MM

Adverse Effects of Drugs – Comprehensive Study Notes

Learning Objectives

  • Describe the nature of predictable / pharmacological adverse effects

  • Describe the nature of unpredictable / non-pharmacological adverse effects

  • Describe the nature of idiosyncratic / dose-independent adverse effects

  • Define the therapeutic index (TI) and outline management of drugs with a low TI
    • Formula: TI = \frac{TD{50}}{ED{50}}
    • Low TI ⇒ narrow safety window, mandates therapeutic drug monitoring, individualised dosing & patient education

  • Identify the two major causes of drug–drug interactions (DDIs)
    • Plasma-protein displacement
    • Cytochrome P450 (CYP)–mediated interactions

  • List populations needing special prescribing consideration & explain why (children, women, pregnancy, elderly, ethnic groups, co-morbid, poly-pharmacy)

Adverse Drug Events (ADE) – Epidemiology & Cost

  • 82\% of American adults take ≥1 medication; 29\% take ≥5 (poly-pharmacy)

  • Annual burden (USA)
    • 1.3\,\text{million} emergency-department visits
    • 350{,}000 hospitalisations
    • \$3.5\,\text{billion} in additional medical costs
    • ≈40\% deemed preventable

Principal Drug Classes Implicated in ADEs

  • Overall ADE incidence ≈ 4/1000 prescriptions

  • Antibiotics (≈16\% of ADEs)
    • Risk of ADE ≈1/1000 (allergy most common)
    • Benefit (prevent serious URTI complication) ≈1/4000

  • Anticoagulants (≈32\% of patients >65 y)
    • Warfarin, rivaroxaban, dabigatran in top-10 ADE causes

  • Opioid analgesics
    • Prescription-opioid death rate > heroin death rate

  • Insulin – high-alert drug for hypoglycaemia & dosing errors

Unwanted vs Desirable Effects – Context Matters

  • Opiates
    • Pain therapy → constipation unwanted
    • Diarrhoea therapy → constipation desirable

  • H1 antihistamines
    • Allergy treatment → drowsiness unwanted
    • Motion-sickness prophylaxis → drowsiness useful

Mechanistic Classification of Toxicity

  • Pharmacological (predictable)
    • Excess of intended action (class-wide)
    • Alternative receptor / pathway within same class
    – Aspirin: anti-inflammatory vs bleeding
    – H1 antihistamines: multiple receptor blockade (H1, mACh, 5-HT)

  • Non-pharmacological (unpredictable)
    • Specific agents within class
    • Distinct mechanism, e.g. ACE-inhibitor–induced cough (bradykinin)

  • Overdose toxicity – dose dependent

  • Idiosyncratic – dose independent, genetically or immunologically determined

  • Organ-specific categorisation
    • Hepatotoxic, nephrotoxic, neurotoxic, etc.

Historical Lessons – Drug Teratogenicity

  • Thalidomide
    • Introduced 1957 (sedative/anti-emetic)
    • Withdrawn 1961 after limb malformations
    • Key whistle-blowers: William McBride, Widukind Lenz

  • Diethylstilbestrol (DES)
    • Synthetic estrogen (FDA 1941) for miscarriage prevention & others
    • 1971: linked to clear-cell adenocarcinoma (CCA) of vagina/cervix in “DES daughters” & pregnancy complications

Sources of ADEs

  • Active Pharmaceutical Ingredient (API)
    • Well-characterised pre-approval; toxicity may be
    – Species-specific
    – Metabolite-mediated (often uncharacterised pre-marketing)

  • Contaminants
    • Synthetic by-products or degradation products
    • Often batch-specific; may cause rare cancers or acute poisoning

  • Excipients – generally regarded as safe (GRAS) but can trigger hypersensitivity in susceptible patients

Metabolism: ‘Detoxification’ vs ‘Toxification’

  • Many clinically significant toxicities stem from reactive metabolites formed post-approval

  • Major biotransformation enzymes (approximate share of marketed drugs’ metabolism)
    • \text{CYP3A} ≈30\%
    • \text{CYP2D6} ≈20\%
    • \text{CYP2C9} ≈15\% etc.

Case Study – Paracetamol (Acetaminophen)

  • Toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)

  • Detoxified by conjugation with glutathione (GSH)

  • Overdose depletes GSH
    • Antidote: N-acetylcysteine (orally active GSH precursor)

Poly-pharmacy & Drug Interactions

  • Phase III trials usually test 1 background standard therapy → limited interaction data

  • Phase IV (post-marketing) expands permissible combinations

  • Clinician approach
    • Identify typical co-medications for disease
    • Map metabolic pathways (CYPs, UGT, transporters)
    • Monitor pharmacovigilance alerts

CYP-Mediated DDIs – Key Players

  • Inducers (↑ enzyme expression)
    • Rifampicin, carbamazepine, barbiturates, dexamethasone, tobacco smoke

  • Inhibitors (↓ clearance)
    • Ketoconazole (3A4), fluconazole (2C9), quinidine (2D6), macrolides, grapefruit juice

  • Substrate examples
    • 3A4: midazolam, nifedipine, cyclosporin, atorvastatin, warfarin
    • 2D6: debrisoquine, codeine, tamoxifen
    • 2C9: phenytoin, warfarin, tolbutamide, NSAIDs

  • Interaction schema (PXR-RXR activation → ↑CYP3A transcription) affects oral contraceptives, immunosuppressants etc.

Plasma-Protein Binding Interactions

  • Drugs compete for albumin / α1-acid glycoprotein sites
    • Displacement ↑ free (active) fraction

  • Example table (binding 95%→90% doubles unbound from 5\% to 10\%; 50%→45% only 10% relative change) → clinically relevant when drug A has high binding & narrow TI

Contaminants & Degradation

  • Manufacturing variations & storage (heat, light, humidity) generate carcinogenic nitrosamines (e.g. NDMA in ranitidine, ARBs; NTTP in sitagliptin)

  • Global incidents:
    • Maiden Pharmaceuticals cough syrup – 60 paediatric deaths (Gambia 2022)
    • Diethylene/ethylene glycol contamination – India & Indonesia

Generics, Bioequivalence & Quality Concerns

  • Patent expiry (20 y) → multiple generic manufacturers
    • Different synthetic routes, salt forms, excipients, impurity profiles, GMP standards

  • FDA definition of bioequivalence: 0.80 \le CI \le 1.25 for C_{max} & AUC

  • Clinical caveat
    • Brand = AUC 1.0; Generic B = 0.8; Generic C = 1.25
    • Switching C→B ⇒ dose drop of \approx37\% → possible therapeutic failure

  • Ranbaxy case: widespread GMP violations, \$500\,\text{million} felony fine, API import ban (2014)

Limitations of Phase III Trials

  • Designed for success → recruit ‘ideal’ patients
    • Clear diagnosis, early disease, age 18–70, no co-morbidities, no poly-pharmacy

  • Under-representation of
    • Children, elderly, pregnant women, ethnic minorities, co-morbidities

Special Populations & Dose Adjustment

  • Hepatic impairment
    • ↓ CYP activity → ↑ half-life, require dose reduction or longer interval

  • Renal impairment
    • ↓ GFR → accumulate renally cleared drugs/metabolites

  • Racial / Ethnic variability
    • Genetic polymorphisms in CYP2D6, NAT2, HLA, etc.
    • Under-representation in trials (e.g. Asians 1.6% vs 5.9% census)

  • Debate on race as surrogate biomarker
    • Social construct vs genotype correlation
    • Ideal: pharmacogenetic testing; pragmatic: race-informed dosing where high risk

Pharmacogenetics & Precision Medicine

  • Variants affect pharmacodynamics, PK, toxicity (e.g. HLA-B*57:01 & abacavir hypersensitivity)

  • Personalised medicine tailors dose/drug to individual genotype/phenotype

  • Challenges: cost, reduced market size, statistical validity (post-hoc subgroup claims)

Post-Marketing Surveillance (Phase IV)

  • Detects ADEs with incidence <0.1\% (rare but serious)

  • Pharmacovigilance workflow
    • Spontaneous reporting: Yellow Card (UK 1964), FDA MedWatch
    • Prescription Event Monitoring (via national health systems) → true incidence estimates

Factors Contributing to Medication Errors

  • Prescriber factors: inadequate pharmacology training, limited patient knowledge, risk mis-perception, fatigue/stress, poor communication

Information Resources

  • SmPC (EU) – definitive source for indications, dosing, ADEs, special populations
    • Sections 1–6 cover product data, benefits, risks, administration, special warnings

  • Risk-Mitigation Frameworks
    • EMA Risk Management Plan (RMP) utilises SmPC
    • FDA Risk Evaluation & Mitigation Strategy (REMS) – company specific (black-box warnings, registries, certification)