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AUTACOIDS AND RELATED DRUGS - PHARMACOLOGY PAPER 2

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HISTAMINE AND ANTIHISTAMINICS

SN 1. Second Generation (Non-Sedative) Antihistaminics vs Conventional (First Gen) - Compare & Contrast

1. No sedation - safe for patients operating machinery/driving
2. Once daily dosing - better compliance
3. No anticholinergic side effects
4. Longer duration of action

1. Allergic rhinitis
2. Chronic urticaria

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SN 2. H1 Antihistaminics - Uses & Adverse Effects

1. Allergic disorders - Urticaria, hay fever, allergic rhinitis, atopic dermatitis
2. Motion sickness - Dimenhydrinate, promethazine (1st gen only)
3. Nausea & vomiting - Promethazine (antiemetic)
4. Pruritus - Diphenhydramine
5. Premedication - Promethazine (sedation + anticholinergic)
6. Common cold - To reduce rhinorrhoea (drying effect)
7. Insomnia - 1st gen (sedative property)
8. Anaphylaxis - Adjuvant to adrenaline

• CNS: Sedation, drowsiness, dizziness, impaired cognition, paradoxical excitement (especially in children)
• Anticholinergic: Dry mouth, blurred vision, urinary retention, constipation, tachycardia
• GIT: Nausea, epigastric distress, anorexia
• CVS: QT prolongation with astemizole and terfenadine (withdrawn from market)
• Others: Photosensitivity (especially promethazine)

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SN 3. Antihistaminics - Classify, Four Uses

• 1st Gen (Sedating): Diphenhydramine, Chlorpheniramine, Promethazine, Dimenhydrinate, Hydroxyzine
• 2nd Gen (Non-sedating): Cetirizine, Loratadine, Fexofenadine, Desloratadine, Levocetirizine

1. Allergic rhinitis and urticaria
2. Motion sickness (promethazine, dimenhydrinate)
3. Nausea and vomiting (promethazine)
4. Pruritus of varied origin

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5-HT, ANTAGONISTS AND DRUG THERAPY OF MIGRAINE

SN 1. Prophylaxis of Migraine - Four Drugs, Adverse Effects, Sumatriptan MOA

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• Sumatriptan is a selective 5-HT1B/1D receptor agonist ("triptan")
• 5-HT1D action: Inhibits release of vasoactive peptides (CGRP, substance P) from trigeminal nerve endings - anti-neurogenic inflammation
• 5-HT1B action: Causes vasoconstriction of dilated intracranial blood vessels (reverses meningeal vasodilation of migraine)
• Net effect: Aborts acute migraine attack
• Used only for acute/abortive treatment, NOT prophylaxis

• Chest tightness, heaviness (coronary vasoconstriction - most important)
• Flushing, tingling, warm sensation
• Dizziness, fatigue
• Contraindicated in ischaemic heart disease, uncontrolled hypertension, cerebrovascular disease

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PROSTAGLANDINS, LEUKOTRIENES AND PLATELET ACTIVATING FACTOR

SN 1. Prostaglandin Analogues - Therapeutic Uses During Pregnancy and Labour

1. Induction of labour - Dinoprostone, Misoprostol
2. Cervical ripening (priming before induction) - Dinoprostone gel/pessary intracervically
3. Medical abortion (MTP) - Misoprostol + Mifepristone (up to 9 weeks)
4. Mid-trimester abortion - Carboprost, Gemeprost
5. Postpartum haemorrhage - Carboprost (when oxytocin fails), Misoprostol (rectal/sublingual)

1. Unfavourable cervix (Bishop score < 6) - Dinoprostone for ripening
2. When oxytocin is contraindicated
3. Intrauterine fetal death
4. Grand multipara (oxytocin risk of uterine rupture is higher; PGs safer in low dose)

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SN 2. Prostaglandins - Four Therapeutic Uses with Agent of Preference

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NSAIDS AND ANTIPYRETIC-ANALGESICS

SN 1. NSAIDs - Classify, Important Uses, Two Adverse Effects

• Salicylates: Aspirin, Sodium salicylate
• Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen
• Acetic acid derivatives: Indomethacin, Diclofenac, Ketorolac
• Enolic acid (Oxicam): Piroxicam, Meloxicam (preferential COX-2)
• Anthranilic acid (Fenamic acid): Mefenamic acid
• Pyrazolone: Phenylbutazone (largely obsolete)

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1. Pain relief - headache, dysmenorrhoea, musculoskeletal pain
2. Rheumatoid arthritis and osteoarthritis
3. Fever (antipyretic)
4. Postoperative analgesia
5. Gout - Indomethacin (acute attack)
6. Bartter's syndrome - Indomethacin
7. Patent ductus arteriosus closure - Indomethacin IV
8. Dysmenorrhoea - Mefenamic acid, Ibuprofen
9. Pericarditis - Aspirin, Ibuprofen

1. GI toxicity - Peptic ulceration, GI bleeding (due to COX-1 inhibition reducing protective PGE2 in gastric mucosa; also direct irritation)
2. Renal toxicity - Acute renal failure, fluid retention, papillary necrosis (COX-1 in kidney maintains renal blood flow; inhibition causes renal ischaemia especially in hypovolaemia)

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SN 2. Opioids vs NSAIDs - Major Differences

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SN 3. Diclofenac Sodium - Write in Brief

• Class: Phenylacetic acid derivative NSAID (Acetic acid derivative)
• MOA: Non-selective COX inhibitor (preferentially inhibits COX-2 at therapeutic doses); also reduces arachidonic acid availability. Reduces PG synthesis.
• Pharmacokinetics: Well absorbed orally; extensive first-pass metabolism; highly protein bound; t1/2 = 1-2 hours; available as tablets, SR, topical gel, injections
• Uses:
  1. Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis
  2. Acute musculoskeletal pain, post-traumatic pain
  3. Dysmenorrhoea
  4. Postoperative pain (injectable form)
  5. Topical: Osteoarthritis of knee, soft tissue injury
• Adverse Effects:
  • GI: Peptic ulceration, hepatotoxicity (dose-related; monitor LFT)
  • CVS: Modest increase in cardiovascular risk
  • Renal: Salt/water retention
  • Local: Injection site pain (IM)
• Preparations: Voltaren, Voveran; available as 50 mg, 75 mg tabs; SR 100 mg; 1% topical gel; 75 mg/3mL injection
• Note: Has lowest GI toxicity among NSAIDs; considered safer than indomethacin

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NSAIDS LAQ

LAQ 1. Aspirin vs COX-2 Inhibitors - Compare & Contrast

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LAQ 2. NSAIDs - Full Answer

• Irreversibly acetylates serine residue of COX-1 and COX-2 enzymes
• Inhibits arachidonic acid conversion to PGG2 (first step in PG synthesis)
• At low dose (75-150 mg): selectively inhibits platelet COX-1 (TXA2) - antiplatelet
• At higher dose: anti-inflammatory and antipyretic

1. Antipyretic and analgesic - headache, fever, myalgia
2. Anti-inflammatory - RA, acute rheumatic fever (drug of choice)
3. Antiplatelet - MI prophylaxis, unstable angina, post-CABG (75-150 mg/day)
4. Acute MI - 325 mg stat (loading dose), then 75 mg/day
5. Kawasaki disease - high dose
6. Gout - high dose (> 3g/day) uricosuric; avoid in gout (low dose causes urate retention)

1. GI - Peptic ulceration, GI bleeding (most common)
2. Salicylism - Tinnitus, deafness, vertigo, nausea (chronic toxicity)
3. Reye's syndrome - Fatal hepatic encephalopathy in children with viral fever (contraindicated < 12 years)
4. Aspirin-sensitive asthma - Bronchoconstriction via increased leukotrienes
5. Bleeding tendency - Antiplatelet effect
6. Metabolic - Respiratory alkalosis (early) then metabolic acidosis (salicylate toxicity)
7. Hypersensitivity - Urticaria, angioedema

• Children < 12 years (Reye's syndrome)
• Peptic ulcer, bleeding disorders
• Asthma (aspirin-sensitive)
• Gout (low dose - retains urate)
• Last trimester of pregnancy (premature closure of PDA)

1. Better GI tolerability - reduced peptic ulceration
2. No antiplatelet effect - safe perioperatively
3. Same analgesic/anti-inflammatory efficacy as non-selective NSAIDs
4. Useful in patients with prior GI history who need NSAIDs

1. Increased cardiovascular risk (thrombosis) - rofecoxib withdrawn (VIOXX)
2. No cardioprotective antiplatelet effect
3. Expensive
4. Similar renal toxicity as non-selective NSAIDs
5. Celecoxib: sulfonamide allergy cross-reactivity

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ANTIRHEUMATOID AND ANTIGOUT DRUGS

SN 1. Gout - Drugs Used and MOA

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SN 2 & 3. Methotrexate in Rheumatoid Arthritis - Pharmacological Basis

• MTX is a folic acid antagonist - inhibits dihydrofolate reductase (DHFR)
• This reduces available tetrahydrofolate (THF)
• Reduced purines and pyrimidines → antiproliferative on rapidly dividing cells (lymphocytes, synoviocytes)
• Most important mechanism in RA: Intracellular MTX polyglutamates accumulate → inhibit AICAR transformylase → adenosine accumulates → adenosine has potent anti-inflammatory action (inhibits neutrophil adhesion, reduces cytokine release - TNF-α, IL-1, IL-6)
• Also inhibits leucocyte function and T-cell activation

• Hepatotoxicity - hepatic fibrosis with chronic use (most serious); monitor LFT
• Pulmonary toxicity - interstitial pneumonitis (MTX lung)
• Myelosuppression - leucopenia, thrombocytopenia
• Mucositis / stomatitis - oral ulcers (folate deficiency)
• Teratogenicity - category X; strictly contraindicated in pregnancy
• GI - nausea, vomiting, diarrhoea
• Rescue: Leucovorin (folinic acid) - given after high-dose MTX to rescue normal cells

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Exam Tips:

• Questions marked with * are high-yield repeat questions
• For SN questions: answer in 3-4 points with a mini table if comparing two drugs
• For LAQ: Use Classification → MOA → Uses → ADR → Contraindications structure
• Colchicine MOA and Methotrexate in RA are common exam favorites
• Sumatriptan (5-HT1B/1D agonist) is always asked - remember it's for ACUTE migraine, not prophylaxis
• Aspirin's irreversible COX inhibition and its role in antiplatelet therapy is a recurring theme