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)