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Heparin - As per KDT & Shanbhag

Note: The library does not contain the KDT (Tripathi's Essentials of Medical Pharmacology) or Shanbhag textbooks directly. The following is compiled from Katzung's Basic & Clinical Pharmacology (16th ed.) and Lippincott Illustrated Reviews: Pharmacology - both of which cover the same content in the standard format used by KDT and Shanbhag for Indian pharmacology teaching.

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1. Introduction

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2. Chemistry

• Heparin is a heterogeneous mixture of sulfated mucopolysaccharides (glycosaminoglycans)
• It is strongly acidic due to sulfate and carboxylic acid groups
• Molecular weight range: 5,000-30,000 Da (unfractionated heparin, UFH)
• Contains repeating sulfated disaccharide units of D-glucosamine - D-iduronic acid and D-glucosamine - D-glucuronic acid
• Only ~1/3 of commercial heparin molecules have anticoagulant activity - those possessing the unique pentasaccharide sequence required for high-affinity antithrombin binding

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3. Mechanism of Action

1. Antithrombin III (AT-III) is an alpha-globulin that slowly inhibits serine proteases - thrombin (IIa), factor IXa, and factor Xa
2. Heparin binds to AT-III via its unique pentasaccharide sequence, causing a conformational change in AT-III
3. This change exposes AT-III's active site, accelerating inactivation of clotting factors by 1000-fold
4. Once the AT-III-protease complex forms, heparin is released intact and acts as a true catalytic cofactor (not consumed)
5. UFH inhibits thrombin (IIa), IXa, and Xa (requires chain long enough to bridge AT-III and thrombin simultaneously)
6. LMWH inhibits factor Xa selectively - the short chain can bind AT-III but cannot simultaneously bridge thrombin

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4. Pharmacokinetics

• aPTT therapeutic target for UFH: 1.5-2.5x control (institution specific)
• UFH plasma level: 0.2-0.4 unit/mL (protamine titration) or 0.3-0.7 unit/mL (anti-Xa)
• LMWH anti-Xa monitoring required in: obesity, renal impairment, pregnancy

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5. Uses / Indications

1. Deep Vein Thrombosis (DVT) - treatment and prophylaxis
2. Pulmonary Embolism (PE) - acute treatment
3. Acute Coronary Syndromes (STEMI, NSTEMI, unstable angina) - including during percutaneous coronary intervention (PCI)
4. Prophylaxis of postoperative venous thrombosis - e.g., hip/knee replacement surgeries
5. Arterial thromboembolism - prevention and treatment
6. Cardiac and arterial surgery - maintaining patency of circuits
7. Anticoagulant of choice in pregnancy - does not cross the placenta due to large size and negative charge
8. Hemodialysis - prevention of clotting in extracorporeal circuits
9. Peripheral arterial occlusion - thromboembolic events
10. Bridging anticoagulation - when transitioning to/from warfarin

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6. Adverse Effects

6.1 Bleeding (Most Common)

• The major adverse effect of heparin
• Risk factors: elderly women, renal failure, high doses, prolonged therapy
• Management: discontinue heparin; protamine sulfate for reversal

6.2 Heparin-Induced Thrombocytopenia (HIT)

• Immune-mediated reaction
• Type I (non-immune): mild, transient thrombocytopenia in first 1-2 days, benign
• Type II (immune): occurs 5-10 days after starting heparin; antibodies against heparin-PF4 complex form, activating platelets
• Paradoxically causes thrombosis (venous and arterial), not just bleeding
• Platelet count must be monitored frequently
• Management: Stop heparin immediately; switch to argatroban (direct thrombin inhibitor) or other non-heparin anticoagulant
• LMWHs are not recommended in HIT (cross-sensitivity possible)

6.3 Osteoporosis

• With long-term use (>3 months), especially in pregnancy
• More common with UFH than LMWH

6.4 Hypersensitivity Reactions

• Heparin is derived from porcine sources - antigenic
• Reactions: chills, fever, urticaria, anaphylactic shock

6.5 Hypoaldosteronism

• Rare; heparin suppresses aldosterone synthesis - may cause hyperkalemia

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7. Contraindications

• Active bleeding or high bleeding risk
• Severe thrombocytopenia
• History of HIT
• Hypersensitivity to heparin
• Intracranial hemorrhage
• Uncontrolled hypertension
• Patients undergoing spinal/epidural anesthesia (increased risk of spinal hematoma)

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8. Drug Interactions

• Aspirin, NSAIDs, antiplatelet drugs: Increased bleeding risk
• Warfarin: Additive anticoagulation
• Protamine sulfate: Antidote - directly antagonizes heparin
• Drugs that decrease heparin effect: digitalis, tetracyclines, antihistamines, nicotine

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9. Antidote - Protamine Sulfate

• A basic protein derived from fish sperm/testes, rich in arginine
• The positively charged protamine forms a stable 1:1 ionic complex with negatively charged heparin, inactivating it
• Dose: 1 mg protamine neutralizes 100 units of heparin
• Given by slow IV infusion (rapid infusion causes hypotension, bradycardia)
• Excess protamine itself acts as a weak anticoagulant - avoid overdosage
• Protamine has incomplete neutralization of LMWH anti-Xa activity (~60%)

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10. UFH vs LMWH - Comparison

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11. Preparations and Doses

• IV bolus: 5,000 units, followed by continuous infusion of 1,000-1,500 units/hour (titrated to aPTT)
• SC (prophylaxis): 5,000 units every 8-12 hours
• Available as: Heparin sodium injection 1,000, 5,000, 10,000, 25,000 units/mL

• DVT prophylaxis: 40 mg SC once daily
• DVT/PE treatment: 1 mg/kg SC every 12 hours (or 1.5 mg/kg SC once daily)
• ACS: 1 mg/kg SC every 12 hours

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Summary Points (High-Yield for Exams)

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Warfarin - As per Shanbhag (& KDT Style)

Note: The library does not contain the Shanbhag pharmacology textbook directly. The following is compiled and presented in the Shanbhag/KDT teaching format using Lippincott Illustrated Reviews: Pharmacology and Katzung's Basic & Clinical Pharmacology (16th ed.) - both follow the same Indian pharmacology curriculum framework.

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1. Introduction

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2. Chemistry

• Warfarin is a racemic mixture of R- and S-enantiomers
• S-warfarin is 3-5x more potent than R-warfarin
• Both are metabolized by CYP450 (S by CYP2C9, R by CYP1A2 and CYP3A4)
• Structural analog of vitamin K - this is the basis of competitive antagonism

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3. Mechanism of Action

1. Clotting factors II, VII, IX, X (and anticoagulant proteins C and S) require vitamin K as a cofactor for their synthesis in the liver
2. During synthesis, vitamin K-dependent carboxylase converts glutamic acid (Glu) residues to gamma-carboxyglutamic acid (Gla) residues on these factors
3. Gla residues are essential - they bind Ca²+ ions, which allows the factors to bind to platelet membranes and become active
4. During this carboxylation, vitamin K is oxidized to vitamin K epoxide (inactive)
5. Vitamin K epoxide reductase (VKORC1) normally regenerates active (reduced) vitamin K from the epoxide
6. Warfarin inhibits VKORC1 - trapping vitamin K in the epoxide form → no regeneration of active vitamin K
7. Result: clotting factors produced are incomplete (10-40% activity), with deficient Gla residues - biologically inactive

• Factor I (fibrinogen) - NOT affected
• Factors II, VII, IX, X - synthesis inhibited
• Proteins C and S (natural anticoagulants) - also inhibited

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4. Why is There a Delay in Action?

• Onset of action is delayed by 8-12 hours (peak effect: 72-96 hours)
• This is because warfarin does NOT destroy already-circulating clotting factors
• It only prevents synthesis of new ones
• The delay equals the time needed to deplete the pool of existing clotting factors
• Half-lives of factors: Factor VII = 6 h (shortest) → Factor II = 60 h (longest)
• Factor VII falls first (shortest t½), so PT/INR rises first

Warfarin Paradox (Important Exam Point!)

• Initially, warfarin also depletes Protein C (t½ ~6 hours, same as factor VII)
• Protein C is a natural anticoagulant
• So early warfarin therapy causes a transient pro-thrombotic (hypercoagulable) state
• This is why heparin must be overlapped with warfarin for 5-7 days when starting warfarin in acute thrombosis

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5. Pharmacokinetics

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6. Uses / Therapeutic Indications

1. Atrial fibrillation - prevention of stroke and systemic embolism
2. Prosthetic (mechanical) heart valves - prevention of thromboembolism
3. DVT and PE - treatment and secondary prevention
4. Post-orthopedic surgery (hip/knee replacement) - VTE prophylaxis
5. Protein C or S deficiency - secondary prophylaxis
6. Antiphospholipid syndrome - prevention of recurrent thrombosis
7. Post-MI - in selected patients with mural thrombus

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7. Monitoring

• Prothrombin time (PT) - test of the extrinsic pathway (factors VII, X, V, II, fibrinogen)
• Reported as INR (International Normalized Ratio) - standardized PT ratio
• Normal INR: ~1.0
• Therapeutic INR for most indications: 2.0 - 3.0
• Mechanical heart valves / high thrombotic risk: 2.5 - 3.5
• PT should be checked regularly; more frequently when starting or adjusting dose

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8. Dosing

• Starting dose: 5-10 mg/day orally
• Maintenance dose: 2-10 mg/day (individualized; average ~5 mg/day)
• Dose adjusted based on INR
• If PT activity < 20% (INR excessively high): reduce or omit dose

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9. Adverse Effects

9.1 Bleeding (Most Common and Serious)

• Can occur at any site - GI tract, urinary tract, intracranial
• Risk increases with higher INR
• Management:
  • Minor bleeding: withdraw drug or give oral Vitamin K₁ (phytomenadione)
  • Major bleeding: IV Vitamin K₁ + fresh frozen plasma (FFP) / prothrombin complex concentrate (PCC)
  • Reversal takes ~24 hours even with Vitamin K (time needed to synthesize new factors)

9.2 Teratogenicity (MOST IMPORTANT)

• Warfarin embryopathy (exposure in 1st trimester, especially weeks 6-12):
  • Nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata)
  • Abnormal bone formation
• CNS abnormalities (2nd/3rd trimester): dorsal midline dysplasia, Dandy-Walker syndrome
• Fetal hemorrhage
• WARFARIN IS ABSOLUTELY CONTRAINDICATED IN PREGNANCY
• Use heparin or LMWH instead (does not cross placenta)

9.3 Skin Necrosis

• Occurs in first 1-2 weeks of therapy
• Seen in patients with hereditary Protein C deficiency
• Warfarin rapidly depletes Protein C → thrombosis in skin microvasculature → necrosis
• Sites: breast, fatty tissues, buttocks, thighs, intestine
• Prevented by: starting with heparin overlap; using low initial doses

9.4 Purple Toe Syndrome

• Rare complication
• Painful, blue-tinged discoloration of toes
• Caused by cholesterol microemboli from disrupted atherosclerotic plaques
• Paradoxically occurs in patients on warfarin

9.5 Other

• Alopecia (hair loss)
• Skin rashes
• GI disturbances (nausea, diarrhea)

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10. Drug Interactions (Highly Tested!)

Drugs that INCREASE warfarin effect (increased bleeding risk):

Drugs that DECREASE warfarin effect (thrombosis risk):

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11. Contraindications

• Pregnancy (absolute)
• Active bleeding or high bleeding risk
• Severe hepatic disease
• Severe hypertension (risk of hemorrhagic stroke)
• History of warfarin-induced skin necrosis (Protein C deficiency)
• Recent neurosurgery, eye surgery
• Patient non-compliance (critical - requires regular monitoring)
• Hemorrhagic stroke

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12. Antidote - Vitamin K₁ (Phytomenadione)

• Mechanism: Provides exogenous vitamin K to overcome the competitive inhibition by warfarin and regenerate active vitamin K for clotting factor synthesis
• Route: Oral (for minor over-anticoagulation) or slow IV infusion (for major bleeding)
• IV is preferred for serious bleeding - acts within 6-12 hours
• Caveat: Reversal takes ~24 hours (time needed to synthesize new clotting factors)
• Too much Vitamin K makes the patient refractory to warfarin for days (if long-term anticoagulation is still needed)
• For immediate reversal (life-threatening bleeding): Fresh Frozen Plasma (FFP) or Prothrombin Complex Concentrate (PCC) + Vitamin K

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13. Warfarin vs Heparin - Key Comparison (High-Yield)

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14. Summary - High-Yield Points for Exams

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Directly Acting Oral Anticoagulants (DOACs) - As per Shanbhag Style

Also called NOACs (New/Novel Oral Anticoagulants) or TSOACs (Target-Specific Oral Anticoagulants). The library does not contain the Shanbhag textbook directly; this is presented in the standard Shanbhag/KDT Indian pharmacology curriculum format using Lippincott Illustrated Reviews: Pharmacology and Katzung's Basic & Clinical Pharmacology (16th ed.).

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1. Introduction

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2. Classification

DIRECTLY ACTING ORAL ANTICOAGULANTS (DOACs)
│
├── Direct Thrombin Inhibitors (Factor IIa inhibitors)
│   └── Dabigatran etexilate (Pradaxa)
│
└── Direct Factor Xa Inhibitors
    ├── Rivaroxaban (Xarelto)
    ├── Apixaban (Eliquis)
    ├── Edoxaban (Savaysa/Lixiana)
    └── Betrixaban (Bevyxxa)

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3. Site of Action in the Coagulation Cascade

Intrinsic pathway          Extrinsic pathway
        ↓                        ↓
    Factor IXa + VIIIa     Factor VIIa + TF
              ↓
          Factor Xa ←──── [APIXABAN, RIVAROXABAN, EDOXABAN]
              ↓
    Prothrombin (II) → Thrombin (IIa) ←──── [DABIGATRAN]
              ↓
    Fibrinogen → Fibrin → CLOT

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4. DABIGATRAN

4.1 Mechanism of Action

• Prodrug: Dabigatran etexilate → converted to dabigatran (active form) by plasma esterases after oral absorption
• Active drug is a direct, competitive inhibitor of thrombin (Factor IIa)
• Inhibits both free thrombin AND clot-bound thrombin (advantage over heparin, which cannot inactivate clot-bound thrombin)
• Does NOT require antithrombin as cofactor

4.2 Pharmacokinetics

4.3 Therapeutic Uses

1. Stroke prevention in non-valvular atrial fibrillation (NVAF) - primary indication
2. Treatment of DVT and PE (after 5-7 days of initial parenteral anticoagulant)
3. Prevention of recurrent DVT/PE
4. VTE prophylaxis after hip or knee replacement surgery
5. Contraindicated in mechanical prosthetic heart valves and bioprosthetic valves

4.4 Dose

• AF stroke prevention: 150 mg twice daily (CrCl >30 mL/min)
• Reduced dose: 75 mg twice daily (CrCl 15-30 mL/min)
• No monitoring required (routine)

4.5 Adverse Effects

• Bleeding - major adverse effect
• GI side effects - most common and distinctive: dyspepsia, abdominal pain, esophagitis, GI bleeding (due to tartaric acid capsule used to enhance absorption)
  • Take with food or full glass of water to reduce GI irritation
• Higher bleeding risk in: elderly (>75 years), renal failure
• No HIT, no osteoporosis

4.6 Antidote

• Idarucizumab (Praxbind) - humanized monoclonal antibody Fab fragment
• Binds dabigatran with very high affinity, neutralizes its effect
• Dose: 5 g IV (for life-threatening bleeding or urgent surgery)
• Also: dialysis can remove dabigatran (low protein binding)

4.7 Monitoring

• Routine monitoring NOT required
• If needed: Thrombin time (TT) or Ecarin Clotting Time (ECT) can reflect drug effect
• aPTT is prolonged but not reliably quantitative

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5. RIVAROXABAN

5.1 Mechanism of Action

• Direct, competitive inhibitor of Factor Xa (both free and prothrombinase complex-bound Xa)
• Inhibits Factor Xa in the final common pathway, preventing conversion of prothrombin to thrombin
• Does NOT require antithrombin as cofactor

5.2 Pharmacokinetics

5.3 Therapeutic Uses

1. Stroke prevention in NVAF
2. DVT and PE treatment
3. VTE prevention after hip/knee replacement
4. Reduction of cardiovascular events in coronary artery disease (CAD) - 2.5 mg BD + aspirin
5. Prevention of thrombotic events in peripheral arterial disease (PAD)
6. Prevention of recurrent DVT/PE

5.4 Dose

• DVT/PE treatment: 15 mg twice daily x 3 weeks, then 20 mg once daily
• AF: 20 mg once daily with evening meal
• VTE prophylaxis (hip): 10 mg once daily for 35 days
• VTE prophylaxis (knee): 10 mg once daily for 12 days
• No routine monitoring

5.5 Adverse Effects

• Bleeding - major adverse effect
• Less GI side effects than dabigatran
• Liver enzyme elevation (rare)
• Use with caution in hepatic impairment

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6. APIXABAN

6.1 Mechanism of Action

• Direct, selective inhibitor of Factor Xa (free and bound Xa)
• Same mechanism as rivaroxaban, but different pharmacokinetic profile

6.2 Pharmacokinetics

6.3 Therapeutic Uses

1. Stroke prevention in NVAF
2. DVT/PE treatment and prevention
3. VTE prophylaxis post-orthopedic surgery
4. Reduction of recurrent DVT/PE

6.4 Dose

• AF: 5 mg twice daily (2.5 mg BD if dose reduction criteria met)
• DVT/PE treatment: 10 mg twice daily x 7 days, then 5 mg twice daily

6.5 Adverse Effects

• Bleeding - lowest risk of major bleeding among DOACs (based on ARISTOTLE trial data)
• GI side effects less common than dabigatran

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7. EDOXABAN

7.1 Mechanism of Action

• Direct Factor Xa inhibitor

7.2 Pharmacokinetics

7.3 Therapeutic Uses

• Stroke prevention in NVAF
• DVT/PE treatment and prevention (after initial 5-10 days of parenteral anticoagulant)

7.4 Dose

• AF / VTE: 60 mg once daily (30 mg once daily for dose reduction)

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8. Antidote for Factor Xa Inhibitors

• Andexanet alfa (Andexxa) - recombinant modified Factor Xa "decoy" molecule
  • Competes with native Factor Xa for binding to the inhibitor
  • Rapidly reverses anti-Xa effect of apixaban and rivaroxaban
  • FDA-approved for life-threatening bleeding
  • Low dose: 400 mg IV bolus at 30 mg/min → 4 mg/min infusion for 120 min
  • High dose: 800 mg IV bolus → 8 mg/min infusion for 120 min
• 4-factor Prothrombin Complex Concentrate (PCC) - used as alternative
• No specific antidote for edoxaban; andexanet alfa and PCC are used

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9. Comparison of All DOACs

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10. Advantages of DOACs over Warfarin

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11. Common Contraindications for ALL DOACs

• Pregnancy and lactation (all are teratogenic / insufficient safety data)
• Mechanical prosthetic heart valves (warfarin preferred - DOACs inferior, especially dabigatran)
• Severe renal failure (CrCl <15-30 mL/min, drug-dependent)
• Severe hepatic failure (impairs metabolism + coagulopathy)
• Active major bleeding
• Valvular atrial fibrillation (rheumatic MS) - warfarin preferred

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12. Drug Interactions (Common to DOACs)

• P-gp inhibitors: Amiodarone, verapamil, dronedarone, clarithromycin, ketoconazole, itraconazole
• CYP3A4 inhibitors (Xa inhibitors): Same azoles, HIV protease inhibitors

• P-gp/CYP3A4 inducers: Rifampicin, carbamazepine, phenytoin, phenobarbitone, St. John's wort

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13. Summary - High-Yield Points for Exams

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Methyl Alcohol (Methanol) Poisoning - As per Shanbhag Style

The library does not contain the Shanbhag textbook directly. This is presented in the standard Shanbhag/KDT Indian pharmacology curriculum format, compiled from Katzung's Basic & Clinical Pharmacology (16th ed.), Goodman & Gilman's Pharmacological Basis of Therapeutics, and Tintinalli's Emergency Medicine.

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1. Introduction

• Illicit/adulterated liquor (most common cause in India)
• Industrial solvents, paint removers, shellac, varnish
• Antifreeze, windshield-washing fluids
• "Canned heat" (Sterno) products
• Accidental ingestion; occupational inhalation or skin absorption

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2. Metabolism - The Key to Understanding Toxicity

CH₃OH (Methanol)
    ↓ Alcohol Dehydrogenase (ADH) + NAD⁺
H₂CO (Formaldehyde)
    ↓ Aldehyde Dehydrogenase (ALDH) / Catalase
HCOO⁻ (Formic acid / Formate)   ← THE TOXIC METABOLITE
    ↓ Folate-dependent pathway (THF)
CO₂ + H₂O (harmless end products)

• Methanol itself has LOW toxicity - it is only a mild inebriant
• Toxicity is ENTIRELY due to its metabolites - formaldehyde and especially formic acid
• Humans are uniquely susceptible because formate is cleared slowly (folate-dependent clearance is limited)
• Conversion of methanol to toxic metabolites is slow (6-30 hours) → explains the characteristic latent period between ingestion and onset of serious symptoms
• Co-ingestion of ethanol delays toxicity (ethanol competitively occupies ADH, slowing methanol metabolism)

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3. Why is Formic Acid so Toxic?

1. Inhibits cytochrome c oxidase (Complex IV in mitochondria) → blocks oxidative phosphorylation → histotoxic hypoxia
2. This drives anaerobic metabolism → lactic acidosis
3. The increased NADH/NAD⁺ ratio (from ADH reaction) also favors conversion of pyruvate → lactate → worsens lactic acidosis
4. The resulting acidosis (↓pH) further worsens formate toxicity:
   • Acidemia favors the undissociated formic acid form (over formate ion)
   • Undissociated formic acid crosses membranes more readily → enters retina, optic nerve, and brain
   • Lower pH also increases tubular reabsorption of formate → prolongs elimination
5. Optic nerve and retinal ganglion cells are especially sensitive → characteristic ocular toxicity

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4. Clinical Features

4.1 Latent Period (6-24 hours)

• Duration shortened if: large dose ingested, no co-ingestion of ethanol
• Duration prolonged if: ethanol co-ingested (ethanol competes with methanol for ADH)

4.2 Stages of Toxicity

• Mild euphoria, drunkenness (weaker than ethanol)
• Nausea, vomiting, gastritis, abdominal pain
• Headache, dizziness
• Elevated osmolal gap (methanol itself contributes to osmolality before metabolism)

• Relative asymptomatic interval
• Methanol being metabolized to formic acid but clinical signs not yet obvious

• Bradycardia
• Prolonged coma
• Seizures
• Severe resistant acidosis (pH <7.0)
• Fixed dilated pupils

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5. Diagnosis

5.1 Laboratory Findings

5.2 Diagnostic Formula (for exam)

• Osmolal gap = Measured serum osmolality - Calculated osmolality
• Calculated osmolality = 2[Na] + [glucose/18] + [BUN/2.8]
• Elevated osmolal gap early + elevated anion gap later = classic pattern of methanol/toxic alcohol poisoning

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6. Treatment

Step 1: General Supportive Measures (ABC)

• Airway - secure airway, intubate if necessary (respiratory depression, coma)
• Breathing - supplemental oxygen, ventilatory support
• Circulation - IV fluids, vasopressors for shock
• Gastric lavage - only if within 1-2 hours of ingestion (methanol absorbed rapidly)
• Monitor blood gases, electrolytes, renal function, visual acuity regularly

Step 2: Correct Metabolic Acidosis

• IV Sodium Bicarbonate (NaHCO₃)
• Alkalinization serves a dual purpose:
  1. Corrects acidosis
  2. Converts formic acid → formate ion (ionized form) → less membrane-permeable → cannot enter CNS/retina as easily → reduces ocular and CNS toxicity
• Also increases renal excretion of formate (ionized form not reabsorbed as readily)

Step 3: Inhibit Toxic Metabolite Formation (THE KEY TREATMENT)

A. Fomepizole (4-methylpyrazole) - PREFERRED ANTIDOTE

• Mechanism: Potent competitive inhibitor of alcohol dehydrogenase (ADH)
• Blocks methanol → formaldehyde → formic acid conversion
• Route: Intravenous infusion
• Dose:
  • Loading dose: 15 mg/kg IV
  • Then: 10 mg/kg every 12 hours x 4 doses (48 hours)
  • Then: 15 mg/kg every 12 hours (because fomepizole induces its own CYP450 metabolism after 48 hours)
  • Continue until serum methanol <20-30 mg/dL
  • During hemodialysis: administer every 4 hours (dialysis removes fomepizole)
• Advantages: Safe, predictable, no CNS depression, no monitoring of serum levels required
• Adverse effects: Burning at infusion site, headache, nausea, dizziness (mild and transient)
• Do NOT combine with ethanol (fomepizole prolongs ethanol half-life)

B. Ethanol - ALTERNATIVE (when fomepizole unavailable)

• Mechanism: Ethanol has 10-20x higher affinity for ADH than methanol → competitively displaces methanol from ADH → methanol cannot be metabolized to toxic products → methanol eliminated unchanged by lungs and kidneys
• Route: IV (5% ethanol in 5% dextrose) or oral (whisky/brandy - 40% ethanol)
• Target blood ethanol level: 100-150 mg/dL (must be maintained continuously)
• Loading dose (oral): ~0.6 g/kg (e.g., 1 mL/kg of absolute alcohol)
• Maintenance: 0.1-0.2 g/kg/hour (adjust based on serum ethanol monitoring)
• Disadvantages:
  • CNS depression, hypoglycemia (especially in children)
  • Difficult to titrate, requires frequent monitoring
  • Unreliable in alcoholic patients (high tolerance → faster clearance)
  • Cannot be used with fomepizole
  • During hemodialysis: ethanol is also dialyzed → dose must be increased

Step 4: Remove Methanol and Toxic Metabolites

Hemodialysis - INDICATIONS (Any one of the following):

• Serum methanol >50 mg/dL
• Severe metabolic acidosis (pH <7.15-7.2)
• Visual symptoms or signs of optic nerve injury
• Renal failure
• Clinical deterioration despite other treatment
• Large ingestion with rising osmolal gap

Step 5: Folinic Acid (Leucovorin) or Folic Acid

• Formate is cleared by the folate-dependent one-carbon metabolism pathway
• Folate administration may enhance formate elimination by providing the cofactor for this pathway
• Folinic acid (leucovorin) 1 mg/kg IV (up to 50 mg) every 4-6 hours
• May be of benefit in enhancing formate clearance; simple and safe to administer

Step 6: Treatment of Ocular Involvement

• No specific treatment for formate-induced optic nerve damage once established
• Early ADH inhibition and alkalinization are the primary preventive strategies
• Ophthalmology consultation

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7. Summary of Treatment Algorithm

METHANOL POISONING SUSPECTED
↓
1. SUPPORTIVE: ABC, IV access, O₂
2. CORRECT ACIDOSIS: IV Sodium Bicarbonate
3. INHIBIT METABOLISM:
   → Fomepizole (preferred) 15 mg/kg IV loading
   → OR Ethanol (if fomepizole unavailable) - target 100-150 mg/dL
4. CONSIDER HEMODIALYSIS if:
   → Methanol >50 mg/dL
   → Severe acidosis, visual symptoms, renal failure
5. FOLINIC ACID - to enhance formate elimination
6. MONITORING: ABG, electrolytes, visual acuity, serum methanol levels

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8. Mechanism of Ethanol as Antidote - Detailed (Shanbhag Favourite)

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9. High-Yield Summary Table

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