Folic acid: 400 mcg OD pre-conception and until 12 weeks (all women); 5 mg if on antiepileptics, previous NTD, diabetes, BMI >30
UKTIS (UK Teratology Information Service): expert resource for prescribers - advises on drug safety in pregnancy
Overview
Key Facts
Prescribing in pregnancy is a common clinical challenge. The key principle is to use the minimum effective dose of the safest available drug, balanced against the risk of untreated disease to both mother and fetus.
Epidemiology
~50% of pregnancies are unplanned - teratogen exposure may occur before pregnancy is recognised
~90% of pregnant women take at least one medication during pregnancy
Congenital anomalies: ~2–3% of births; drug-related in ~1–2%
Most drugs are excreted into breast milk to some degree, but the infant dose is usually <1–2% of the maternal dose and clinically insignificant. The benefits of breastfeeding usually outweigh the risks of maternal medication. Key drugs to avoid include cytotoxics, amiodarone, lithium (relative), and radioactive iodine. The BNF, UKTIS, and LactMed database provide guidance.
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Key Facts
Most drugs are compatible with breastfeeding: infant exposure usually <1–2% of maternal dose
Factors affecting drug transfer to milk: lipophilicity, protein binding, molecular weight, ionisation, maternal plasma level
Relative infant dose (RID): <10% of maternal weight-adjusted dose is generally considered safe
Drugs to AVOID: cytotoxics, amiodarone, ergotamine, radioactive iodine, gold salts
Paracetamol, ibuprofen, most penicillins: safe in breastfeeding
Benefits of breastfeeding usually outweigh the risks of most medications - do not unnecessarily stop breastfeeding
LactMed (NIH): evidence-based database for drug safety in breastfeeding
Overview
Key Facts
The decision to prescribe during breastfeeding should consider the importance of the drug to the mother, the safety of the drug for the infant, and the benefits of continuing breastfeeding. Unnecessary avoidance of medication or unnecessary cessation of breastfeeding should be avoided.
Principles of Drug Transfer into Breast Milk
Most drugs enter breast milk by passive diffusion
Factors promoting transfer: high lipophilicity, low protein binding, low molecular weight (<500 Da), non-ionised form, high maternal plasma levels
Colostrum: more permeable than mature milk - first few days higher transfer, but volumes are small
Timing: drug levels in milk mirror plasma levels - feed just before next dose (trough level) to minimise exposure
Pharmacokinetic Considerations
Infant oral bioavailability: many drugs poorly absorbed orally by infant (e.g. aminoglycosides, heparin) → minimal systemic exposure even if present in milk
Infant metabolism: neonates have immature hepatic and renal function → impaired drug clearance
Premature infants: most vulnerable - immature organ function, higher susceptibility
Pathophysiology
Drug in maternal plasma
crosses alveolar epithelium of mammary gland by passive diffusion
enters breast milk
Milk:plasma ratio: <1 for most drugs (lower concentration in milk than plasma)
Relative infant dose (RID) = (dose via milk / maternal dose) adjusted for weight - RID <10% generally safe
Elderly patients (≥65 years) are at increased risk of adverse drug reactions due to altered pharmacokinetics, pharmacodynamics, multi-morbidity, polypharmacy, and frailty. ADRs cause ~10% of hospital admissions in the elderly. Key principles: 'start low, go slow', regular medication review, use STOPP/START criteria, and deprescribe where appropriate. NICE NG5 and NG56 provide guidance.
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Key Facts
ADRs cause ~10% of hospital admissions in patients >65 years - most are preventable
'Start low, go slow': use lower starting doses and titrate cautiously
Reduced renal function: GFR declines ~1 mL/min/year after age 40 - affects drug clearance even with normal creatinine
Increased drug sensitivity: CNS (sedatives, opioids), cardiovascular (antihypertensives), haemostasis (anticoagulants)
Anticholinergic burden: cumulative effect → confusion, falls, constipation, urinary retention - use ACB calculator
STOPP/START criteria: systematic screening for inappropriate prescribing and omissions in elderly
Beers criteria: American Geriatrics Society - list of potentially inappropriate medications in older adults
Overview
Key Facts
The elderly are the largest consumers of prescribed medications and the most vulnerable to adverse drug effects. Age-related physiological changes, multi-morbidity, and polypharmacy combine to create a high-risk prescribing environment.
Epidemiology
UK: >65s represent ~18% of population but receive ~50% of all prescriptions
~30% of >65s take ≥5 regular medications
ADRs: ~10% of hospital admissions in elderly; >70% preventable
Falls: medication-related falls account for significant morbidity and mortality
Pharmacokinetic Changes
Absorption: relatively unchanged; slight reduction in gastric acid and motility
Distribution
increased body fat
increased Vd for lipophilic drugs (diazepam, amiodarone); decreased lean body mass
decreased Vd for water-soluble drugs; decreased albumin
Excretion: reduced GFR (~1 mL/min/year decline after 40) → reduced renal drug clearance; serum creatinine may be misleadingly normal due to reduced muscle mass
Pharmacodynamic Changes
Increased sensitivity to CNS drugs (benzodiazepines, opioids)
Increased sensitivity to anticoagulants
Impaired baroreceptor reflexes → postural hypotension with antihypertensives
Reduced beta-adrenoceptor sensitivity → reduced response to beta-agonists
Impaired thermoregulation → hypothermia risk with sedatives
Pathophysiology
Physiological reserve declines with age → reduced ability to compensate for drug effects
Homeostatic mechanisms (baroreceptors, glucose regulation, temperature) less effective
Cognitive impairment → medication non-adherence and error
Frailty → increased vulnerability to adverse drug effects
Pain management follows the WHO analgesic ladder (paracetamol → weak opioid → strong opioid) with adjuvants at each step. Neuropathic pain requires specific agents (amitriptyline, gabapentin, pregabalin per NICE CG173). Multimodal analgesia combining different mechanisms is preferred. The UK faces an opioid prescribing crisis requiring careful risk-benefit assessment and regular review.
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Key Facts
WHO analgesic ladder
Step 1 (paracetamol ± NSAID)
Step 2 (weak opioid, e.g. codeine)
Step 3 (strong opioid, e.g. morphine)
Multimodal analgesia: combining drugs with different mechanisms improves efficacy and reduces side effects
Neuropathic pain (NICE CG173): first-line - amitriptyline 10–75 mg ON, gabapentin 300–3600 mg/day, or pregabalin 150–600 mg/day
Paracetamol 1 g QDS: first-line for most pain; max 4 g/day in adults (reduce in liver disease, low weight)
Codeine: pro-drug → morphine via CYP2D6; ~10% of population are poor metabolisers (no analgesia); avoid in children <12
Morphine: gold standard strong opioid; start 5–10 mg PO 4-hourly (opioid-naïve); titrate to effect
Faculty of Pain Medicine: opioids should be trialled for 2–4 weeks with clear goals; stop if no benefit
Overview
Key Facts
Pain is one of the most common reasons for seeking medical attention. Effective pain management requires assessment of pain type (nociceptive, neuropathic, mixed), severity, and underlying cause. The goal is to improve function and quality of life, not just reduce pain scores.
Epidemiology
Chronic pain affects ~28% of UK adults (~28 million people)
~7.8 million people in UK live with chronic pain that is moderate to severely disabling
Opioid prescribing in UK has increased significantly - ~5.6 million opioid prescriptions/quarter
Opioids are potent analgesics acting at mu, kappa, and delta receptors. Essential for severe acute and cancer pain but increasingly scrutinised for chronic non-cancer pain due to limited long-term efficacy and significant risks (dependence, tolerance, respiratory depression). The Faculty of Pain Medicine 'Opioids Aware' resource guides UK prescribing. Always prescribe laxatives concurrently and review regularly.
Chronic non-cancer pain: limit trial to 2–4 weeks; stop if no meaningful benefit; maximum ~120 mg oral morphine equivalent/day
Opioids Aware (FPM): UK resource - strong opioids for chronic pain should rarely exceed 120 mg oral morphine equivalent/day
Overview
Key Facts
Opioids remain the most effective analgesics for severe acute and cancer pain. However, their role in chronic non-cancer pain is increasingly questioned due to limited long-term efficacy and substantial harms including dependence, hyperalgesia, and death.
Epidemiology
UK: ~5.6 million opioid prescriptions per quarter
~500,000 people prescribed opioids for >3 years in England
Opioid-related deaths: ~2,000/year in England and Wales (rising)
Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. Effective for pain, inflammation, and fever. Major risks include GI bleeding, cardiovascular events, and renal impairment. Ibuprofen and naproxen are preferred for lowest CV risk. Always co-prescribe PPI for patients at GI risk. Contraindicated in severe CKD, active GI bleeding, and third trimester of pregnancy.
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Key Facts
COX inhibition: COX-1 (constitutive - GI protection, platelet function, renal blood flow) and COX-2 (inducible - inflammation, pain, fever)
GI risk: ~2–4× increased risk of upper GI bleeding/perforation; co-prescribe PPI if risk factors present
CV risk: all NSAIDs increase cardiovascular risk; naproxen has lowest CV risk; diclofenac highest - avoid in CVD
Ibuprofen 400 mg TDS: lowest effective dose; good safety profile; OTC available
Naproxen 500 mg BD: preferred NSAID for patients with CV risk (lowest CV risk per NICE CG177)
Pregnancy: avoid in 3rd trimester - premature closure of ductus arteriosus, oligohydramnios
Overview
Key Facts
NSAIDs are among the most widely prescribed and OTC-available analgesics. They are highly effective for pain and inflammation but carry significant GI, CV, and renal risks. Safe prescribing requires careful patient selection, lowest effective dose, and shortest duration.
Epidemiology
Among the most commonly prescribed drugs worldwide
~15–20 million NSAID prescriptions/year in England
NSAIDs account for ~30% of drug-related hospital admissions (mainly GI bleeding)
The most widely used analgesic and antipyretic in the UK. Mechanism involves central COX inhibition and endocannabinoid modulation. Safe at therapeutic doses but paracetamol overdose is the leading cause of acute liver failure in the UK. N-acetylcysteine (NAC) is the antidote. The Rumack-Matthew nomogram guides treatment decisions. Maximum dose 4 g/day in healthy adults; reduce in liver disease, low body weight, and chronic alcohol use.
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Key Facts
Mechanism: central COX inhibition (possibly COX-3), endocannabinoid system modulation, serotonergic descending pathways
Max dose: 4 g/day (adults >50 kg); reduce to 2–3 g/day in liver disease, chronic alcohol, low body weight (<50 kg)
Overdose: leading cause of acute liver failure in UK; >150 mg/kg (or >12 g in adults) is potentially toxic
Toxic metabolite: NAPQI (N-acetyl-p-benzoquinone imine) - normally conjugated by glutathione; in overdose, glutathione depleted → NAPQI causes hepatocyte necrosis
N-acetylcysteine (NAC): antidote - replenishes glutathione; most effective within 8 hours of ingestion
Rumack-Matthew nomogram: plot paracetamol level at ≥4 hours post-ingestion against time → guides NAC treatment
Staggered overdose: if ingested over >1 hour or uncertain timing → treat with NAC if total dose ≥150 mg/kg in 24 hours
King's College criteria: predict need for liver transplant in paracetamol-induced ALF - pH <7.3, INR >6.5, creatinine >300, grade III-IV encephalopathy
Overview
Key Facts
Paracetamol is the first-line analgesic for most pain presentations and is a key component of multimodal analgesia. Its safety profile at therapeutic doses is excellent, but overdose is a major clinical problem and a common exam topic.
Epidemiology
Most commonly used analgesic in UK; OTC and prescription
~100,000 presentations/year to UK EDs with paracetamol overdose
Leading cause of acute liver failure in UK (~40–50% of cases)
~150–200 deaths/year from paracetamol poisoning in UK (declining with NAC and legislation)
Pharmacology
Absorption: rapidly absorbed orally; peak levels at 30–60 minutes (4 hours with modified-release or co-ingested drugs)
Metabolism
90% hepatic conjugation (glucuronidation and sulfation)
non-toxic metabolites; ~5% via CYP2E1
NAPQI (toxic)
At therapeutic doses: NAPQI is rapidly conjugated by glutathione → non-toxic
CT head: if encephalopathy to exclude other causes
Management
Therapeutic Use
Adults >50 kg: 1 g QDS orally (max 4 g/24 hours)
Low body weight (<50 kg): 15 mg/kg per dose (max 60 mg/kg/day)
Liver disease/chronic alcohol: max 2–3 g/day (some guidelines suggest 4 g short-term is acceptable)
IV paracetamol: 1 g over 15 minutes QDS (max 4 g/24h); weight-based if <50 kg - BEWARE ten-fold dosing errors in neonates/infants
Overdose Management
Immediate:
Activated charcoal 50 g: if within 1 hour of ingestion (rarely achievable)
Paracetamol level at ≥4 hours: plot on Rumack-Matthew nomogram using 100 mg/L treatment line (UK)
N-Acetylcysteine (NAC):
Indicated if: level above treatment line on nomogram; staggered overdose ≥150 mg/kg; uncertain timing; already symptomatic
New 2-bag regimen (SNAP protocol - 2023): 100 mg/kg in 200 mL over 2 hours, then 200 mg/kg in 1000 mL over 10 hours
Anaphylactoid reactions to NAC: common (~15%) - flushing, urticaria, bronchospasm; slow/pause infusion, give antihistamine; usually restart at slower rate
Most effective within 8 hours: virtually 100% hepatoprotective if given within 8 hours
Severe Hepatotoxicity:
ITU admission: coagulopathy, encephalopathy, acidosis, renal failure
Continue NAC infusion at 150 mg/kg/16 hours until INR falling and ALT declining
IV fluids, glucose, correct coagulopathy
Avoid FFP (unless actively bleeding) - obscures INR prognostic value
Contact liver transplant centre early if King's College criteria met
Referral Criteria
Liver transplant centre: King's College criteria or rapidly deteriorating liver function
Psychiatric assessment: all intentional overdoses
Toxicology: complex overdoses, late presentation, uncertainty
Prognosis
NAC within 8 hours: mortality <0.5%
NAC at 8–24 hours: still beneficial but less effective
Without NAC: mortality ~5–10% in significant overdose
King's College criteria met: mortality ~80% without transplant
Most survivors recover completely - liver regenerates fully
UK paracetamol pack-size legislation (1998): reduced deaths by ~43%
Other Relevant Information
King's College Criteria (Paracetamol-Induced ALF)
Criteria for Transplant Listing
pH <7.3 after fluid resuscitation
OR all three of: INR >6.5, Creatinine >300 μmol/L, Grade III–IV encephalopathy
NAC Regimen (SNAP 2-bag Protocol)
Bag
Dose
Volume
Duration
1
100 mg/kg
200 mL glucose 5%
2 hours
2
200 mg/kg
1000 mL glucose 5%
10 hours
Risk Factors for Enhanced Toxicity
Factor
Mechanism
Chronic alcohol
CYP2E1 induction → more NAPQI; depleted glutathione
Antimicrobial agents used to treat bacterial infections. UK prescribing is guided by NICE guidelines, local antimicrobial formularies, and the 'Start Smart - Then Focus' antimicrobial stewardship toolkit. Key classes include penicillins, cephalosporins, macrolides, tetracyclines, fluoroquinolones, and aminoglycosides. Antimicrobial resistance is a global threat; rational prescribing is essential.
Doxycycline 100–200 mg OD: tetracycline; used for atypical pneumonia, acne, Lyme; photosensitivity
Gentamicin: aminoglycoside; IV for serious Gram-negative infections; TDM essential (nephro/ototoxic)
Start Smart - Then Focus: PHE stewardship - review antibiotics at 48–72 hours; stop, switch IV→oral, narrow, change, OPAT
Overview
Key Facts
Antibiotics are among the most prescribed drugs in the UK. Appropriate use is critical to maximise efficacy, minimise side effects, and combat antimicrobial resistance. Local formularies and guidelines should always be consulted.
Epidemiology
~40 million antibiotic prescriptions/year in England
~20% of antibiotic prescriptions considered inappropriate
AMR: ~5,000 deaths/year in UK attributed to drug-resistant infections
C. difficile: ~13,000 cases/year - strongly associated with broad-spectrum antibiotics
CRP/WBC: markers of infection (though non-specific)
During Treatment
Clinical response: review at 48–72 hours (Start Smart - Then Focus)
TDM: gentamicin (trough <1 mg/L; or Hartford nomogram for once-daily), vancomycin (trough 10–15 mg/L or AUC-guided)
Renal function: if on nephrotoxic antibiotics
C. difficile testing: if diarrhoea develops
Special Tests
Allergy testing: penicillin allergy assessment at allergy clinic (most labelled patients are NOT allergic)
Management
Antimicrobial Stewardship
Start Smart: only start antibiotics when there is clinical evidence of bacterial infection; document indication, dose, route, duration
Then Focus (48–72 hour review): stop if no evidence of infection; switch IV→oral if improving; narrow spectrum based on culture results; change if not responding; consider OPAT
Duration: use shortest effective course - many infections require only 5 days (NICE)
Key Prescribing by Class
Penicillins: amoxicillin 500 mg TDS (community infections); flucloxacillin 500 mg–1 g QDS (staphylococcal); benzylpenicillin 1.2 g QDS IV (meningitis, streptococcal)
Drugs used to treat fungal infections ranging from superficial dermatophyte and candidal infections to life-threatening invasive mycoses. Key classes include azoles (fluconazole, itraconazole, voriconazole), polyenes (amphotericin B), echinocandins (caspofungin), and allylamines (terbinafine). Drug interactions (CYP450), hepatotoxicity, and nephrotoxicity are major prescribing considerations.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Azoles
inhibit lanosterol 14-alpha demethylase (CYP51)
impair ergosterol synthesis
fungistatic (mostly)
Fluconazole 50–400 mg OD: first-line for mucosal/systemic Candida; good CSF penetration; renal excretion; fewer interactions than others
fungicidal; nephrotoxic - use liposomal formulation to reduce toxicity
Terbinafine 250 mg OD: allylamine; best for dermatophytes; first-line for onychomycosis and tinea capitis; hepatotoxicity risk; check LFTs
Echinocandins (caspofungin, anidulafungin): inhibit beta-1,3-glucan synthesis; fungicidal for Candida; first-line for invasive candidiasis in unwell patients
CYP450 interactions: azoles are potent CYP inhibitors - check BNF interactions before prescribing
Overview
Key Facts
Antifungal prescribing ranges from topical agents for superficial infections to potent systemic drugs for life-threatening invasive mycoses. Understanding the spectrum, pharmacokinetics, and toxicity of each class is essential for safe and effective prescribing.
Drugs that inhibit viral replication at various stages of the viral life cycle. Key agents include aciclovir (herpes viruses), oseltamivir (influenza), direct-acting antivirals for hepatitis C (sofosbuvir, ledipasvir), and antiretrovirals for HIV. Unlike antibiotics, most antivirals are virostatic rather than viricidal. Drug interactions and resistance are important prescribing considerations.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Aciclovir: guanosine analogue; activated by viral thymidine kinase → inhibits viral DNA polymerase; herpes simplex, VZV; renal excretion (hydration essential for IV)
PrEP (pre-exposure prophylaxis): emtricitabine/tenofovir disoproxil - prevents HIV acquisition in high-risk individuals
PEP (post-exposure prophylaxis): start within 72 hours of HIV exposure; 4-week course of ART
Resistance: HSV resistance to aciclovir (immunocompromised); HIV resistance with non-adherence - genotypic testing guides therapy
Overview
Key Facts
Antiviral drugs target specific stages of viral replication. Unlike bacteria, viruses rely on host cell machinery, making selective toxicity more challenging. Advances in antiviral therapy have transformed outcomes for HIV, hepatitis C, and herpes virus infections.
Classification by Target
Nucleoside/nucleotide analogues: aciclovir, valaciclovir, ganciclovir, tenofovir, lamivudine - incorporate into viral DNA → chain termination
Drugs that inhibit the coagulation cascade to prevent and treat thromboembolic disease. Key classes include heparins (unfractionated and LMWH), vitamin K antagonists (warfarin), and direct oral anticoagulants (DOACs - apixaban, rivaroxaban, edoxaban, dabigatran). DOACs are now first-line for most indications in the UK per NICE guidelines. Bleeding is the major complication; reversal agents are available.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
DOACs: now first-line for AF stroke prevention and VTE - apixaban, rivaroxaban, edoxaban, dabigatran (NICE NG196)
Warfarin: vitamin K antagonist; target INR 2.0–3.0 (AF, VTE) or 2.5–3.5 (mechanical valves); monitor INR regularly
Apixaban 5 mg BD: factor Xa inhibitor; fewest drug interactions; dose reduce if ≥2 of: age ≥80, weight ≤60 kg, Cr ≥133
Dabigatran: direct thrombin inhibitor; 80% renal excretion; avoid if CrCl <30 mL/min; reversal: idarucizumab (Praxbind)
Warfarin reversal: vitamin K (phytomenadione) 1–5 mg IV; prothrombin complex concentrate (PCC) for life-threatening bleeding
DOAC reversal: idarucizumab for dabigatran; andexanet alfa for Xa inhibitors (limited availability); PCC if unavailable
CHA₂DS₂-VASc score: guides anticoagulation decision in AF - score ≥2 (men) or ≥3 (women) → anticoagulate
Overview
Key Facts
Anticoagulants are essential drugs in modern medicine. The introduction of DOACs has simplified management for many patients, but understanding the differences between agents, appropriate patient selection, and bleeding management remains critical.
Epidemiology
AF affects ~1.4 million people in UK - anticoagulation prevents ~70% of strokes
VTE (DVT/PE): ~1 per 1,000/year; anticoagulation is mainstay of treatment
~5 million anticoagulant prescriptions/year in England (DOACs now outnumber warfarin)
Classification
Heparins:
UFH: potentiates antithrombin III → inhibits thrombin (IIa) and Xa; IV/SC; monitored by APTT
Drugs that inhibit platelet activation and aggregation, used primarily in cardiovascular disease prevention. Aspirin irreversibly inhibits COX-1 (thromboxane A2 synthesis); clopidogrel, prasugrel, and ticagrelor inhibit P2Y12 ADP receptors. Dual antiplatelet therapy (DAPT) is standard after ACS and PCI. Key considerations include bleeding risk, interaction with PPIs (clopidogrel), and duration of therapy.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Aspirin 75 mg OD
irreversible COX-1 inhibition
↓ thromboxane A2
↓ platelet aggregation; lifelong for secondary CVD prevention
Clopidogrel 75 mg OD: P2Y12 ADP receptor antagonist; pro-drug (CYP2C19 activation); alternative to aspirin; avoid concurrent omeprazole
Ticagrelor 90 mg BD: reversible P2Y12 inhibitor; faster onset, more potent than clopidogrel; PLATO trial - superior to clopidogrel in ACS
Prasugrel 10 mg OD: irreversible P2Y12; faster onset than clopidogrel; avoid if prior stroke/TIA, age >75, weight <60 kg; TRITON-TIMI 38 trial
DAPT (aspirin + P2Y12 inhibitor): standard after ACS (12 months) and PCI with stent (6–12 months)
Aspirin 300 mg loading: given acutely in STEMI, NSTEMI, unstable angina, ischaemic stroke (after CT excludes haemorrhage)
Clopidogrel 300 mg loading: given with aspirin in ACS; 600 mg for PCI
Bleeding risk: major complication; GI bleeding most common - co-prescribe PPI if GI risk factors present
Overview
Key Facts
Antiplatelet agents are the cornerstone of secondary prevention in cardiovascular disease. Understanding when to use single vs dual antiplatelet therapy, duration of treatment, and management of bleeding complications is essential.
Pharmacology
Aspirin
irreversibly acetylates COX-1
prevents thromboxane A2 synthesis
inhibits platelet aggregation for platelet lifespan (~7–10 days)
Clopidogrel
thienopyridine pro-drug
active metabolite via CYP2C19
irreversibly inhibits P2Y12 ADP receptor
Prasugrel: thienopyridine pro-drug → faster and more complete P2Y12 inhibition than clopidogrel
Ticagrelor
cyclopentyl-triazolo-pyrimidine
reversible, direct P2Y12 inhibition
faster offset than clopidogrel
Cangrelor: IV P2Y12 inhibitor → ultra-short acting; used in cath lab
Pathophysiology
Platelet activation: vascular injury
collagen exposure
platelet adhesion (vWF/GP Ib)
activation (ADP, TXA2)
aggregation (GPIIb/IIIa cross-linking via fibrinogen)
Target BP: <140/90 clinic (or <135/85 ABPM); <150/90 if ≥80 years
ABPM/HBPM: recommended to confirm diagnosis of hypertension before starting treatment
Amlodipine 5–10 mg OD: most commonly prescribed CCB; ankle oedema is commonest side effect
Overview
Key Facts
Hypertension affects ~1 in 3 UK adults and is the leading modifiable risk factor for cardiovascular disease. Optimal BP control reduces risk of stroke by ~40% and MI by ~25%.
Epidemiology
~14 million adults in UK with hypertension; ~5 million undiagnosed
Hypertension: leading risk factor for global mortality
~50% of treated patients do not achieve target BP
NICE NG136 Algorithm
Confirm diagnosis: ABPM (≥135/85 daytime average) or HBPM before starting treatment
Step 1
<55 and non-Black
ACE-i/ARB; ≥55 or Black African/Caribbean
CCB
Step 2: ACE-i/ARB + CCB
Step 3: ACE-i/ARB + CCB + thiazide-like diuretic
Step 4: add spironolactone 25 mg (if K ≤4.5); if K >4.5 → add alpha-blocker (doxazosin) or beta-blocker (bisoprolol)
Investigate for secondary hypertension if: <40 years, resistant HTN, hypokalaemia, specific clinical features
Pathophysiology
BP = cardiac output × systemic vascular resistance
Drugs that increase urine output by acting on the nephron. Key classes: loop diuretics (furosemide), thiazide-like (indapamide, chlortalidone), potassium-sparing (spironolactone, amiloride), and osmotic (mannitol). Used in hypertension, heart failure, oedema, and ascites. Major side effects include electrolyte disturbances (hypokalaemia, hyponatraemia), dehydration, and metabolic effects (gout, hyperglycaemia).
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Loop diuretics (furosemide 20–80 mg OD-BD): act on Na/K/2Cl co-transporter in thick ascending limb of loop of Henle; most potent diuretics
Thiazide-like (indapamide 2.5 mg, chlortalidone 12.5–25 mg): inhibit NaCl co-transporter in DCT; preferred in hypertension (NICE NG136 Step 3)
Spironolactone 25–400 mg: aldosterone antagonist in collecting duct; used in resistant HTN (PATHWAY-2), heart failure (RALES), ascites; risk of hyperkalaemia, gynaecomastia
Amiloride: blocks ENaC in collecting duct; K-sparing; used with thiazide to prevent hypokalaemia
Hypokalaemia: major risk with loops and thiazides - can precipitate arrhythmias (especially with digoxin)
Hyponatraemia: common with thiazides in elderly - can cause confusion, falls, seizures
Gout
loops and thiazides reduce uric acid excretion
hyperuricaemia
acute gout
Metolazone: thiazide-like diuretic added to loop diuretic for diuretic resistance in severe heart failure - potent combination (monitor closely)
Overview
Key Facts
Diuretics are fundamental drugs in the management of hypertension, heart failure, and fluid overload. Understanding their sites of action in the nephron, efficacy, and side effects is essential for safe prescribing.
Competitive antagonists at beta-adrenoceptors that reduce heart rate, contractility, and renin release. Used in heart failure (bisoprolol, carvedilol), angina, post-MI, arrhythmias, thyrotoxicosis, and migraine prophylaxis. No longer first-line for hypertension (NICE NG136). Contraindicated in asthma (non-selective) and decompensated heart failure. Key agents: bisoprolol (beta-1 selective), propranolol (non-selective), atenolol, carvedilol.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Beta-1 selective: bisoprolol, atenolol, metoprolol - preferred; less risk of bronchospasm
Non-selective: propranolol, carvedilol, labetalol - block beta-1 AND beta-2; avoid in asthma
Post-MI: bisoprolol or carvedilol - mortality benefit; start within 24 hours when stable
Contraindicated in asthma: beta-2 blockade → bronchospasm; COPD - use beta-1 selective with caution
Rebound on withdrawal: do NOT stop suddenly - receptor up-regulation → rebound tachycardia, hypertension, angina; taper over 2–4 weeks
Propranolol: non-selective; used for anxiety, tremor, thyrotoxicosis symptom control, migraine prophylaxis, portal hypertension (variceal bleed prevention)
Labetalol: combined alpha + beta-blocker; first-line for hypertension in pregnancy (NICE NG133)
Overview
Key Facts
Beta-blockers are versatile drugs with established mortality benefits in heart failure and post-MI. Understanding selectivity, contraindications, and the importance of gradual withdrawal is essential.
Beta-1 selective agents: preferentially block beta-1 → cardiac effects with less bronchospasm; selectivity is dose-dependent (lost at high doses)
Non-selective agents: block both beta-1 and beta-2 → cardiac + bronchial + vascular + metabolic effects
Intrinsic sympathomimetic activity (ISA): pindolol, acebutolol - partial agonist activity; less bradycardia but less mortality benefit; rarely used now
Pathophysiology
Beta-blockade
↓ heart rate, ↓ contractility, ↓ AV conduction, ↓ renin
↓ cardiac output, ↓ myocardial oxygen demand
In heart failure: chronic sympathetic activation damages myocardium → beta-blockers reverse this (start low, go slow - initial transient worsening possible)
Treatment: atropine 500 mcg IV (bradycardia), IV glucagon 5–10 mg (positive inotrope bypassing beta-receptor), IV fluids, consider insulin-glucose therapy
Drugs that block L-type voltage-gated calcium channels in cardiac and smooth muscle. Two main subclasses: dihydropyridines (amlodipine, nifedipine - vascular selectivity, vasodilation) and non-dihydropyridines (verapamil, diltiazem - cardiac selectivity, rate control). First-line for hypertension in patients ≥55 or of Black African/Caribbean heritage (NICE NG136). Also used in angina and arrhythmias.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Dihydropyridines (amlodipine, nifedipine)
vascular smooth muscle selective
vasodilation
↓ BP; reflex tachycardia; ankle oedema
Non-dihydropyridines (verapamil, diltiazem): cardiac selective → ↓ HR, ↓ conduction, ↓ contractility; used for rate control in AF
Amlodipine 5–10 mg OD: most commonly prescribed CCB; first-line for HTN in ≥55 or Black African/Caribbean (NICE NG136)
Verapamil: avoid with beta-blockers → risk of complete heart block, asystole, severe heart failure
Diltiazem: rate-limiting CCB; used for angina and AF rate control; avoid with beta-blockers
Ankle oedema: most common side effect of amlodipine (~10%); NOT fluid overload - due to precapillary vasodilation; does NOT respond to diuretics
Nifedipine MR: used for Raynaud's phenomenon, hypertension in pregnancy (alongside labetalol)
Constipation: significant side effect of verapamil (direct gut smooth muscle relaxation)
Overview
Key Facts
CCBs are widely used antihypertensives and antianginals. The distinction between dihydropyridine and non-dihydropyridine subclasses is clinically critical, as they have fundamentally different effects and drug interaction profiles.
Pharmacology
L-type calcium channels: found in cardiac myocytes, vascular smooth muscle, and AV/SA node
Blocking calcium entry
reduced intracellular calcium
reduced contraction
Dihydropyridines
preferentially act on vascular smooth muscle
vasodilation
↓ SVR
↓ BP; reflex sympathetic activation
↑ HR
Non-dihydropyridines: preferentially act on cardiac tissue → ↓ HR (chronotropy), ↓ AV conduction (dromotropy), ↓ contractility (inotropy); minimal reflex tachycardia
Pathophysiology
Hypertension: CCBs reduce SVR through arteriolar vasodilation
Angina: reduce myocardial oxygen demand (↓ afterload, ↓ HR with non-DHP) and improve coronary flow (vasodilation)
Arrhythmias (non-DHP): slow AV nodal conduction → control ventricular rate in AF/atrial flutter
Clinical Presentation
Indications
Hypertension: amlodipine/nifedipine MR - first-line in ≥55 or Black heritage; Step 1 NICE NG136
Stable angina: amlodipine (if beta-blocker contraindicated/insufficient) or diltiazem
Prinzmetal (vasospastic) angina: CCBs are treatment of choice - coronary vasodilation
AF rate control: verapamil or diltiazem - alternative to beta-blocker (not combined)
Raynaud's phenomenon: nifedipine MR 10–20 mg BD
Hypertension in pregnancy: nifedipine MR (alongside labetalol)
ACE inhibitors (ramipril, enalapril, lisinopril) and ARBs (losartan, candesartan, valsartan) inhibit the renin-angiotensin-aldosterone system. First-line for hypertension in <55 years/non-Black, heart failure (mortality benefit), diabetic nephropathy, and post-MI. ACE-i cause dry cough in ~10–15%; ARBs are the alternative. Both are teratogenic. Key trials: HOPE, SOLVD, ONTARGET.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
ACE inhibitors
block angiotensin-converting enzyme
↓ angiotensin II, ↓ aldosterone, ↑ bradykinin (
cough, angioedema)
ARBs
block angiotensin II type 1 (AT1) receptor
similar effects without bradykinin accumulation
no cough
Ramipril 1.25–10 mg OD: most commonly prescribed ACE-i; HOPE trial - mortality benefit in high CV risk
Dry cough (~10–15%): bradykinin-mediated; switch to ARB (losartan, candesartan)
Angioedema: rare (~0.1–0.5%); may be life-threatening; more common in Black patients; stop ACE-i permanently; ARB with caution
First-dose hypotension: especially if dehydrated, on diuretics, elderly → start at low dose
Teratogenic: contraindicated in pregnancy - renal dysgenesis, oligohydramnios; use labetalol/nifedipine instead
Monitor U&Es: check 1–2 weeks after starting; >30% rise in creatinine or K+ >5.5 → investigate (renal artery stenosis?), consider stopping
Overview
Key Facts
ACE inhibitors and ARBs are among the most important drug classes in cardiovascular medicine. They have proven mortality benefits in heart failure and post-MI, and are renoprotective in diabetic nephropathy.
Pharmacology
RAAS pathway
renin (from kidney)
angiotensinogen
angiotensin I
ACE
angiotensin II
vasoconstriction + aldosterone release
ACE inhibitors: block ACE → ↓ Ang II production + ↑ bradykinin (beneficial vasodilation but causes cough)
Initial creatinine rise on starting: expected (up to 30%) due to ↓ efferent tone → ↓ filtration pressure; >30% suggests bilateral renal artery stenosis
Clinical Presentation
Indications
Hypertension: first-line in <55, non-Black (NICE NG136 Step 1)
Statins (HMG-CoA reductase inhibitors) are the cornerstone of lipid-lowering therapy and cardiovascular prevention. Atorvastatin 20 mg is first-line for primary prevention (QRISK ≥10%) and 80 mg for secondary prevention (NICE CG181). Additional agents include ezetimibe, PCSK9 inhibitors (alirocumab, evolocumab), bempedoic acid, and inclisiran. Key trials: 4S, HPS, JUPITER, FOURIER.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Atorvastatin 20 mg OD: first-line for primary prevention (10-year QRISK ≥10%); take at night (but atorvastatin can be any time due to long half-life)
Atorvastatin 80 mg OD: first-line for secondary prevention (established CVD)
Mechanism
inhibit HMG-CoA reductase
↓ hepatic cholesterol synthesis
↑ LDL receptor expression
↓ LDL cholesterol
Myopathy/rhabdomyolysis: most serious side effect; check CK if muscle symptoms; increased risk with CYP3A4 inhibitors + simvastatin/atorvastatin
Ezetimibe 10 mg: inhibits intestinal cholesterol absorption (NPC1L1 transporter); add to statin if target not reached (IMPROVE-IT trial)
Check lipids 3 months after starting: aim >40% reduction in non-HDL cholesterol (NICE CG181)
Overview
Key Facts
Statins are among the most prescribed drugs globally and have the strongest evidence base of any drug class for cardiovascular prevention. For every 1 mmol/L reduction in LDL, there is a ~22% reduction in major vascular events.
Epidemiology
~8 million adults in UK take statins
CVD remains leading cause of death in UK
LDL cholesterol: causal risk factor for atherosclerotic CVD
Pharmacology
Statins
competitively inhibit HMG-CoA reductase (rate-limiting step in cholesterol synthesis)
Pioglitazone: thiazolidinedione; improves insulin sensitivity; weight gain, fluid retention, fracture risk, bladder cancer association
HbA1c target: 48 mmol/mol (6.5%) for most; 53 mmol/mol (7.0%) if on agents causing hypoglycaemia; individualise in frail elderly
NICE NG28: updated algorithm - consider SGLT2i/GLP-1 RA earlier, especially with CVD, CKD, or heart failure
Overview
Key Facts
Type 2 diabetes management has been revolutionised by SGLT2 inhibitors and GLP-1 RAs, which offer benefits beyond glycaemic control. Treatment selection should consider cardiovascular risk, renal function, weight, and hypoglycaemia risk.
Epidemiology
~4 million people with diabetes in UK (~90% type 2)
Diabetes: leading cause of CKD, blindness, and non-traumatic amputation in UK
NHS spends 10% of budget on diabetes (£10 billion/year)
Exogenous insulin is essential in type 1 diabetes and used in advanced type 2 diabetes when oral/injectable agents are insufficient. Classified by onset and duration: rapid-acting (insulin aspart, lispro), short-acting (Actrapid), intermediate (isophane/NPH), long-acting (glargine, detemir, degludec). Basal-bolus regimen is standard for T1DM. Hypoglycaemia is the most dangerous complication. NICE NG17 (T1DM) and NG28 (T2DM) provide UK guidance.
Basal-bolus regimen: long-acting OD/BD (glargine/detemir/degludec) + rapid-acting with meals (aspart/lispro/glulisine)
Insulin glargine (Lantus/Toujeo): long-acting; ~24-hour duration; peakless; OD injection
Insulin aspart (NovoRapid): rapid-acting; onset 10–15 min; peak 1–2 hours; duration 3–5 hours; given immediately before meals
Hypoglycaemia: most dangerous acute complication - glucose <3.5 mmol/L; treat with fast-acting carbohydrate; if unconscious: IV glucose 10% (200 mL) or IM glucagon 1 mg
DKA: insulin deficiency → hyperglycaemia + ketoacidosis; T1DM; treat with fixed-rate IV insulin (0.1 units/kg/hr) + fluids + K replacement (JBDS protocol)
HbA1c target: 48 mmol/mol (6.5%) for most T1DM; 53 mmol/mol (7.0%) for T2DM on insulin; individualise
Insulin safety: NEVER omit basal insulin in T1DM (DKA risk); ALWAYS double-check dose; high-risk medication for prescribing errors
Overview
Key Facts
Insulin therapy is lifesaving in type 1 diabetes and commonly required in advanced type 2 diabetes. Insulin prescribing errors are among the most common and dangerous medication errors in hospitals.
Synthetic analogues of cortisol with potent anti-inflammatory and immunosuppressive effects. Used in asthma, COPD exacerbations, autoimmune diseases, inflammatory conditions, and adrenal insufficiency. Major long-term side effects include osteoporosis, diabetes, adrenal suppression, infections, and Cushing's syndrome. Gradual tapering is essential after prolonged courses to avoid adrenal crisis.
Hydrocortisone: used for adrenal replacement (15–25 mg/day in divided doses); also IV for acute adrenal crisis (100 mg stat)
Dexamethasone: most potent; long-acting; used in cerebral oedema, croup, antiemesis, COVID-19 (RECOVERY trial)
Adrenal suppression
courses >3 weeks (or equivalent)
HPA axis suppression
must NOT stop abruptly; taper gradually
Steroid emergency card: all patients on long-term steroids should carry one (sick day rules: double dose during illness)
Osteoporosis prevention: bone protection (alendronate 70 mg weekly + calcium/vitamin D) if expected to take steroids ≥3 months
Cushingoid side effects: moon face, central obesity, striae, thin skin, easy bruising, proximal myopathy, hypertension, diabetes, cataracts
Overview
Key Facts
Corticosteroids are among the most versatile and widely used drugs in medicine. Their potent anti-inflammatory effects make them invaluable, but their extensive side effect profile requires careful prescribing, monitoring, and patient education.
Infection: increased susceptibility; may mask infection signs; TB reactivation
Endocrine: adrenal suppression, growth retardation in children
Red Flags
Adrenal crisis: collapse, hypotension, hypoglycaemia, confusion after abrupt steroid withdrawal or during intercurrent illness → IV hydrocortisone 100 mg stat
Sepsis in steroid-treated patient: may not mount typical inflammatory response; maintain high index of suspicion
Steroid-induced psychosis: agitation, hallucinations, mania - usually with high doses; reduce dose
New vertebral fracture: back pain in patient on long-term steroids → DEXA, X-ray
Differential Diagnosis
Complication
Presentation
Management
Adrenal crisis
Hypotension, confusion, hypoglycaemia
IV hydrocortisone 100 mg, IV fluids
Steroid-induced diabetes
Hyperglycaemia, polyuria
Monitor glucose, treat as per guidelines
Osteoporotic fracture
Back pain, hip pain
Bone protection, DEXA, orthopaedic
Steroid psychosis
Agitation, hallucinations
Reduce dose, antipsychotic if needed
Opportunistic infection
Atypical presentation, immunosuppressed
Low threshold for investigation
Diagnosis / Investigation
Before Starting Long-Term Steroids
Baseline: weight, BP, blood glucose/HbA1c, bone profile, lipids
Drugs that suppress the immune system, used in organ transplantation, autoimmune diseases, and inflammatory conditions. Key agents include azathioprine, methotrexate, mycophenolate, ciclosporin, tacrolimus, and biologic therapies. Require careful monitoring due to infection risk, bone marrow suppression, hepatotoxicity, and nephrotoxicity. TPMT testing is mandatory before azathioprine.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Azathioprine 1–3 mg/kg/day: purine analogue; used in IBD, autoimmune hepatitis, SLE, vasculitis; CHECK TPMT before starting (bone marrow toxicity if deficient)
Methotrexate 7.5–25 mg ONCE weekly: folate antagonist; used in RA, psoriasis, Crohn's; supplement with folic acid 5 mg (not on MTX day); teratogenic
Mycophenolate mofetil 1–1.5 g BD: inosine monophosphate dehydrogenase inhibitor; transplant, SLE, vasculitis; GI side effects; teratogenic
Infection risk: all immunosuppressants increase infection susceptibility - screen for TB, hepatitis B before starting
Monitoring: FBC, LFTs, U&Es regularly - frequency depends on agent
Overview
Key Facts
Immunosuppressants are essential for transplant survival and control of autoimmune diseases. Their use requires balancing efficacy against significant risks including infection, malignancy, and organ toxicity.
Drugs used to prevent seizures in epilepsy and related conditions. Choice depends on seizure type: sodium valproate or lamotrigine for generalised; carbamazepine or lamotrigine for focal. NICE NG217 provides UK guidance. Valproate is highly teratogenic (MHRA Pregnancy Prevention Programme). Drug interactions via CYP450 enzymes are clinically important. Switching formulations should be avoided for narrow TI AEDs.
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Key Facts
Focal seizures first-line: lamotrigine or carbamazepine (NICE NG217)
Generalised tonic-clonic first-line: sodium valproate (males) or lamotrigine (females of childbearing potential)
Absence seizures: sodium valproate or ethosuximide (NICE first-line); carbamazepine can WORSEN absences
Sodium valproate: MHRA Pregnancy Prevention Programme - must NOT be prescribed to women of childbearing potential unless on effective contraception + enrolled in PPP
Lamotrigine: broad-spectrum; rash risk (SJS/TEN) - slow titration essential; levels fall in pregnancy
Carbamazepine: enzyme inducer (CYP3A4); auto-induction; NTD risk (~1%); HLA-B*1502 screen in SE Asian patients
Levetiracetam: broad-spectrum; renally cleared; few interactions; psychiatric side effects (irritability, depression)
Status epilepticus
IV lorazepam 4 mg
if persistent: IV phenytoin 15–20 mg/kg or IV levetiracetam 60 mg/kg
if refractory: anaesthesia (propofol/thiopental)
Overview
Key Facts
Epilepsy affects ~600,000 people in the UK (~1% prevalence). AEDs are the mainstay of treatment; ~70% of patients achieve seizure freedom with appropriate medication. Choosing the right drug for the seizure type and patient profile is critical.
Mechanisms of Action
Sodium channel blockers: carbamazepine, lamotrigine, phenytoin, lacosamide - stabilise inactivated state of Na channels
Consistent formulations: for phenytoin, carbamazepine, valproate - do NOT switch brands/generics without specialist advice (narrow TI)
Driving: DVLA rules - must be seizure-free for 12 months (Group 1 licence) or 10 years (Group 2/HGV)
Status Epilepticus (NICE NG217)
Benzodiazepine: IV lorazepam 4 mg (repeat once at 10 min) or buccal midazolam 10 mg
Second-line (if seizure continues): IV phenytoin 15–20 mg/kg (with cardiac monitoring) OR IV levetiracetam 60 mg/kg (max 4.5 g) OR IV valproate 40 mg/kg
Refractory: rapid sequence induction and general anaesthesia (propofol, thiopental)
Pregnancy
Pre-conception counselling: essential for all women with epilepsy
Folic acid 5 mg/day: pre-conception through first trimester (all women on AEDs)
Valproate: AVOID - MHRA PPP; switch to lamotrigine or levetiracetam BEFORE conception
Lamotrigine: levels fall in pregnancy - monitor monthly, increase dose as needed
Do NOT stop AEDs abruptly: seizure risk to mother and fetus
Referral Criteria
Epilepsy specialist: all new diagnoses, treatment failure, drug-resistant epilepsy
Epilepsy surgery centre: drug-resistant focal epilepsy (consider after failure of 2 appropriate AEDs)
Pregnancy planning: pre-conception counselling with epilepsy specialist
Prognosis
~70% of patients achieve seizure freedom with AEDs
Drug-resistant epilepsy (~30%): defined as failure of 2 appropriate AEDs at adequate doses
Epilepsy surgery: can cure up to 60–70% of selected focal epilepsy patients
SUDEP (sudden unexpected death in epilepsy): ~1 in 1,000 patients/year; risk reduced by seizure control and adherence
Valproate in pregnancy: up to 40% neurodevelopmental problems - preventable with alternative AEDs
Lamotrigine in pregnancy: good safety profile; dose adjustment needed due to increased clearance
Drugs used to treat depression, anxiety disorders, OCD, PTSD, and neuropathic pain. SSRIs (sertraline, fluoxetine, citalopram) are first-line per NICE CG90/NG222. Other classes include SNRIs (venlafaxine, duloxetine), TCAs (amitriptyline), MAOIs (phenelzine), and mirtazapine. Take 4–6 weeks for therapeutic effect. Discontinuation syndrome is common - taper gradually. Risk of serotonin syndrome with combinations.
TCAs (amitriptyline): effective for neuropathic pain and migraine prophylaxis; dangerous in overdose (cardiac arrhythmia, seizures)
Mirtazapine 15–45 mg ON: NaSSA; sedating at low doses (H1 antagonism); useful if insomnia/weight loss; fewer sexual side effects
NICE NG222: treatment of depression - stepped care model; CBT + medication for moderate-severe
Overview
Key Facts
Depression affects ~1 in 6 UK adults. Antidepressants are effective for moderate-severe depression and many anxiety disorders. The choice of antidepressant should consider efficacy, side effect profile, safety in overdose, and patient preference.
Drugs primarily used in schizophrenia and other psychotic disorders, also for bipolar disorder, severe agitation, and antiemesis. Classified as first-generation/typical (haloperidol, chlorpromazine) or second-generation/atypical (olanzapine, quetiapine, risperidone, aripiprazole, clozapine). Block dopamine D2 receptors. Major side effects include extrapyramidal symptoms, metabolic syndrome, QT prolongation, and neuroleptic malignant syndrome. Clozapine is reserved for treatment-resistant schizophrenia.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Mechanism: dopamine D2 receptor antagonism (all antipsychotics); atypicals also have 5-HT2A antagonism
First-generation (typical): haloperidol, chlorpromazine - more EPS, less metabolic effects
Clozapine: ONLY for treatment-resistant schizophrenia (failed 2 adequate antipsychotic trials); risk of agranulocytosis (~1%) → mandatory blood monitoring (CPMS)
Metabolic syndrome: olanzapine and clozapine worst - weight gain, diabetes, hyperlipidaemia → monitor metabolic parameters
Extrapyramidal side effects (EPS): acute dystonia, akathisia, parkinsonism, tardive dyskinesia - worst with typicals; treat with procyclidine
Neuroleptic malignant syndrome (NMS): rare, life-threatening - rigidity, hyperthermia, autonomic instability, raised CK → stop antipsychotic, supportive care, dantrolene/bromocriptine
QT prolongation: risk with haloperidol, pimozide, amisulpride, ziprasidone → ECG monitoring; avoid combinations with other QT-prolonging drugs
Overview
Key Facts
Antipsychotics are the mainstay of treatment for schizophrenia and are widely used in other psychiatric and medical conditions. Understanding the distinction between typical and atypical agents, and their respective side effect profiles, is essential.
Epidemiology
Schizophrenia: ~1% lifetime prevalence
Antipsychotics prescribed to ~1.5 million people in England (including non-psychotic indications)
ECG: before haloperidol, pimozide, amisulpride (QTc)
FBC: baseline (mandatory for clozapine)
LFTs, U&Es: baseline
Prolactin: if relevant symptoms develop
Monitoring
Metabolic parameters: at 3 months, 12 months, then annually - weight, glucose/HbA1c, lipids, BP
ECG: if on QT-prolonging agent or if dose increased
Prolactin: if amenorrhoea, galactorrhoea, sexual dysfunction
EPS assessment: clinical at each review
Clozapine-Specific Monitoring (CPMS)
FBC
weekly for 18 weeks
fortnightly for 1 year
monthly lifelong
Must not dispense unless blood result registered and satisfactory
Metabolic monitoring: as above but more frequent
Troponin and CRP: if chest pain/tachycardia (myocarditis screening)
Special Tests
Clozapine levels: therapeutic range 0.35–0.5 mg/L; toxicity >1.0 mg/L; affected by smoking (CYP1A2 induction - levels fall if smoking; RISE if stopped)
CK: if NMS suspected
Management
Schizophrenia (NICE CG178)
First episode:
Oral atypical antipsychotic + psychological interventions (CBT, family therapy)
Choice guided by side effect profile and patient preference
Aripiprazole: least metabolic/sedative effects
Olanzapine: effective but metabolic risk
Risperidone: effective but hyperprolactinaemia
Quetiapine: sedating; useful if insomnia/agitation
Treatment-resistant schizophrenia:
Failed 2 adequate trials of different antipsychotics (at least 1 atypical) → clozapine
Clozapine: start 12.5 mg OD → slow titration to 300–450 mg/day
Register with Clozapine Patient Monitoring Service (CPMS)
Depot/Long-Acting Injectable (LAI)
For adherence difficulties: flupentixol decanoate, zuclopenthixol decanoate, paliperidone palmitate, aripiprazole LAI
Managing Side Effects
EPS: reduce dose; anticholinergic (procyclidine 5 mg PO/IM) for acute dystonia/parkinsonism; propranolol for akathisia
Metabolic syndrome: lifestyle advice, switch to less metabolically active drug (aripiprazole); metformin if weight gain significant
Hyperprolactinaemia: switch to aripiprazole (D2 partial agonist - reduces prolactin)
NMS: stop antipsychotic immediately; ICU; IV fluids, cooling; dantrolene 1 mg/kg IV, bromocriptine 2.5 mg TDS
Referral Criteria
Psychiatry: all psychotic disorders; clozapine initiation
Bronchodilators are medications that relax airway smooth muscle, used in asthma and COPD. They include beta-2 agonists, antimuscarinics, and methylxanthines.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
SABAs (e.g., salbutamol 100-200mcg inhaled PRN) provide rapid relief within 5 minutes, lasting 4-6 hours
LABAs (e.g., salmeterol 50mcg BD, formoterol 12mcg BD) should never be used as monotherapy in asthma (NICE NG80)
LAMAs (e.g., tiotropium 18mcg OD via HandiHaler) are first-line maintenance in COPD (NICE NG115)
Aminophylline has a narrow therapeutic index; target plasma level 10-20 mg/L, requiring therapeutic drug monitoring
Ipratropium bromide (250-500mcg nebulised QDS) is used acutely in severe asthma alongside salbutamol
Beta-2 agonists can cause hypokalaemia, tremor, tachycardia, and lactic acidosis in high doses
Umeclidinium/vilanterol (Anoro Ellipta) is a LAMA/LABA combination used in COPD maintenance
The TORCH trial demonstrated salmeterol/fluticasone reduced exacerbations in COPD but did not significantly reduce mortality
Overview
Key Facts
Bronchodilators are the cornerstone of pharmacological management in obstructive airways disease. They work by relaxing bronchial smooth muscle through different mechanisms.
Epidemiology
Asthma affects approximately 5.4 million people in the UK, while COPD affects around 1.2 million diagnosed patients. Bronchodilators are among the most commonly prescribed medications in the NHS, with over 50 million inhaler prescriptions annually.
Aetiology
Bronchodilators target the reversible component of airway obstruction:
Methylxanthines: Phosphodiesterase inhibition → increased cAMP; also adenosine receptor antagonism
Pathophysiology
Airway narrowing in obstructive disease results from:
Bronchial smooth muscle contraction (targeted by bronchodilators)
Mucosal oedema and inflammation (targeted by corticosteroids)
Mucus hypersecretion
Airway remodelling (irreversible in COPD)
Beta-2 receptors are G-protein coupled receptors (Gs) that activate adenylyl cyclase. Chronic use leads to receptor downregulation (tachyphylaxis), particularly with regular SABA use.
Clinical Presentation
Indications for Bronchodilator Use
Acute asthma: Wheeze, dyspnoea, chest tightness, cough - SABA is first-line rescue therapy
COPD: Progressive breathlessness, chronic cough, sputum production
Inhaled corticosteroids (ICS) are the mainstay anti-inflammatory therapy in asthma and are used in combination with bronchodilators in COPD with eosinophilic features.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Beclometasone dipropionate is the reference ICS; low dose = 200-400mcg/day, medium = 400-800mcg/day, high = >800mcg/day
Fluticasone propionate is approximately twice as potent as beclometasone; low dose = 100-250mcg/day
ICS reduce asthma exacerbations by approximately 50% and are first-line preventer therapy (NICE NG80)
Local side effects include oral candidiasis (thrush) and dysphonia - mitigated by using a spacer and mouth rinsing
Systemic side effects at high doses include adrenal suppression, osteoporosis, cataracts, and growth retardation in children
In COPD, ICS increase risk of pneumonia (TORCH and INSPIRE trials) - use only with eosinophilic/asthmatic features
MHRA safety alert: High-dose ICS carry risk of adrenal crisis, particularly on abrupt withdrawal
ICS should not be used as monotherapy - always in combination with bronchodilator in COPD
Overview
Key Facts
Inhaled corticosteroids are synthetic glucocorticoids delivered directly to the airways, minimising systemic exposure while maximising anti-inflammatory effect at the target site.
Epidemiology
Approximately 3.5 million people in the UK use ICS regularly. Over-reliance on SABA rather than regular ICS remains a key contributor to preventable asthma deaths - the National Review of Asthma Deaths (NRAD) found that 39% of asthma deaths occurred in patients not prescribed ICS.
Aetiology
ICS act by:
Binding intracellular glucocorticoid receptors
Translocating to the nucleus and modifying gene transcription (transactivation and transrepression)
Suppressing inflammatory mediator production (IL-4, IL-5, IL-13, TNF-alpha)
Reducing eosinophilic airway inflammation
Decreasing mucus secretion and vascular permeability
Pathophysiology
The therapeutic target is chronic airway inflammation characterised by:
Eosinophil and mast cell infiltration
Th2 cytokine release
Basement membrane thickening
Goblet cell hyperplasia
Smooth muscle hypertrophy (airway remodelling)
ICS reduce all components except established remodelling, highlighting the importance of early initiation.
Clinical Presentation
Indications
Asthma: Any patient requiring SABA more than twice per week or with symptoms more than twice per week
COPD: In combination with LABA ± LAMA when blood eosinophils ≥300 cells/µL or ≥100 with ≥2 exacerbations/year
Eosinophilic bronchitis: Chronic cough with sputum eosinophilia
Side Effects to Recognise
Local: Oral candidiasis (seen in 5-10%), dysphonia (up to 30-50% at high doses), pharyngeal irritation
Systemic (at high doses): Adrenal suppression, reduced bone mineral density, easy bruising, posterior subcapsular cataracts, growth velocity reduction in children (approximately 0.5cm in first year)
Red Flags
Features of adrenal insufficiency on high-dose ICS: fatigue, weight loss, hypotension
Recurrent pneumonia in COPD patients on ICS
Poor growth in children on ICS - plot on growth chart at every review
Proton pump inhibitors (PPIs) irreversibly inhibit the gastric H+/K+ ATPase, potently suppressing acid secretion. They are widely prescribed for GORD, peptic ulcers, and dyspepsia.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
PPIs are irreversible inhibitors of the H+/K+ ATPase (proton pump) on parietal cells
Omeprazole 20mg OD is first-line for GORD (NICE NG12); full effect takes 2-3 days as new proton pumps are synthesised
PPIs are pro-drugs activated in the acidic canaliculi of parietal cells
Long-term use is associated with hypomagnesaemia, vitamin B12 deficiency, C. difficile infection, and increased fracture risk
Omeprazole inhibits CYP2C19 - important interaction with clopidogrel (consider lansoprazole or pantoprazole instead)
PPIs should be reviewed after 4-8 weeks and stepped down or stopped where possible (NICE NG12)
H. pylori eradication: Triple therapy - PPI + amoxicillin 1g BD + clarithromycin 500mg BD or metronidazole 400mg BD for 7 days
NICE recommends annual review of ongoing PPI prescriptions to assess continued need
Overview
Key Facts
PPIs are the most potent class of acid-suppressing drugs, reducing gastric acid secretion by up to 99%. They are among the most commonly prescribed medications worldwide.
Epidemiology
Approximately 15% of the UK adult population is prescribed a PPI at any given time. PPI prescriptions cost the NHS over £100 million annually. There is growing concern about overprescription - up to 50% of long-term PPI use may lack a clear indication.
Aetiology
PPIs target the final common pathway of acid secretion:
Bind covalently to cysteine residues on the alpha-subunit of H+/K+ ATPase
Irreversible inhibition - acid secretion only recovers as new proton pumps are synthesised (half-life of pump turnover approximately 18 hours)
All PPIs are benzimidazole derivatives and pro-drugs activated at pH <4
Pathophysiology
Gastric acid secretion is regulated by three stimulatory pathways:
Histamine (H2 receptors) - from ECL cells
Acetylcholine (M3 receptors) - vagal nerve
Gastrin (CCK-B receptors) - from G cells
All three converge on the H+/K+ ATPase. PPI blockade of this final step provides superior acid suppression compared to H2 receptor antagonists. Prolonged suppression leads to compensatory hypergastrinaemia.
Clinical Presentation
Indications
GORD: Heartburn, acid regurgitation, dysphagia
Peptic ulcer disease: Epigastric pain, relationship to meals
H. pylori eradication: As part of triple therapy
NSAID gastroprotection: Co-prescription with long-term NSAIDs in at-risk patients
Chemotherapy uses cytotoxic drugs to treat cancer by disrupting cell division. Understanding drug classes, mechanisms, and toxicity profiles is essential for safe prescribing.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Alkylating agents (cyclophosphamide, chlorambucil) cross-link DNA strands; cause haemorrhagic cystitis (prevent with mesna)
Antimetabolites (methotrexate, 5-FU, cytarabine) mimic normal substrates; folinic acid rescue used with high-dose methotrexate
Anthracyclines (doxorubicin) cause dose-dependent cardiotoxicity - maximum cumulative dose 450mg/m²
Vinca alkaloids (vincristine) cause peripheral neuropathy; vincristine is never given intrathecally (fatal)
Platinum agents (cisplatin) cause nephrotoxicity (requires aggressive hydration) and ototoxicity
Tumour lysis syndrome: Hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia - prevent with allopurinol or rasburicase
Cell cycle-specific drugs (e.g., methotrexate, vincristine) are most effective on rapidly dividing cells
Overview
Key Facts
Cytotoxic chemotherapy targets rapidly dividing cells and remains a cornerstone of cancer treatment. Drugs are classified by mechanism of action and cell cycle specificity.
Epidemiology
Approximately 375,000 new cancer cases are diagnosed annually in the UK. Chemotherapy is used in approximately 30% of cancer treatments, either as curative intent, adjuvant, neoadjuvant, or palliative therapy.
Aetiology
Chemotherapy agents are classified by mechanism:
Alkylating agents: Form covalent bonds with DNA bases (cyclophosphamide, melphalan, busulfan)
Antimetabolites: Structural analogues that interfere with nucleotide synthesis (methotrexate, 5-FU, gemcitabine)
Cytotoxic antibiotics: DNA intercalation and free radical generation (doxorubicin, bleomycin)
Platinum compounds: DNA cross-linking (cisplatin, carboplatin, oxaliplatin)
Pathophysiology
Chemotherapy exploits the higher growth fraction of tumour cells compared to normal tissues. The log-kill hypothesis states that each cycle kills a constant proportion of cells. Combination chemotherapy uses drugs with different mechanisms and toxicity profiles to maximise efficacy and minimise resistance.
Clinical Presentation
Common Toxicities
Bone marrow suppression: Neutropenia (nadir 7-14 days), thrombocytopenia, anaemia
GI toxicity: Nausea/vomiting (classified as high/moderate/low emetogenic), mucositis, diarrhoea
Alopecia: Common with anthracyclines, taxanes, cyclophosphamide
Targeted therapies are drugs designed to interfere with specific molecular targets involved in tumour growth, offering improved selectivity over conventional chemotherapy.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Imatinib (Gleevec) targets BCR-ABL tyrosine kinase in CML - revolutionised treatment, 5-year survival now >90%
Trastuzumab (Herceptin) targets HER2 receptor in breast cancer - risk of cardiotoxicity (monitor LVEF)
Rituximab targets CD20 on B-lymphocytes - used in NHL, CLL, and autoimmune conditions
Pembrolizumab/nivolumab are PD-1 checkpoint inhibitors - can cause immune-related adverse events (colitis, pneumonitis, hepatitis, thyroiditis)
EGFR inhibitors (erlotinib, gefitinib) used in NSCLC with EGFR mutations - cause characteristic acneiform rash
BRAF inhibitors (vemurafenib, dabrafenib) for BRAF V600E mutant melanoma
Bevacizumab (anti-VEGF) - risk of hypertension, proteinuria, wound healing impairment, GI perforation
Companion diagnostics (biomarker testing) are essential before prescribing most targeted therapies
Overview
Key Facts
Targeted therapies represent a paradigm shift from cytotoxic chemotherapy to precision oncology. They exploit specific molecular alterations in cancer cells, often identified through companion diagnostic testing.
Epidemiology
Targeted therapies are now used in over 50% of new cancer drug approvals. In the UK, NICE technology appraisals determine NHS availability. The Cancer Drugs Fund provides interim access to promising therapies awaiting full evaluation.
Therapeutic drug monitoring (TDM) involves measuring drug levels to optimise dosing for drugs with narrow therapeutic indices, ensuring efficacy while minimising toxicity.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
TDM is essential for drugs with a narrow therapeutic index where toxic and therapeutic levels are close
Digoxin: Therapeutic range 1.0-2.0 nmol/L (0.5-1.0 ng/mL); sample at least 6 hours post-dose
Gentamicin (once-daily dosing): Trough <1 mg/L; use the Hartford nomogram for extended interval dosing
Vancomycin: Target trough 15-20 mg/L for serious infections; AUC/MIC monitoring increasingly used
Phenytoin: Therapeutic range 10-20 mg/L; exhibits zero-order kinetics at therapeutic doses
Theophylline: Range 10-20 mg/L; levels increased by erythromycin, ciprofloxacin; decreased by smoking
TDM is most useful when there is a clear concentration-effect relationship and significant pharmacokinetic variability
Overview
Key Facts
TDM uses measured drug concentrations to individualise dosing, particularly for drugs where clinical response is difficult to assess and the margin between therapeutic and toxic levels is narrow.
Epidemiology
TDM is routinely performed for approximately 20 drugs in clinical practice. In the UK, clinical pharmacology and pharmacy departments coordinate TDM services. The most commonly monitored drugs are gentamicin, vancomycin, lithium, and antiepileptics.
Aetiology
Factors necessitating TDM:
Narrow therapeutic index: Small difference between efficacious and toxic concentrations
Significant inter-individual variability: Due to genetic polymorphisms (CYP2D6, CYP2C19), renal/hepatic function, drug interactions
Medication errors are preventable events that may cause patient harm at any stage of the medicines pathway. They are a major patient safety concern in the NHS.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Medication errors cause an estimated 237 million errors annually in England, with avoidable ADRs causing 1,708 deaths
Prescribing errors occur in 7-10% of medication orders in UK hospitals
The most common error types are wrong dose, wrong drug, and omitted medicines
LASA (Look-Alike Sound-Alike) drugs are a major source of error (e.g., chlorpromazine/chlorpropamide)
Electronic prescribing reduces prescribing errors by approximately 50% but introduces new error types
The NHS Patient Safety Strategy uses a Just Culture approach to learning from errors
All serious medication errors must be reported via the Yellow Card Scheme (MHRA) and local incident reporting systems
Overview
Key Facts
Medication errors can occur at any stage: prescribing, dispensing, administering, or monitoring. They represent the third most common cause of preventable deaths globally.
Epidemiology
The 2018 University of Sheffield/York study commissioned by the Department of Health estimated:
237 million medication errors per year in England
66 million potentially clinically significant errors
Avoidable ADRs: ~1,708 deaths and ~181,626 bed-days per year
Estimated NHS cost: £98.5 million per year in additional bed-days alone
Medicines reconciliation is the process of creating an accurate list of a patient's medications at every care transition, identifying and resolving discrepancies to prevent errors.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Medicines reconciliation should occur within 24 hours of admission to hospital (NICE NG5)
Up to 70% of patients have at least one discrepancy between their admission medications and GP records
The most common discrepancies are omitted medicines, incorrect doses, and unintentional additions
Medicines reconciliation reduces medication errors at care transitions by up to 70%
A minimum of two sources should be used to verify medication history (e.g., patient, GP summary, community pharmacy)
The process should be pharmacist-led where possible (NICE NG5)
Discharge medicines reconciliation is equally important - unintentional changes must be communicated to GP
Overview
Key Facts
Medicines reconciliation is a critical patient safety process that prevents medication errors at transitions of care. NICE defines it as 'the process of identifying an accurate list of a person's current medicines and comparing them with the current list in use, recognising any discrepancies, and documenting any changes.'
Epidemiology
Studies show:
30-70% of patients have at least one medication discrepancy on admission
12-17% of these discrepancies have the potential to cause harm
50% of medication errors at hospital discharge involve discrepancies not communicated to primary care
NICE estimates that effective reconciliation could prevent ~30,000 ADR-related admissions per year in England
Drug overdose and poisoning are common emergency presentations. Knowledge of specific antidotes, risk assessment tools, and management protocols is essential for safe clinical practice.
PSA · MRCP Part 1 · PLAB 1 · UKMLA
Key Facts
Paracetamol overdose is the commonest cause of acute liver failure in the UK - use the treatment nomogram and give N-acetylcysteine (NAC)
TOXBASE (National Poisons Information Service) is the UK's primary clinical toxicology database for management guidance
Activated charcoal (50g PO) is effective if given within 1 hour of ingestion of most toxins
Benzodiazepine overdose: Rarely fatal in isolation → flumazenil (use cautiously - seizure risk in mixed overdose/chronic use)
Salicylate (aspirin) overdose: Tinnitus, mixed respiratory alkalosis + metabolic acidosis → alkaline diuresis, haemodialysis if severe
Staggered paracetamol overdoses are highest risk - always treat with NAC if >75mg/kg over 24 hours
Overview
Key Facts
Poisoning accounts for over 170,000 hospital presentations per year in England. It is the leading cause of death in young adults (15-35 years) and is frequently associated with mental health conditions and substance misuse.
Epidemiology
>100,000 ED attendances for self-poisoning per year in England
Paracetamol is involved in ~50% of poisoning presentations
~5,000 deaths from poisoning per year in the UK (including drug misuse deaths)
Self-poisoning accounts for ~80% of self-harm hospital presentations
Aetiology
Intentional self-harm: ~80% of poisoning presentations (impulsive in many)
Accidental ingestion: Especially in children under 5 years
Recreational drug use: MDMA, cocaine, novel psychoactive substances