---

Q1 - Anaphylaxis: Management, Dale Phenomenon, Adrenaline

Anaphylaxis - Definition & Pathophysiology

• Vasodilation + increased capillary permeability → hypotension
• Bronchospasm → dyspnoea
• Angioedema, urticaria
• GI symptoms (nausea, vomiting)

Management of Anaphylaxis

1. Adrenaline (Epinephrine) - DRUG OF CHOICE
   • Dose: 0.5 mg (0.5 mL of 1:1000) IM into anterolateral thigh
   • Repeat every 5-15 min if needed
   • Acts on α1: vasoconstriction → reverses hypotension + reduces angioedema
   • Acts on β2: bronchodilation → reverses bronchospasm
   • Acts on β1: increases cardiac output
2. IV fluid resuscitation (normal saline)
3. Oxygen (high flow)
4. Antihistamines: Chlorpheniramine 10 mg IM/IV (H1 blocker) - adjunct only
5. Corticosteroids: Hydrocortisone 200 mg IV - prevents late-phase reaction
6. Salbutamol nebulisation if bronchospasm persists
7. Position: Supine with legs raised (Trendelenburg); if airway compromise - sitting up

Dale's Phenomenon (Adrenaline Reversal)

• Henry Dale showed that if an animal is pre-treated with an ergot alkaloid (e.g., ergotamine - an α-blocker), then given adrenaline, the pressor (vasoconstrictor) effect is reversed to a depressor (vasodilator) effect.
• Mechanism: Adrenaline acts on both α (vasoconstriction) and β2 (vasodilation) receptors. When α receptors are blocked, only β2 effects remain → net vasodilation → BP falls instead of rising.
• This demonstrates that adrenaline has a dual (α + β) action and the net effect depends on which receptors are active.
• Clinically relevant: In a patient on non-selective α-blockers (phentolamine, phenoxybenzamine), giving adrenaline for anaphylaxis can paradoxically worsen hypotension.

Adrenaline - Side Effects (SIE) and Contraindications (CI)

Note: In anaphylaxis, there are NO absolute contraindications to adrenaline - the risk of not giving it outweighs all risks.

Adrenaline Dilution

• 1:1000 = 1 mg/mL → used for IM injection in anaphylaxis (0.5 mL = 0.5 mg)
• 1:10,000 = 0.1 mg/mL → used for IV injection in cardiac arrest (10 mL = 1 mg)
• 1:100,000 to 1:200,000 → used with local anaesthetics to prolong duration

Why Adrenaline is Given with Local Anaesthetics (Anaesthesia)

1. Vasoconstriction (α1 effect): Reduces local blood flow → slows systemic absorption of the local anaesthetic → prolongs its duration of action (e.g., lignocaine duration doubles)
2. Reduces toxicity: By keeping the drug localised, systemic toxic effects (CNS toxicity, cardiac toxicity) are reduced
3. Reduces bleeding: Vasoconstriction at the injection site provides a bloodless operative field
4. Economic: Allows use of smaller dose of local anaesthetic

Caution: Adrenaline-containing local anaesthetics should NOT be used in ring blocks of fingers, toes, penis, ears, nose (end arteries - risk of ischaemic necrosis) or with halothane anaesthesia (risk of ventricular fibrillation).

---

Q2 - Arachidonic Acid Metabolites, COX Inhibition & Aspirin

Arachidonic Acid Metabolites - Overview

Membrane Phospholipids
        ↓ (Phospholipase A2)
  Arachidonic Acid
    ↙              ↘
COX pathway      LOX pathway
    ↓                ↓
Prostaglandins    Leukotrienes
Thromboxanes      LTB4 (chemotaxis)
Prostacyclin      LTC4, LTD4, LTE4
                  (bronchoconstriction)

COX-1 (Constitutive)

• Present in all tissues (stomach, kidneys, platelets)
• Produces protective prostaglandins (PGE2, PGI2) in gastric mucosa
• Produces Thromboxane A2 (TXA2) in platelets → platelet aggregation, vasoconstriction

COX-2 (Inducible)

• Induced by inflammation, cytokines, mitogens
• Produces prostaglandins of inflammation, pain, fever
• Also constitutively present in kidneys, brain, endothelium
• Endothelial COX-2 produces PGI2 (Prostacyclin) → anti-aggregatory, vasodilatory

COX-1 Inhibition Effects

• Reduced gastric mucosal protection → peptic ulcer, GI bleeding
• Reduced TXA2 in platelets → anti-platelet effect (useful in low-dose aspirin)

COX-2 Inhibition Effects

• Anti-inflammatory, antipyretic, analgesic
• Reduced PGI2 → pro-thrombotic tendency (concern with selective COX-2 inhibitors)

Selective vs Non-Selective NSAIDs

ASPIRIN

Mechanism of Action

• Irreversibly acetylates and inhibits COX-1 and COX-2 enzymes
• Non-selective COX inhibitor at higher doses
• At low doses (75-150 mg): predominantly COX-1 inhibition in platelets
  • Platelets have no nucleus → cannot synthesise new COX → effect lasts platelet lifetime (7-10 days)
  • Reduces TXA2 → anti-platelet effect

Pharmacological Effects

• Analgesic (mild-moderate pain)
• Antipyretic
• Anti-inflammatory (at high doses > 3 g/day)
• Anti-platelet (low dose)
• Uricosuric at very high doses; urate retention at low/moderate doses

Side Effects (SIE)

• GI: Nausea, vomiting, epigastric pain, peptic ulcer, GI bleeding (COX-1 inhibition)
• Bleeding: Prolonged bleeding time (anti-platelet effect)
• Salicylism: Tinnitus, vertigo, deafness (chronic high-dose)
• Reye's Syndrome: Hepatic encephalopathy in children with viral illness (avoid in < 12 years)
• Aspirin-sensitive asthma: Due to shunting of AA to LOX pathway → excess leukotrienes → bronchospasm
• Metabolic: Respiratory alkalosis (early) → metabolic acidosis (late) in poisoning
• Platelet dysfunction

Uses

• Mild-to-moderate pain (headache, dysmenorrhea)
• Fever
• Acute MI, unstable angina, TIA, stroke prevention (75-150 mg/day)
• Kawasaki disease (high dose)
• Rheumatic fever (high dose)
• Post-PTCA/stenting (dual antiplatelet with clopidogrel)

Contraindications (CI)

• Children < 12 years (Reye's syndrome)
• Active peptic ulcer / GI bleeding
• Aspirin-sensitive asthma
• Haemophilia, anticoagulant therapy (bleeding risk)
• Gout (low/moderate dose raises urate)
• Last trimester of pregnancy (premature closure of ductus arteriosus)

Why Low-Dose Aspirin is Preferred in MI (Two-Edged Sword)

• At LOW dose (75-150 mg): Selectively inhibits COX-1 in platelets → reduces TXA2 → anti-platelet, anti-thrombotic → protective in MI
• At HIGH dose: Also inhibits endothelial COX-2 → reduces Prostacyclin (PGI2, which is anti-aggregatory) → the anti-platelet benefit is blunted
• Hence, higher doses are counterproductive for cardiovascular protection
• Called a "Two-Edged Sword" because:
  • One edge = reduces TXA2 (beneficial, anti-platelet)
  • Other edge = reduces PGI2 (harmful, pro-aggregatory) - especially at high doses
  • Low dose tips the balance favourably by sparing endothelial COX-2 relatively

---

Q3 - Paracetamol (PCM) Poisoning

Mechanism of Toxicity

• Paracetamol is normally metabolised by glucuronidation and sulphation (90%) and by CYP2E1 to NAPQI (N-acetyl-p-benzoquinone imine) - a toxic metabolite (10%)
• NAPQI is detoxified by glutathione in the liver
• In overdose: Glucuronidation and sulphation are saturated → more NAPQI produced → depletes glutathione → NAPQI binds covalently to hepatocytes → centrilobular hepatic necrosis

Stages of Paracetamol Poisoning

Treatment

1. Gastric lavage if within 1-2 hours
2. Activated charcoal within 1 hour (reduces absorption)
3. N-Acetylcysteine (NAC) - Antidote of choice
   • Replenishes glutathione stores
   • IV protocol: 150 mg/kg over 15 min → 50 mg/kg over 4 hours → 100 mg/kg over 16 hours (Prescott protocol)
   • Oral: 140 mg/kg loading, then 70 mg/kg every 4 hours x 17 doses
   • Most effective within 8-10 hours; still beneficial up to 24-36 hours
4. Methionine (oral alternative to NAC)
5. Treat liver failure supportively; consider liver transplantation in fulminant failure
6. Use Rumack-Matthew nomogram to assess risk based on plasma paracetamol level and time

---

Q4 - Methanol Poisoning + Alcohol Withdrawal

Methanol (Wood Alcohol) Poisoning

Mechanism

• Methanol itself is relatively non-toxic
• Metabolised by alcohol dehydrogenase (ADH) → Formaldehyde → Formic acid
• Formic acid causes metabolic acidosis with high anion gap and optic nerve toxicity → blindness

Features

• Initial: Inebriation (similar to ethanol but milder), nausea/vomiting
• Latent period: 12-24 hours (while metabolites accumulate)
• Late: Severe headache, blurred vision → blindness (optic disc hyperaemia then pallor), severe metabolic acidosis (high AG), Kussmaul breathing, coma, death

Investigations

• ABG: Metabolic acidosis with high anion gap
• Serum methanol level
• Osmolar gap (elevated early, before metabolism)

Treatment

1. Gastric lavage (if early)
2. Ethanol (or Fomepizole) - Antidote: Competitive inhibitor of ADH → prevents metabolism of methanol to toxic metabolites
   • Ethanol: IV 10% in D5W - target blood ethanol level 100-150 mg/dL
   • Fomepizole (4-methylpyrazole): Now preferred - specific ADH inhibitor, no CNS depression, predictable kinetics
3. Sodium bicarbonate: Corrects metabolic acidosis
4. Folinic acid (leucovorin): Enhances formate metabolism
5. Haemodialysis: Removes methanol and formate; indicated for severe acidosis, renal failure, visual impairment, high methanol levels (> 50 mg/dL)
6. Supportive: Mechanical ventilation if needed

---

Alcohol Withdrawal

Mechanism

Timeline & Features

Treatment of Alcohol Withdrawal

1. Benzodiazepines - Drug of choice (enhance GABA-A activity, mimic alcohol's CNS depressant effect)
   • Chlordiazepoxide or Diazepam (long-acting) - preferred
   • Lorazepam or Oxazepam - in liver disease (no active metabolites)
   • Fixed-schedule or symptom-triggered (CIWA-Ar scale) dosing
2. Thiamine (Vitamin B1) 100 mg IV/IM - given BEFORE glucose to prevent Wernicke's encephalopathy
3. Magnesium sulphate (if hypomagnesaemia)
4. Beta-blockers (propranolol), clonidine - for autonomic symptoms (adjuncts)
5. IV fluids and electrolyte correction
6. Carbamazepine - alternative to BZDs (preferred in some European guidelines)
7. Phenobarbitone - if BZD-resistant seizures

---

Q5 - 2nd Generation Antihistamines: Advantages Over 1st Generation

1st Generation H1 Antihistamines

2nd Generation H1 Antihistamines

Advantages of 2nd Gen over 1st Gen

Key Examples and Notes

• Fexofenadine: Most non-sedating; active metabolite of terfenadine; no cardiac toxicity; substrate of P-gp
• Cetirizine: Slightly sedating (most sedating among 2nd gen); active metabolite of hydroxyzine
• Levocetirizine: R-enantiomer of cetirizine; less sedating than cetirizine
• Loratadine: Non-sedating; metabolised to Desloratadine (active)
• Desloratadine: Active metabolite of loratadine; most potent among 2nd gen
• Rupatadine: Has anti-PAF activity in addition to H1 blockade (useful in urticaria)
• Bilastine: Newest; highly selective, does not cross BBB

---

Q6 - Beta Blocker Classification, Receptors, MOA, Propranolol & Metoprolol

Beta Adrenergic Receptors

Classification of Beta Blockers

1. By Cardioselectivity (β1 selectivity)

2. By Intrinsic Sympathomimetic Activity (ISA / Partial Agonist Activity)

3. With Additional Properties

4. By Generation

• 1st gen: Non-selective (Propranolol)
• 2nd gen: Cardioselective (Atenolol, Metoprolol)
• 3rd gen: Vasodilatory (Carvedilol, Nebivolol, Labetalol)

Mechanism of Action (MOA)

• Heart: ↓ HR (negative chronotropy), ↓ contractility (negative inotropy), ↓ AV conduction (negative dromotropy) → ↓ cardiac output → ↓ BP
• JGA: ↓ Renin release → ↓ Angiotensin II → ↓ Aldosterone → ↓ BP (long-term)
• Vasomotor centre: Central reduction in sympathetic tone
• Bronchi: Bronchoconstriction (β2 block - unwanted effect)

Note on Propranolol

Note on Metoprolol

---

Q7 - Management of Asthma + Status Asthmaticus

Asthma - Quick Recap

Management of Asthma

Step-wise (GINA Guidelines)

Drug Classes and Examples

Status Asthmaticus

Features of Severe/Life-Threatening Attack

• SpO2 < 92%, PaO2 < 60 mmHg
• Silent chest (no wheeze - air entry too reduced to wheeze = ominous sign)
• Hypercapnia (PaCO2 > 45 mmHg = respiratory failure/fatigue)
• Bradycardia, hypotension
• Exhaustion, altered consciousness
• Peak expiratory flow (PEF) < 33% predicted

Management of Status Asthmaticus

1. Oxygen: High-flow 40-60% oxygen; target SpO2 94-98%
2. Salbutamol (SABA): Nebulised salbutamol 5 mg every 20 min (or continuous) + Ipratropium bromide 0.5 mg nebulised every 4-6 hours (combination more effective)
3. Systemic Corticosteroids:
   • IV Hydrocortisone 100-200 mg (or oral prednisolone 40-50 mg) - reduce airway inflammation; takes 4-6 hours to act
   • Continue for 5-7 days
4. IV Magnesium Sulphate (MgSO4) 1.2-2 g IV over 20 min: Smooth muscle relaxant; used if inadequate response to initial treatment - effective bronchodilator; safe
5. IV Aminophylline: 5 mg/kg loading dose over 20 min (if not on theophylline) - added if poor response; requires ECG monitoring
6. IV Salbutamol: If inhaled route ineffective
7. Heliox (Helium + Oxygen): Reduces turbulent airflow; improves drug delivery to distal airways
8. Non-invasive ventilation (CPAP/BiPAP): In impending respiratory failure
9. Intubation and mechanical ventilation: For imminent respiratory arrest, altered consciousness, rising PaCO2
   • Use permissive hypercapnia strategy to avoid barotrauma
10. IV Ketamine: Has bronchodilator properties - used in intubated patients
11. Isoflurane (inhalation anaesthetic): Potent bronchodilator used as last resort in intubated patients

Note: Antibiotics only if clear evidence of bacterial infection (most exacerbations are viral or allergen-triggered). Sedatives/anxiolytics are contraindicated (may suppress respiratory drive).

---