IC5 - I

• Adverse drug reactions (ADRs) are undesirable or harmful effects of drugs given in conventional therapeutic settings
• ADRs can range from minor to serious to potentially fatal
• ADRs can mimic many disease conditions
• ADRs are not the same as drug-drug interactions
• Type A (Augmented ADR):

  • Due to excess of normal, predictable effects
  • Dose-related
  • Common and occurs in everyone if sufficient dosage is taken
  • Examples: Warfarin (anticoagulant) leading to bleeding, Digoxin causing nausea
• Type B (Bizarre ADR):

  • Uncommon
  • Not predictable from the drug's primary action
  • Not dose-related
  • Includes idiosyncratic reactions due to genetic abnormalities and immunologic reactions like allergic reactions
  • Examples: Anaesthetics causing malignant hyperthermia, Penicillin leading to anaphylaxis
• Type C (Continuous use ADR):

  • Predictable in most cases
  • Due to long-term use
  • Examples: NSAIDs causing nephropathy, Corticosteroids leading to Cushing syndrome
• Type D (Delayed ADR):

  • Delayed effects that may occur even after cessation of drug use
  • Examples: Alkylating agents causing carcinogenesis, Retinoids and Thalidomide leading to teratogenesis
• Type E (End of use ADR):

  • Occur after withdrawal of the drug, especially with abrupt withdrawal
  • Usually predictable
  • Examples: Corticosteroids leading to adrenocortical insufficiency
• Hypersensitivity reactions include allergic reactions categorized into 4 types: Type I to Type IV
• Type I (IgE-mediated):

  • Immediate hypersensitivity with maximal response within 30 minutes
  • Clinical manifestations include allergic reactions like rhinitis, angioedema, and systemic anaphylaxis
  • Examples: B-lactam antibiotics causing anaphylaxis
• Type II (Cytotoxic ADR):

  • Involves cytotoxic antibodies against drug hapten-coated cells
  • Clinical effects include haemolytic anaemia, neutropenia, and thrombocytopenia
  • Examples: Penicillin leading to haemolytic anaemia
• Type III (Immune complex-mediated):

  • Also known as Arthus reaction
  • Clinical manifestations include serum sickness, lymphadenopathy, and nephropathy
  • Examples: Penicillins, cephalosporins, and sulfonamides causing immune complex-mediated reactions
• Type IV (Delayed cell-mediated):

  • Mediated by Th1 cells
  • Clinical manifestations include erythema and induration
  • Examples: Allergic contact dermatitis, TB dermal test
• Common drugs giving rise to ADRs include Oestrogens, NSAIDs, and Corticosteroids
• Oestrogens:

  • Therapeutic uses include Hormone Replacement Therapy (HRT) and Oral Contraceptive Pills (OCP)
  • ADRs include thromboembolism, hypertension, breast cancer, endometrial cancer, and hepatic adenoma
• NSAIDs:

  • Therapeutic uses include reducing pain, fever, and inflammation by inhibiting cyclo-oxygenase (COX)
  • ADRs include GI bleeding, tinnitus, pulmonary eosinophilia, GI ulceration, vertigo, and renal failure
• NSAIDs Adverse Drug Reactions (ADRs):

  • GI bleeding
  • Tinnitus
  • Pulmonary eosinophilia
  • GI ulceration
  • Vertigo
  • Alveolitis
  • Nausea
  • Headache
  • Stevens-Johnson Syndrome
  • Vomiting
  • Renal failure
  • Toxic epidermal necrolysis (TEN)
  • Pancreatitis
  • Papillary necrosis
  • Haematuria
  • Liver damage
  • Fluid retention
  • Hypersensitivity
  • Gastric ulceration due to inhibition of COX-1, preventing the creation of prostaglandins that protect the gastric mucosa
• Corticosteroids Therapeutic uses:

  • Cortisol (glucocorticoid) and aldosterone (mineralocorticoid) produced in the adrenal cortex
  • "Corticosteroids" generally refers to glucocorticoids
  • Anti-inflammatory agents (systemic or topical) inhibit molecules promoting inflammation
  • Uses: Autoimmune disease, asthma, allergic rhinitis, urticaria (hives), atopic eczema
  • Replacement therapy for pituitary or adrenal insufficiency
  • Effects: Immunosuppressive, anti-inflammatory effects, Metabolic effects affecting carbohydrate, fat, and protein metabolism
• Corticosteroids Adverse Drug Reactions:

  • Mental disturbances
  • Suppression of growth in children
  • Adrenocortical atrophy
  • Diabetes (iatrogenic)
  • Immunosuppression
  • Cushing syndrome symptoms:
  • Moon facies
  • Central obesity
  • Violaceous striae (purple stretch marks)
  • Easy bruising
  • Hirsutism
  • Male pattern balding
  • Acne
  • Acanthosis nigricans
  • Peptic ulcer
  • Proximal muscle weakness
  • Osteoporosis
  • Avascular necrosis of the hip
  • Weight gain
• Liver Dose-related reactions:

  • Pathology and associated drugs:
  • Hepatocellular necrosis: Paracetamol, Cytotoxic drugs (e.g., Methotrexate), Salicylates, Vitamin A
  • Acute fatty liver: Tetracycline (IV)
  • Granulomatous hepatitis: Phenylbutazone, hydralazine, allopurinol
  • Focal Nodular Hyperplasia: Oral contraceptives (OCP)
  • Liver cell adenoma (benign tumour): OCP, anabolic steroids
  • Fatty liver
• Gastrointestinal tract ADRs:

  • Gastritis: NSAIDs
  • Peptic ulcers: NSAIDs, Corticosteroids
  • Jejunal ulcers: Enteric-coated potassium
  • Pseudomembranous colitis: Antibiotics
  • Gingival hyperplasia: Phenytoin
• Urinary Tract ADRs:

  • Acute tubulo-interstitial nephritis: Methicillin, rifampicin, sulphonamides
  • Acute tubular necrosis: Gentamicin
  • Analgesic nephropathy (papillary necrosis): Compound analgesics containing phenacetin, acetaminophen, NSAIDs
  • Haemorrhagic cystitis: Cyclophosphamide
• Bone Marrow ADRs:

  • Many drugs affect the bone marrow, usually cytotoxic/anti-neoplastic drugs
  • Myelosuppression (usually reversible)
  • Normal marrow vs. Aplastic marrow
• Principles of avoiding and minimizing ADRs (in clinical practice):

  • Patient factors: Intrinsic (age, gender, genetic factors, organ dysfunction, previous ADRs, habits), Extrinsic (environmental factors, nutrition)
  • Prescriber factors: Drug-drug interactions, Incorrect administration, Dose, Duration
  • Drug factors: Interactions, Pharmaceutical issues
  • Vulnerable patient groups: Elderly, Neonates, infants, Women, Renal or hepatic impairment history of ADRs
• Steps to minimize ADRs in clinical practice:

  • Appropriate use of drugs
  • Prescribe correct dose, route, and frequency
  • Check previous ADR history and allergies
  • Be cautious of polypharmacy and interactions
  • Perform necessary lab monitoring
  • Communicate common ADRs clearly
• How to reduce the incidence of ADRs:

  • Always check for allergies and drug interactions
  • Advise discontinuation of medication if an ADR occurs
• Summary:

  • Definition of ADRs and types
  • Hypersensitivity reactions
  • Commonly used drugs and affected organ systems
  • Principles of preventing/minimizing ADRs
• types of adverse drug reactions

  A: Augmented; common

  B: Bizarre; idiosyncratic; infrequent

  C: Chronic, continuous; rare

  D: Delayed; rare

  E: End of use; rare
• Type A (Augmented ADR) mechanism

  1. due to the drug's primary pharmacological effect: warfarin causing bleeding
  2. due to low therapeutic index: digoxin causing nausea
  3. predictable, dose related, preventable
• Type B (bizarre ADR) mechanism (poorly understood)

  1. immunologic mechanism (allergic/hypersensitivity reaction): penicillin causing anaphylaxis
  2. idiosyncratic. genetic basis; how the drug is metabolised: anaesthetics causing malignant hyperthermia
  3. not predictable, not dose related, can be life threatening
• Type C (chronic, continuous ADR) mechanism:

  1. continuous reaction to long-term use
  2. analgesics causing nephropathy
  3. neuroleptics causing tardive dyskinesia
  4. predictable, dose dependent
• Type D (delayed ADR) mechanism

  1. delayed reactions
  2. alkylating agents causing carcinogenesis
  3. predictable and dose dependent
• type E (end-of-use ADR) mechanism

  1. end of use reactions
  2. glucocorticoid withdrawal symptoms like adrenocortical deficiency
  3. benzodiazepine withdrawal causing insomnia and anxiety
  4. predictable and dose related