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ASSIGNMENT - 15/07/2026

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Q1. 5-HT Receptor Agonists and Antagonists - Examples and Therapeutic Uses

Introduction

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Classification with Examples and Uses

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Important Drug Details

• Examples: Sumatriptan, Zolmitriptan, Eletriptan, Rizatriptan, Naratriptan
• MOA: Activate 5-HT1B/1D receptors → constriction of intracranial blood vessels + inhibition of trigeminal nerve pain transmission
• Use: Acute treatment of migraine (NOT for prophylaxis)

• Examples: Ondansetron, Granisetron, Palonosetron
• MOA: Block 5-HT3 receptors in GI tract and vomiting center
• Use: CINV, post-operative vomiting, radiation sickness

• Examples: Cyproheptadine, Methysergide
• Cyproheptadine: Antihistamine + serotonin antagonist → used in migraine prophylaxis, allergies, appetite stimulation in children
• Methysergide: Used in prophylaxis of carcinoid syndrome and migraine

• Buspirone: Anxiolytic (no sedation, no dependence) - used in Generalized Anxiety Disorder

• Fluoxetine, Sertraline, Paroxetine, Escitalopram
• Use: Depression, OCD, Panic disorder, Social phobia, PTSD, Bulimia

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Summary of Therapeutic Uses

• Migraine (acute): Triptans (Sumatriptan)
• CINV: Ondansetron
• Anxiety: Buspirone
• Depression: SSRIs, Vortioxetine
• Schizophrenia: Risperidone (5-HT2A + D2 antagonist)
• GI prokinetic: Metoclopramide (5-HT4 agonist + D2 antagonist)

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Q2. Drug Therapy of Migraine Including Prophylaxis

Introduction

1. Acute (Abortive) Treatment
2. Prophylactic Treatment

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A) ACUTE TREATMENT OF MIGRAINE

• Aspirin 900 mg + Metoclopramide 10 mg
• NSAIDs: Ibuprofen, Naproxen
• Paracetamol (acetaminophen)

• MOA: Agonist at 5-HT1B/1D → vasoconstriction of dilated cranial vessels + inhibition of trigeminal nociception
• Begin as soon as possible after onset of migraine
• Repeat once in 24 hours if needed
• Contraindications: Ischemic heart disease, uncontrolled hypertension, within 24 hours of ergotamines

• MOA: 5-HT1B/1D agonist + alpha-adrenoceptor agonist → vasoconstriction
• Ergotamine: Oral/sublingual for moderate-severe migraine
• DHE: IV/IM/Nasal spray - faster acting, less nausea
• AE: Nausea, vomiting, peripheral vasoconstriction, ergotism (prolonged use)
• CI: Ischemic heart disease, hypertension, pregnancy

• Lasmiditan: 5-HT1F agonist - no vasoconstriction (safe in cardiovascular disease)
• Rimegepant, Ubrogepant: CGRP receptor antagonists (gepants)
• Anti-CGRP monoclonal antibodies: Erenumab, Fremanezumab, Galcanezumab

• Metoclopramide, Domperidone, Prochlorperazine (given with analgesics)

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B) PROPHYLAXIS OF MIGRAINE

• Headaches occur > 4 times/month
• Attacks are prolonged or disabling
• Acute treatments fail
• Overuse of abortive medications

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Q3. Prostaglandin Analogues - Classification, Pharmacological Actions, Therapeutic Uses, Adverse Effects, and Contraindications

Introduction

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Classification

• Misoprostol (PGE1 analogue - also acts on PGE2 receptors)
• Dinoprostone (natural PGE2)

• Misoprostol
• Alprostadil

• Carboprost (15-methyl PGF2α)
• Dinoprost (natural PGF2α)

• Epoprostenol
• Iloprost
• Treprostinil
• Beraprost

• Latanoprost
• Travoprost
• Bimatoprost
• Tafluprost

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Pharmacological Actions

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Therapeutic Uses

• Cervical ripening: Dinoprostone (PGE2) gel/insert
• Labor induction: Dinoprostone
• Post-partum hemorrhage (PPH): Carboprost (15-methyl PGF2α) 250 mcg IM when oxytocin fails
• Medical abortion: Misoprostol + Mifepristone (within 9 weeks)
• MTP (Medical Termination of Pregnancy): Misoprostol + Methotrexate

• Peptic ulcer disease (NSAID-induced): Misoprostol - 200 mcg QID
• Prophylaxis of NSAID-induced ulcers in high-risk patients

• Glaucoma (open-angle): Latanoprost, Travoprost, Bimatoprost (eye drops, once daily at night) - reduce IOP by increasing uveoscleral outflow

• Epoprostenol (IV infusion), Iloprost (inhaled), Treprostinil (SC/IV/inhaled), Beraprost (oral)

• Alprostadil (PGE1): Intracavernous injection or urethral suppository

• Alprostadil: To KEEP PDA open in neonates with ductus-dependent congenital heart disease (e.g., pulmonary atresia) until surgery

• Alprostadil, Iloprost: Critical limb ischemia

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Adverse Effects

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Contraindications

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Q4. Role of Leukotrienes and Leukotriene Antagonists

Introduction

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Synthesis

• LTA4 → LTB4 (via LTA4 hydrolase)
• LTA4 → LTC4 → LTD4 → LTE4 (cysteinyl leukotrienes, CysLTs)

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Role of Leukotrienes in Disease

• Potent chemotactic agent for neutrophils and eosinophils
• Promotes neutrophil adhesion to vascular endothelium
• Amplifies inflammatory response

• Bronchoconstriction (100-1000 times more potent than histamine)
• Increased mucus secretion in airways
• Mucosal edema and airway wall thickening
• Key mediators in: Asthma, Allergic rhinitis, Urticaria, Anaphylaxis

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Leukotriene Antagonists

Classification:

• Montelukast (most widely used)
• Zafirlukast
• Pranlukast (available in Japan)

• Zileuton (inhibits all leukotrienes by blocking 5-LOX)

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Pharmacological Actions of LTRAs

• Block CysLT1 receptors → prevent bronchoconstriction
• Reduce airway inflammation and edema
• Decrease mucus hypersecretion
• Prevent exercise-induced bronchoconstriction

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Therapeutic Uses

• Preferred in children due to concerns about inhaled corticosteroid (ICS) side effects (growth suppression)
• Effective in allergic rhinitis (montelukast is the only LTRA approved for this)
• Do NOT replace ICS for moderate-severe asthma - used as add-on therapy
• Effective in aspirin-sensitive asthma (since aspirin blocks COX → more arachidonic acid diverted to LOX pathway)

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Adverse Effects

• Montelukast: Headache, GI disturbances; rarely neuropsychiatric effects (mood changes, suicidal ideation - FDA black box warning, 2020)
• Zafirlukast: Hepatotoxicity (liver function monitoring needed), drug interactions (inhibits CYP2C9)
• Zileuton: Hepatotoxicity, monitoring of LFTs required

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Important Association

• LTRAs (Montelukast, Zafirlukast) have been rarely associated with Eosinophilic Granulomatosis with Polyangiitis (EGPA/Churg-Strauss syndrome) - especially when used during reduction of steroid therapy (unmasking effect).

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ASSIGNMENT - 16/07/2026

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Q1. Aspirin - Pharmacological Actions, Therapeutic Uses, Adverse Effects, Contraindications and Poisoning

Introduction

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Mechanism of Action (MOA)

• COX-1 inhibition → ↓ Thromboxane A2 (TXA2) → antiplatelet effect (irreversible, lasting lifetime of platelet = 7-10 days)
• COX-2 inhibition → ↓ Prostaglandin E2 and I2 → anti-inflammatory, analgesic, antipyretic effects

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Pharmacological Actions

1. Analgesic: Moderate pain (headache, dental, musculoskeletal) - peripheral + central COX inhibition
2. Antipyretic: Inhibits PGE2 synthesis in hypothalamus → reset thermostat → sweating
3. Anti-inflammatory: High dose (4-6 g/day) - reduces PGs, prevents inflammatory response
4. Antiplatelet: Low dose (75-325 mg/day) - irreversibly inhibits TXA2 in platelets → antiplatelet aggregation
5. Uricosuric: Very high dose (>5 g/day) - blocks tubular reabsorption of uric acid (NOT used clinically for this)
6. Urate retention: Low-moderate dose - paradoxically blocks tubular secretion → ↑ uric acid

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Therapeutic Uses

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Adverse Effects

1. GI: Nausea, vomiting, epigastric pain, peptic ulcer, GI bleeding (due to direct irritation + ↓ prostaglandin-mediated mucosal protection)
2. Antiplatelet/Bleeding: Prolonged bleeding time, hemorrhage
3. Renal: Acute renal failure (especially in dehydrated patients - PGs maintain renal blood flow)
4. Aspirin-sensitive asthma: In ~10% of asthmatics - due to shunting of arachidonic acid to leukotriene pathway
5. Salicylism: Tinnitus, vertigo, hearing loss (at doses > 3-4 g/day)
6. Reye's Syndrome: Hepatic encephalopathy in children with viral infections (influenza, varicella) - AVOID in children < 12 years
7. Prolonged labor: High doses near term
8. Drug interactions: Warfarin (↑ bleeding), Methotrexate (↑ toxicity), Probenecid (antagonism)

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Contraindications

• Children < 12 years (Reye's syndrome)
• Peptic ulcer disease
• Bleeding disorders / on anticoagulants
• Aspirin-sensitive asthma
• Gout (low-moderate doses increase uric acid)
• Last trimester of pregnancy (premature closure of ductus arteriosus)
• Renal/hepatic failure

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Aspirin Poisoning (Salicylate Toxicity)

1. Mild (Salicylism): Tinnitus, vertigo, sweating, nausea, vomiting
2. Moderate: Hyperventilation, respiratory alkalosis (direct stimulation of respiratory center)
3. Severe: Metabolic acidosis (accumulation of salicylate + lactic acid + ketones), hyperthermia, hypoglycemia, dehydration, seizures, pulmonary edema, coma

• Early: Respiratory alkalosis (stimulation of respiratory center)
• Late: Metabolic acidosis (children predominantly get metabolic acidosis)
• Combined picture is characteristic of salicylate poisoning

1. Gastric lavage / Activated charcoal (if within 1-2 hours)
2. IV fluids - correct dehydration, electrolyte imbalance
3. Urinary alkalinization: IV Sodium bicarbonate → urine pH > 7.5 → ion trapping → increased renal excretion of salicylate
4. Correct hypoglycemia: IV Dextrose
5. Cooling measures for hyperthermia
6. Vitamin K if bleeding
7. Hemodialysis: Severe poisoning, renal failure, serum salicylate > 700 mg/L

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Q2. Paracetamol (Acetaminophen) - MOA, Adverse Effects, Acute Poisoning, Treatment, Clinical Uses

Introduction

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Mechanism of Action (MOA)

1. Central COX inhibition: Inhibits COX-3 (a splice variant of COX-1) in CNS → reduces central prostaglandin synthesis → antipyresis and analgesia
2. Endocannabinoid pathway: Paracetamol metabolite (AM404) activates TRPV1 receptors and inhibits endocannabinoid reuptake → analgesia
3. Serotonergic pathway: Activates descending serotonergic pain inhibitory pathways
4. Peroxidase enzyme inhibition: Inhibits peroxidase component of PG synthesis in non-inflamed tissues

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Pharmacokinetics

• Well absorbed orally
• Metabolized in liver:
  • 90% conjugated with glucuronide/sulfate → non-toxic, excreted in urine
  • 5-10% metabolized by CYP2E1 (and CYP3A4) → toxic metabolite NAPQI (N-acetyl-p-benzoquinoneimine)
  • NAPQI is normally detoxified by glutathione (GSH)

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Clinical Uses

• Mild-moderate pain: Headache, dental pain, post-operative pain
• Fever (drug of choice in children - safe, no Reye's syndrome risk)
• Osteoarthritis pain (adjunct)
• Pain in patients who cannot take NSAIDs (peptic ulcer, asthma, anticoagulant use)
• Preferred analgesic in pregnancy
• Drug of choice in patients with aspirin allergy

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Adverse Effects (Therapeutic Doses)

• Generally well tolerated
• Rare: Skin rash, thrombocytopenia
• Hepatotoxicity: Only at overdose (see below)
• Nephrotoxicity: Long-term heavy use
• Does NOT cause GI irritation or antiplatelet effects (advantage over aspirin)

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Acute Paracetamol Poisoning

• Overdose → glutathione stores depleted → NAPQI accumulates → covalently binds hepatocyte proteins → centrilobular hepatic necrosis

• Serum paracetamol level (Rumack-Matthew nomogram to assess risk)
• LFTs (AST, ALT, bilirubin), PT/INR
• Renal function, blood glucose

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Treatment of Paracetamol Poisoning

1. Activated charcoal - if within 1-2 hours of ingestion
2. N-Acetylcysteine (NAC):
   • Replenishes glutathione stores
   • IV: 150 mg/kg over 15 min → 50 mg/kg over 4 hrs → 100 mg/kg over 16 hrs
   • Oral: 140 mg/kg loading, then 70 mg/kg q4h x 17 doses
   • Effective up to 24 hours; may help even beyond 24 hours in severe toxicity
3. Supportive care: IV glucose (hypoglycemia), clotting factors, dialysis
4. Liver transplantation - in fulminant hepatic failure

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Q3. Pharmacological Management of Rheumatoid Arthritis (RA)

Introduction

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Drug Classification

• Ibuprofen, Naproxen, Diclofenac, Celecoxib (COX-2 selective)
• Reduce pain and swelling but do NOT prevent joint damage
• Used as adjunct with DMARDs

• Prednisolone, Methylprednisolone
• Short-term for acute flares; intra-articular injections for single joint flares
• Bridge therapy while waiting for DMARDs to take effect (slow-acting)

• Folic acid 5 mg/week given alongside to reduce toxicity

• Tofacitinib, Baricitinib, Upadacitinib
• MOA: Inhibit Janus kinase (JAK) → block cytokine signaling
• Oral drugs, effective alternative to biologicals

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Treatment Strategy (ACR Guidelines)

1. Newly diagnosed RA: Start Methotrexate immediately (+ NSAIDs/low-dose steroids as bridge)
2. Inadequate response to Methotrexate: Add another csDMARD (triple therapy: MTX + HCQ + Sulfasalazine) or switch to biological DMARD
3. Moderate-severe RA with poor prognosis: Biological DMARD (TNF-alpha inhibitor preferred first)
4. If TNF-alpha inhibitor fails: Try different TNF inhibitor OR switch to non-TNF biological (Rituximab, Abatacept, Tocilizumab)
5. Biologicals are reserved for persistent moderate-high disease activity with poor prognosis indicators

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Key Adverse Effects to Remember

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Q4. Drugs Used in Gout - Classify and Describe Management of Acute and Chronic Gout

Introduction

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Classification of Drugs Used in Gout

1. NSAIDs (first line)
2. Colchicine (second line)
3. Corticosteroids (when above are contraindicated)
4. IL-1 inhibitors (Canakinumab, Anakinra - refractory cases)

• Allopurinol (first line)
• Febuxostat (second line)

• Probenecid
• Benzbromarone
• Sulfinpyrazone

• Rasburicase (recombinant)
• Pegloticase (PEGylated uricase)

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MANAGEMENT OF ACUTE GOUT

• Indomethacin 50 mg TID for 5-7 days (traditional first choice)
• Naproxen 500 mg BD, Ibuprofen 800 mg TID
• High-dose initial, taper when symptoms resolve
• Contraindicated in: Renal failure, peptic ulcer, anticoagulant use

• MOA: Inhibits microtubule polymerization → inhibits neutrophil migration; blocks NLRP3 inflammasome → ↓ IL-1β
• Dose: 1.2 mg at first sign, then 0.6 mg 1 hour later (low-dose regimen - equally effective, less toxic)
• Effective if given within 24 hours of attack onset
• Adverse effects: Nausea, vomiting, diarrhea (most common), abdominal pain; rarely myelosuppression, rhabdomyolysis, neuropathy
• Contraindicated in: Severe renal/hepatic impairment; avoid with CYP3A4 and P-gp inhibitors (e.g., clarithromycin, cyclosporine)

• Oral prednisolone 30-40 mg/day tapered over 7-10 days
• Intra-articular triamcinolone for mono/oligoarticular gout
• IV/IM methylprednisolone for polyarticular acute gout

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MANAGEMENT OF CHRONIC GOUT (Long-term / Prophylaxis)

• Recurrent acute attacks (≥ 2/year)
• Tophi
• Uric acid nephropathy / nephrolithiasis
• Serum urate > 9 mg/dL

• MOA: Competitive and suicide inhibitor of xanthine oxidase (XO) → ↓ conversion of hypoxanthine/xanthine to uric acid
• Dose: Start 100 mg/day, increase monthly to 300-600 mg/day (titrate to target uric acid)
• Active metabolite: Oxipurinol (alloxanthine)
• Adverse effects: Skin rash (common), Stevens-Johnson syndrome/toxic epidermal necrolysis (rare but severe), GI upset; allopurinol hypersensitivity syndrome (AHS) - fever, rash, hepatitis, renal failure
• HLA-B*5801 allele carriers (Han Chinese, Korean, Thai) are at high risk for severe skin reactions - screen before use
• Drug interaction: Azathioprine/6-mercaptopurine - avoid combination (allopurinol inhibits their metabolism → toxicity)

• MOA: Non-purine selective inhibitor of XO (both oxidized and reduced forms)
• Dose: 40-80 mg/day
• Advantage: Can be used in mild-moderate renal impairment (unlike allopurinol)
• Adverse effects: LFT elevation, cardiovascular events (FDA warning - higher CV mortality vs allopurinol; avoid in established CV disease)

• MOA: Inhibits URAT1 transporter in renal proximal tubule → blocks reabsorption → ↑ uric acid excretion
• Dose: 500 mg BD, gradually increase to 1-2 g/day
• Contraindicated: Renal insufficiency (GFR < 30), uric acid overproducers, uric acid nephrolithiasis
• Increase fluid intake (> 2 L/day) to prevent kidney stones
• Drug interactions: Reduces excretion of penicillin (historically used to prolong penicillin action), NSAIDs, methotrexate

• MOA: Convert uric acid → allantoin (highly soluble, easily excreted)
• Rasburicase: Short-term use for tumor lysis syndrome
• Pegloticase: For refractory chronic gout - IV infusion every 2 weeks
• Contraindicated in G6PD deficiency (allantoin production generates H2O2 → hemolysis)

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Colchicine Prophylaxis During ULT Initiation:

• When starting ULT, mobilization of urate deposits can trigger acute attacks
• Give Colchicine 0.6 mg OD or BD for 3-6 months as prophylaxis while initiating ULT

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Summary Table: Acute vs Chronic Gout

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ASSIGNMENT - 15/07/2026

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Q1. 5-HT Receptor Agonists and Antagonists

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Introduction

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Classification of 5-HT Receptors and Drugs

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Important Drugs - Brief Details

A) Triptans (5-HT1B/1D Agonists)

• Examples: Sumatriptan, Zolmitriptan, Rizatriptan, Eletriptan
• MOA: Constrict dilated cranial vessels + inhibit trigeminal nerve pain
• Use: Acute migraine attack
• Routes: Oral, SC injection (Sumatriptan), Nasal spray

B) 5-HT3 Antagonists ("Setrons")

• Examples: Ondansetron, Granisetron, Palonosetron
• MOA: Block 5-HT3 in GI tract and vomiting centre
• Uses: CINV, post-operative nausea, radiation sickness

C) 5-HT2 Antagonists

• Cyproheptadine: Antihistamine + 5-HT2 antagonist → Migraine prophylaxis, Appetite stimulant in children
• Methysergide: 5-HT2 antagonist → Migraine prophylaxis, Carcinoid syndrome
• Ketanserin: 5-HT2A + alpha1 antagonist → Hypertension

D) 5-HT1A Partial Agonist

• Buspirone: Anxiolytic; no sedation, no dependence → Used in GAD

E) SSRIs (5-HT reuptake inhibitors)

• Fluoxetine, Sertraline, Paroxetine, Escitalopram
• Uses: Depression, OCD, Panic disorder, PTSD, Social phobia

F) 5-HT4 Agonists (Prokinetics)

• Metoclopramide, Cisapride, Mosapride
• Uses: GERD, Gastroparesis, Nausea

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Summary of Therapeutic Uses

• Migraine (acute) → Triptans (Sumatriptan)
• Migraine (prophylaxis) → Cyproheptadine, Methysergide
• CINV → Ondansetron
• Anxiety → Buspirone
• Depression → SSRIs (Fluoxetine)
• Schizophrenia → Risperidone (D2 + 5-HT2A antagonist)
• GI motility → Metoclopramide (5-HT4 agonist + D2 antagonist)

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Q2. Drug Therapy of Migraine Including Prophylaxis

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Introduction

1. Acute (Abortive) Treatment - stops an ongoing attack
2. Prophylactic Treatment - prevents future attacks

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A) ACUTE TREATMENT

Step 1 - Mild Attacks

• Aspirin 600-900 mg + Metoclopramide 10 mg (metoclopramide improves gastric absorption)
• NSAIDs: Ibuprofen 400-800 mg, Naproxen 500 mg
• Paracetamol 1 g (if NSAIDs not tolerated)

Step 2 - Moderate to Severe Attacks

Triptans (FIRST LINE - Drug of Choice)

• MOA: 5-HT1B/1D agonists → constrict dilated cranial vessels + block trigeminal pain transmission
• Examples:

• Start as soon as migraine begins
• May repeat once after 2 hours
• Contraindications: IHD, uncontrolled hypertension, within 24 hrs of ergotamines

Ergotamine / Dihydroergotamine (DHE)

• MOA: 5-HT1B/1D + alpha-agonist → vasoconstriction
• Ergotamine: 1-2 mg oral/sublingual
• DHE: IV/IM/Nasal spray - faster, less nausea
• ADRs: Nausea, vomiting, peripheral ischemia, ergotism (prolonged use)
• CI: IHD, hypertension, pregnancy

Anti-emetics (given with above drugs)

• Metoclopramide, Domperidone, Prochlorperazine

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B) PROPHYLACTIC TREATMENT

• Give for minimum 3-6 months continuously
• Propranolol is most commonly used for prophylaxis

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Key Points (for exam)

• Triptans = acute treatment ONLY, NOT prophylaxis
• Ergotamine: avoid in IHD and hypertension
• Methysergide: retroperitoneal/cardiac fibrosis on long-term use (limit to 6 months)
• Prophylaxis: Propranolol is first choice; Amitriptyline if depression co-exists

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Q3. Prostaglandin Analogues

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Introduction

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Classification

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Pharmacological Actions

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Therapeutic Uses

1. Obstetric Uses

• Cervical ripening / Labor induction: Dinoprostone (PGE2) gel - intravaginal/intracervical
• Post-partum hemorrhage (PPH): Carboprost (15-methyl PGF2α) 250 mcg IM - when oxytocin fails
• Medical abortion (MTP): Misoprostol + Mifepristone (up to 9 weeks)
• 2nd trimester abortion: Misoprostol 400 mcg intravaginal

2. Gastroenterology

• NSAID-induced peptic ulcer (prevention and treatment): Misoprostol 200 mcg QID

3. Ophthalmology

• Open-angle glaucoma: Latanoprost, Travoprost, Bimatoprost (eye drops, once daily at night)

4. Pulmonary Arterial Hypertension (PAH)

• Epoprostenol (IV), Iloprost (inhaled), Treprostinil (SC/inhaled/IV)

5. Erectile Dysfunction

• Alprostadil: Intracavernous injection or intraurethral suppository

6. Patent Ductus Arteriosus (PDA) - to KEEP OPEN

• Alprostadil IV: In cyanotic CHD (pulmonary atresia) until surgery

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Adverse Effects

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Contraindications

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Q4. Role of Leukotrienes and Leukotriene Antagonists

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Introduction

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Synthesis (Simplified)

Arachidonic acid → (5-LOX + FLAP) → LTA4
LTA4 → LTB4 (via LTA4 hydrolase)
LTA4 → LTC4 → LTD4 → LTE4 (Cysteinyl Leukotrienes = CysLTs)

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Role of Leukotrienes

LTB4 (Dihydroxy leukotriene):

• Potent chemotaxis of neutrophils and eosinophils
• Promotes neutrophil adhesion to endothelium
• Amplifies inflammation

Cysteinyl Leukotrienes - LTC4, LTD4, LTE4 (formerly called SRS-A):

• Bronchoconstriction - 100-1000x more potent than histamine
• ↑ Mucus secretion
• Mucosal edema
• Key role in: Asthma, Allergic rhinitis, Urticaria, Anaphylaxis

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Leukotriene Antagonists - Classification

1. CysLT1 Receptor Antagonists (LTRAs)

2. 5-Lipoxygenase Inhibitors

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Pharmacological Actions of LTRAs

• Block CysLT1 receptors → prevent bronchoconstriction
• Reduce airway inflammation and edema
• Decrease mucus hypersecretion
• Prevent exercise-induced and aspirin-induced bronchoconstriction

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Therapeutic Uses

• Preferred in children (avoids ICS-related growth suppression)
• Montelukast = only LTRA approved for allergic rhinitis
• Effective in aspirin-exacerbated asthma (NSAID blocks COX → more AA diverted to LOX → ↑ LTs)
• Used as add-on with ICS in moderate asthma, NOT as replacement
• Oral drugs - convenient, once daily

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Adverse Effects

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ASSIGNMENT - 16/07/2026

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Q1. Aspirin - Pharmacological Actions, Therapeutic Uses, ADRs, Contraindications and Poisoning

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Introduction

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Mechanism of Action

• ↓ TXA2 (via COX-1 in platelets) → antiplatelet effect (lasts 7-10 days = platelet lifespan)
• ↓ PGE2, PGI2 → anti-inflammatory + antipyretic + analgesic
• COX-1 inhibition is permanent (platelets cannot synthesize new COX); COX-2 inhibition is reversible in nucleated cells

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Pharmacological Actions

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Therapeutic Uses

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Adverse Effects

1. GI: Nausea, vomiting, epigastric pain, peptic ulcer, GI bleeding (direct irritation + ↓ mucosal PGs)
2. Bleeding: Prolonged bleeding time (due to irreversible antiplatelet effect)
3. Salicylism: Tinnitus, deafness, vertigo (at 3-4 g/day)
4. Reye's Syndrome: Hepatic encephalopathy in children with viral illness - AVOID in <12 years
5. Aspirin-sensitive asthma: Bronchoconstriction in ~10% asthmatics (↑ LT synthesis)
6. Renal: Acute kidney injury (in dehydrated/elderly patients)
7. Pregnancy: Avoid in 3rd trimester (premature closure of ductus arteriosus)

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Contraindications

• Children < 12 years (Reye's syndrome)
• Peptic ulcer disease
• Bleeding disorders / anticoagulant therapy
• Aspirin-sensitive asthma
• Gout (low/moderate dose causes uric acid retention)
• Third trimester of pregnancy
• Renal/hepatic failure

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Aspirin Poisoning (Salicylate Toxicity)

Toxic dose: > 150 mg/kg

Features:

• Mild: Tinnitus, nausea, vomiting, sweating (Salicylism)
• Moderate: Hyperventilation → Respiratory alkalosis (direct stimulation of respiratory center)
• Severe: Metabolic acidosis (accumulation of salicylate + lactic acid), hyperthermia, hypoglycemia, dehydration, seizures, coma

Treatment:

1. Activated charcoal (within 1-2 hours of ingestion)
2. Gastric lavage (early)
3. IV fluids - rehydration + correct electrolytes
4. Sodium bicarbonate IV (urinary alkalinization → pH > 7.5 → ion trapping → ↑ urinary excretion of salicylate)
5. IV Dextrose - correct hypoglycemia
6. Cooling for hyperthermia
7. Hemodialysis - severe poisoning, serum salicylate > 700 mg/L, renal failure

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Q2. Paracetamol - MOA, ADRs, Acute Poisoning, Treatment, Clinical Uses

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Introduction

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Mechanism of Action (MOA)

1. Central COX inhibition: Selectively inhibits COX in CNS (low-peroxide environment) → ↓ PGE2 in hypothalamus → antipyresis; ↓ central PGs → analgesia
2. Cannot inhibit peripheral COX at inflammatory sites (high peroxide = inactivates paracetamol) → no anti-inflammatory action
3. Serotonergic pathway: Activates descending 5-HT pain inhibitory pathways
4. Endocannabinoid system: Active metabolite AM404 inhibits endocannabinoid reuptake → analgesia

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Pharmacokinetics (Key points)

• Well absorbed orally; Peak effect: 30-60 min
• Metabolized in liver:
  • 90%: Glucuronide/sulfate conjugation → non-toxic → excreted in urine
  • 10%: CYP2E1/CYP3A4 → toxic metabolite NAPQI
  • NAPQI detoxified by Glutathione (GSH) → non-toxic mercapturic acid

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Clinical Uses

• Mild-moderate pain: Headache, toothache, post-operative pain
• Fever - Drug of choice in children (no Reye's syndrome risk)
• Patients who cannot take NSAIDs (peptic ulcer, asthma, anticoagulants)
• Preferred in pregnancy
• Osteoarthritis pain (symptomatic relief)

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Adverse Effects (Therapeutic Doses)

• Generally very well tolerated
• No GI irritation (advantage over NSAIDs)
• No antiplatelet effect
• Rare: Skin rash, thrombocytopenia
• Hepatotoxicity and nephrotoxicity only with overdose

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Acute Paracetamol Poisoning

Toxic dose: >150 mg/kg (>7.5 g in adults)

Mechanism: Overdose → Glutathione depleted → NAPQI accumulates → Binds hepatocyte proteins → Centrilobular hepatic necrosis

Clinical Stages:

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Treatment of Paracetamol Poisoning

Antidote: N-Acetylcysteine (NAC) - Most effective within 8-10 hours

1. Activated charcoal - if within 1-2 hours
2. N-Acetylcysteine (NAC):
   • MOA: Replenishes glutathione stores → detoxifies NAPQI
   • IV Protocol: 150 mg/kg over 15 min → 50 mg/kg over 4 hrs → 100 mg/kg over 16 hrs
   • Oral: 140 mg/kg loading, then 70 mg/kg q4h x 17 doses
   • Effective up to 24 hours; beneficial even beyond in severe toxicity
3. Methionine - oral alternative to NAC if unavailable
4. IV Dextrose - for hypoglycemia
5. Supportive care: IV fluids, clotting factors, dialysis
6. Liver transplantation - fulminant hepatic failure

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Q3. Pharmacological Management of Rheumatoid Arthritis (RA)

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Introduction

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Drug Classification

1. NSAIDs (Symptomatic only)

• Ibuprofen, Naproxen, Diclofenac, Indomethacin
• Celecoxib (COX-2 selective - less GI side effects)
• Reduce pain and swelling but do NOT prevent joint damage
• Always used with DMARDs

2. Corticosteroids

• Prednisolone, Methylprednisolone
• Short-term: Acute flares (bridge therapy while DMARDs take effect)
• Intra-articular injection: Single joint flare
• Long-term avoided due to side effects

3. Conventional DMARDs (csDMARDs) - DISEASE MODIFYING (FIRST LINE)

• Methotrexate = anchor drug of RA treatment
• Give Folic acid 5 mg/week with Methotrexate to reduce toxicity
• csDMARDs take 2-3 months to show effect (slow-acting)

4. Biological DMARDs (bDMARDs) - For moderate-severe RA failing csDMARDs

5. JAK Inhibitors (tsDMARDs) - Targeted Synthetic

• Tofacitinib, Baricitinib, Upadacitinib
• MOA: Inhibit Janus Kinase (JAK) → block cytokine signaling
• Oral drugs, effective alternative to biologicals

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Treatment Algorithm (Simplified)

Step 1: Newly diagnosed RA
   → Start METHOTREXATE immediately + NSAIDs/low-dose steroids as bridge

Step 2: Inadequate response to Methotrexate
   → Triple therapy: MTX + HCQ + Sulfasalazine
   OR → Add Leflunomide to MTX

Step 3: Still inadequate / High disease activity
   → Add Biological DMARD (TNF-α inhibitor: Adalimumab/Etanercept)

Step 4: TNF inhibitor fails
   → Switch to non-TNF biological (Rituximab/Tocilizumab)
   OR → JAK inhibitor (Tofacitinib)

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Key Adverse Effects

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Q4. Drugs Used in Gout - Classify and Management of Acute and Chronic Gout

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Introduction

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Classification of Drugs

A) For Acute Gout (Anti-inflammatory)

1. NSAIDs (First line)
2. Colchicine (Second line)
3. Corticosteroids (when above contraindicated)
4. IL-1 inhibitors: Canakinumab, Anakinra (refractory)

B) For Chronic Gout - Urate Lowering Therapy (ULT)

• Allopurinol (First line)
• Febuxostat (Second line)

• Probenecid
• Benzbromarone
• Sulfinpyrazone

• Rasburicase, Pegloticase

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Management of ACUTE GOUT

NSAIDs (First Line)

• Indomethacin 50 mg TID x 5-7 days (traditional drug of choice)
• Naproxen 500 mg BD, Etoricoxib 120 mg/day
• CI: Renal failure, peptic ulcer, anticoagulant use

Colchicine (Second Line)

• MOA: Inhibits microtubule polymerization → ↓ neutrophil migration; blocks NLRP3 inflammasome → ↓ IL-1β
• Dose (low-dose regimen): 1.2 mg at first sign → 0.6 mg after 1 hour (total 1.8 mg only)
• Effective if given within 24 hours of attack onset
• ADRs: Nausea, vomiting, diarrhea, abdominal pain (most common); myelosuppression, rhabdomyolysis (rare)
• CI: Severe renal/hepatic impairment; avoid with CYP3A4 + P-gp inhibitors (clarithromycin, cyclosporine)

Corticosteroids (When NSAIDs/Colchicine Contraindicated)

• Oral Prednisolone 30-40 mg/day tapered over 5-7 days
• Intra-articular Triamcinolone: For single joint involvement

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Management of CHRONIC GOUT

Allopurinol (First Line)

• MOA: Competitive + suicide inhibitor of xanthine oxidase → ↓ conversion of hypoxanthine/xanthine to uric acid
• Active metabolite: Oxipurinol
• Dose: Start 100 mg/day → increase monthly to 300-600 mg/day
• ADRs: Skin rash, Stevens-Johnson syndrome (SJS)/TEN (rare, severe), allopurinol hypersensitivity syndrome (AHS)
• Screen for HLA-B*5801 allele in Han Chinese/Korean/Thai (high risk of SJS)
• Drug interaction: Avoid azathioprine/6-MP (allopurinol inhibits their metabolism → severe toxicity)

Febuxostat (Second Line)

• MOA: Non-purine selective XO inhibitor (both reduced and oxidized forms)
• Dose: 40-80 mg/day
• Advantage: Can use in mild-moderate renal impairment
• ADR: Liver enzyme elevation, cardiovascular risk (FDA warning)

Probenecid (Uricosuric)

• MOA: Inhibits URAT1 transporter in renal proximal tubule → ↓ reabsorption → ↑ uric acid excretion
• Dose: 500 mg BD → increase to 1-2 g/day
• CI: Renal insufficiency (GFR < 30), uric acid overproducers, urolithiasis
• Increase fluid intake >2 L/day to prevent kidney stones

Rasburicase / Pegloticase

• MOA: Convert uric acid → allantoin (soluble, easily excreted)
• Rasburicase: Tumor lysis syndrome
• Pegloticase: Refractory severe tophaceous gout (IV every 2 weeks)
• CI: G6PD deficiency (H2O2 produced → hemolysis)

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Colchicine Prophylaxis During ULT Initiation

• Starting ULT mobilizes urate deposits → can trigger acute attacks
• Give Colchicine 0.6 mg once or twice daily for 3-6 months while starting ULT

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Summary Table

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