Adverse Drug Reactions and Toxicity

ADR Basics - What's the Harm?

• Adverse Drug Reaction (ADR): Harmful, unintended effect of a drug at normal therapeutic doses (WHO definition).
• Severity: Can range from Minor → Moderate → Severe → Lethal.
• Classification (Rawlins & Thompson):

⭐ Type B (Bizarre) reactions are generally unpredictable, not dose-dependent, and often related to patient-specific factors like genetics (e.g., G6PD deficiency) or immune responses (e.g., penicillin allergy).

ADR Mechanisms - How Drugs Go Rogue

• Type A (Augmented): Dose-dependent, predictable from known pharmacology. E.g., Bleeding with anticoagulants, severe hypoglycemia with insulin.
• Type B (Bizarre): Dose-independent, unpredictable; often immune-mediated or due to genetic factors. E.g., Anaphylaxis to penicillin, G6PD deficiency hemolysis with primaquine.
• Hypersensitivity Reactions (Gell & Coombs):

  Type	Name	Mediator(s)	Onset	Drug Examples
  I	Anaphylactic	IgE	Minutes	Penicillin, NSAIDs
  II	Cytotoxic	IgG, IgM	Variable	Methyldopa (hemolysis), Heparin (HIT)
  III	Immune Complex	IgG, IgM	1-3 wks	Sulphonamides, Penicillin (serum sickness)
  IV	Cell-Mediated	T-cells	2-3 days	Allopurinol (SJS/TEN), Topical neomycin

  ⭐ Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) are severe Type IV reactions, often linked to allopurinol, lamotrigine, sulfonamides.

• Other Types:
  • C (Chronic): Prolonged use (e.g., NSAID nephropathy).
  • D (Delayed): After stopping (e.g., tardive dyskinesia).
  • E (End-of-use): Withdrawal (e.g., opioid withdrawal).
  • F (Failure): Unexpected (e.g., antibiotic resistance).

Risk Factors & Susceptibility - Who's at Risk?

• Patient-Specific:
  • Age extremes (neonates, elderly): altered pharmacokinetics (PK), ↓drug metabolism/excretion
  • Genetic factors: e.g., CYP polymorphisms (slow/rapid metabolizers), G6PD deficiency, HLA types (e.g., HLA-B*5701 & abacavir hypersensitivity)
  • Organ dysfunction: renal/hepatic impairment (↓drug clearance, ↑half-life)
  • Polypharmacy: ↑risk of drug-drug interactions (DDIs)
  • Physiological states: pregnancy, lactation (altered PK, fetal/neonatal risk)
  • History: previous ADRs, allergies, atopy
• Drug-Specific:
  • Narrow therapeutic index (NTI): e.g., warfarin, digoxin, lithium, phenytoin, theophylline
  • Dose & duration: high doses, prolonged therapy
  • Properties: inherent toxicity, high allergenic potential (e.g., penicillins)

⭐ Patients with renal impairment are at significantly ↑risk for ADRs from drugs primarily excreted by kidneys (e.g., aminoglycosides, lithium, metformin, many NSAIDs).

Organ Toxicity & Teratogenicity - System Hit List

• Organ-Specific Toxicity:

  Organ	Key Drugs
  Hepatotoxic	Paracetamol, Isoniazid, Halothane
  Nephrotoxic	Aminoglycosides, NSAIDs, Cisplatin
  Neurotoxic	Vincristine (peri), Phenytoin (cereb)
  Cardiotoxic	Doxorubicin, Trastuzumab
  Pulmotoxic	Amiodarone, Bleomycin
  Ototoxic	Aminoglycosides, Furosemide
  Myelosupp.	Chemotherapy, Chloramphenicol

• Teratogenicity: Drug-induced fetal defects. Critical period: 3-8 weeks (organogenesis).

  • Thalidomide: Phocomelia 📌 Tha-limb-domide
  • Warfarin: Nasal hypoplasia, skeletal defects
  • Phenytoin: Fetal hydantoin syndrome
  • Valproate: Neural tube defects
  • ACE Inhibitors/ARBs: Renal dysplasia (2nd/3rd trimester)
  • Isotretinoin: CNS, craniofacial, CV defects
  • Lithium: Ebstein's anomaly

  ⭐ ACE inhibitors and ARBs are contraindicated in pregnancy, especially in the 2nd and 3rd trimesters, due to risks of fetal renal damage and oligohydramnios.

High‑Yield Points - ⚡ Biggest Takeaways

• Type A ADRs are dose-dependent and predictable; Type B ADRs are non-dose-dependent and unpredictable.
• Idiosyncratic reactions are genetically determined (e.g., G6PD deficiency with primaquine).
• Teratogenicity involves drug-induced fetal malformations, with the first trimester being most critical.
• CYP450 enzyme inducers (e.g., rifampicin) ↓ drug effect; inhibitors (e.g., ketoconazole) ↑ drug toxicity.
• Key antidotes: N-acetylcysteine (paracetamol), naloxone (opioids), flumazenil (benzodiazepines).
• Drug interactions (pharmacokinetic & pharmacodynamic) are a major source of ADRs and toxicity.
• Therapeutic Drug Monitoring (TDM) is crucial for drugs with a narrow therapeutic index (e.g., digoxin, lithium).