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CHOLINERGIC PHARMACOLOGY - Complete MBBS Notes

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1. CHOLINERGIC DRUGS - CLASSIFICATION

Classification

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2. ANTICHOLINESTERASES - CLASSIFICATION (Detailed)

By Duration of Inhibition

By Chemical Class

1. Quaternary ammonium compounds (do NOT cross BBB): Neostigmine, Pyridostigmine, Edrophonium
2. Tertiary amines (cross BBB): Physostigmine, Rivastigmine, Donepezil, Galantamine
3. Organophosphates: DFP, Echothiophate, Parathion, Malathion, Nerve agents

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3. REVERSIBLE vs. IRREVERSIBLE ANTICHOLINESTERASES - WHY THE CLASSIFICATION?

Mechanism Explaining the Names

• Anionic site - binds the quaternary N of ACh
• Esteratic site - hydrolyzes the ester bond of ACh (contains serine-OH)

Reversible Inhibitors:

• Edrophonium binds the anionic site by ionic/electrostatic interaction only - easily displaced (very short acting, minutes).
• Neostigmine, Physostigmine, Pyridostigmine bind and carbamylate the esteratic serine. The carbamyl-enzyme complex undergoes spontaneous hydrolysis within 1-8 hours - hence called reversible.
• They are classified reversible because AChE activity is naturally and spontaneously restored within hours.

Irreversible Inhibitors:

• Organophosphates phosphorylate the serine-OH at the esteratic site, forming a stable phosphoryl-enzyme bond.
• This bond is highly stable and does NOT spontaneously hydrolyze.
• Over time (hours), the bond undergoes "aging" (further stabilization/dealkylation), making it completely resistant even to oxime reactivators.
• Hence called irreversible - AChE activity is only restored by synthesis of new enzyme (takes days to weeks).

Conditions Where This Property Is Exploited

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4. NEOSTIGMINE - COMPLETE PHARMACOLOGY

Mechanism of Action

• Muscarinic synapses: smooth muscle, cardiac muscle, glands (parasympathomimetic effects)
• Nicotinic synapses: neuromuscular junction (NMJ) and autonomic ganglia

Pharmacological Actions

Clinical Uses

1. Myasthenia Gravis - standard symptomatic treatment (oral 15-30 mg 3-4 times/day)
2. Reversal of non-depolarizing NMJ blockade (post-anesthesia, given with atropine)
3. Post-operative urinary retention (0.5 mg SC/IM) - contracts detrusor
4. Paralytic ileus - increases GI motility
5. Diagnosis of MG - (edrophonium preferred but neostigmine also used)

Adverse Effects

• Muscarinic (SLUDGE): Salivation, Lacrimation, Urination, Defecation, GI cramps, Emesis
• Bradycardia, bronchospasm, increased secretions
• Cholinergic crisis (overdose): muscle weakness from persistent depolarization at NMJ, resembles myasthenic crisis
• Abdominal cramps, diarrhea, nausea

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5. RATIONALE FOR GIVING ATROPINE WITH NEOSTIGMINE

The Problem

• Desired nicotinic effect at NMJ: muscle strength restoration
• Unwanted muscarinic effects: bradycardia, hypotension, bronchospasm, increased bronchial secretions, intestinal spasm, excessive salivation, miosis

Why Atropine?

• Atropine given before or simultaneously with neostigmine blocks all the unwanted muscarinic side effects.
• The desired nicotinic action at the NMJ (muscle contraction) is left intact.
• Typically, atropine 0.6-1.2 mg IV is given before or with neostigmine 2.5 mg IV.

Key Point

"Nicotinic reversal of neuromuscular blockade can usually be produced safely only when the patient has been protected by atropine or other muscarinic blockers. This prevents the untoward muscarinic effects of bradycardia, hypotension, bronchospasm, or intestinal spasm." - Barash Clinical Anesthesia

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6. MYASTHENIA GRAVIS - DETAILED TREATMENT

Pathophysiology (Brief)

Treatment Plan

A. Anticholinesterase Drugs (Symptomatic Treatment)

• Pyridostigmine (drug of choice) - oral, 60 mg every 4-6 hours; sustained-release 180 mg at bedtime
• Neostigmine - oral 15-30 mg; parenteral 0.5-2.5 mg
• Ambenonium - less used
• These drugs increase ACh at the NMJ, enhancing the response of remaining receptors to nerve impulses.
• Muscarinic side effects (GI cramps, salivation) are managed with atropine or other anticholinergics.
• ⚠ Tolerance to muscarinic effects usually develops over time.

B. Immunosuppressive Therapy

• Glucocorticoids (Prednisolone): most commonly used; promotes remission in most patients. Note: initial worsening of weakness may occur before improvement.
• Azathioprine: steroid-sparing agent; used in long-term management
• Cyclosporine: for refractory cases
• Mycophenolate mofetil
• High-dose cyclophosphamide: for severe refractory cases
• Rituximab: for anti-MuSK positive MG

C. Thymectomy

• Indicated in: thymoma, or disease not adequately controlled by anti-ChE + steroids
• The thymus contains myoid cells with nAChRs and is the likely source of autoreactive T-helper cells
• Improvement is gradual, occurring over months to years

D. Acute Management (Myasthenic Crisis)

• Plasmapheresis (plasma exchange) - removes anti-nAChR antibodies; effect within days
• IV Immunoglobulin (IVIG) - alternative to plasmapheresis; 2 g/kg over 5 days
• Mechanical ventilation if respiratory muscles fail
• Differentiate from cholinergic crisis using edrophonium test:
  • MG crisis: improves with edrophonium → give more neostigmine
  • Cholinergic crisis: worsens with edrophonium → withhold anti-ChE, give atropine

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7. ANTICHOLINESTERASES - THREE THERAPEUTIC USES (with examples)

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8. ORGANOPHOSPHATE POISONING - MANAGEMENT

Mechanism of Toxicity

Clinical Features (SLUDGE + Nicotinic + CNS)

• Salivation, Lacrimation, Urination, Defecation/Diarrhea, GI cramps, Emesis
• Bronchospasm, bronchorrhea (life-threatening)
• Bradycardia, hypotension
• Miosis, blurred vision
• Sweating

• Muscle fasciculations, cramps → progressing to weakness and paralysis
• Respiratory muscle paralysis → ventilatory failure (major cause of death)
• Sympathetic stimulation: pallor, mydriasis (rare), tachycardia, hypertension

• Anxiety, restlessness, tremors, headache, dizziness
• Confusion, delirium, hallucinations
• Seizures, coma

Management

Step 1: Decontamination

• Remove clothing; thoroughly wash skin with soap and water
• Eye exposure: copious irrigation
• GI ingestion: activated charcoal has limited benefit (rapid absorption + vomiting)
• Protective PPE for healthcare providers (chemical-resistant suit, gloves, face mask)

Step 2: Stabilization and Supportive Care

• Airway management first: suction secretions, oxygenation, intubation if needed
• Ventilatory support (respiratory failure is the main cause of death)
• Use non-depolarizing paralytic (e.g., rocuronium 1 mg/kg) for intubation - NOT succinylcholine (metabolized by cholinesterases, prolonged paralysis)
• Benzodiazepines for seizures
• IV fluids for hypotension

Step 3: Antidote Therapy

• Dose: 1-3 mg IV every 5 minutes, doubling dose until "atropinization"
• Pediatric: 0.05 mg/kg IV
• Endpoint of atropinization = drying of airway secretions (NOT HR or pupil size)
• May require 200-500 mg in the first hour in severe cases
• Maintenance infusion: 10-20% of total dose needed/hour
• Atropine reverses muscarinic effects ONLY (does NOT reverse NMJ paralysis)

• Mechanism: Reactivates AChE by breaking the phosphoryl-AChE bond before "aging" occurs
• Must be given EARLY (within 24-48 hours, before aging of the bond)
• Dose: 1-2 g IV over 15-30 minutes; then infusion 200-400 mg/hour
• Pediatric: 20-40 mg/kg IV
• Reverses BOTH muscarinic AND nicotinic effects (restores NMJ function)
• Indications: respiratory depression, fasciculations, seizures, dysrhythmias, hemodynamic instability, or when large amounts of atropine are needed

• For seizures and to reduce CNS excitability

Step 4: Monitoring

• Repeat atropine as needed (muscarinic signs re-emerge)
• ECG monitoring (prolonged QT, ST changes, AV block, tachyarrhythmias)
• Serum cholinesterase levels (plasma and RBC - confirm diagnosis)
• Respiratory function closely monitored

Avoid:

• Succinylcholine (prolonged paralysis)
• Beta-blockers (worsen bradycardia)
• Morphine, phenothiazines (depress respiration)

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9. GENERAL PRINCIPLES OF ACUTE POISONING TREATMENT

1. Resuscitation: Airway (A), Breathing (B), Circulation (C) - immediate priority
2. Decontamination: Remove source of poison - skin washing, eye irrigation, gastric lavage (if indicated within 1 hour), activated charcoal (for many oral poisons)
3. History and identification of poison: empty bottles, circumstantial evidence, clinical toxidrome
4. Specific antidote (if available): e.g., atropine + pralidoxime for OP poisoning; N-acetylcysteine for paracetamol; naloxone for opioids; flumazenil for benzodiazepines
5. Enhanced elimination: forced alkaline diuresis (salicylates), hemodialysis (methanol, ethylene glycol), hemoperfusion (barbiturates) - when applicable
6. Symptomatic treatment: anticonvulsants for seizures, vasopressors for hypotension, cooling for hyperthermia
7. Monitoring: ECG, renal function, hepatic function, vitals, urine output
8. Psychiatric evaluation: in intentional overdose

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10. ATROPINE - FOUR CLINICAL USES

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11. ATROPINE vs. TROPICAMIDE AS MYDRIATICS - COMPARE AND CONTRAST

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12. ATROPINE SUBSTITUTES - IMPORTANT USES AND DRUG OF CHOICE

Classification of Atropine Substitutes

• Ipratropium, Tiotropium, Glycopyrrolate, Propantheline, Homatropine methylbromide

• Dicyclomine, Oxybutynin, Tolterodine, Cyclopentolate, Tropicamide, Scopolamine

Drug of Choice for Each Condition

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Summary Tables for Quick Revision

ACh Receptor Distribution (Relevant to Drug Actions)

Key Drug Comparisons (MBBS Exam Favourite)

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Quick Topic Index

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Key Points to Remember for Exams

1. Atropine with neostigmine - atropine blocks unwanted muscarinic effects while nicotinic NMJ reversal is preserved. Muscarinic effects appear at lower ACh concentrations than nicotinic.
2. Reversible vs. Irreversible: Reversible = carbamylation of esteratic site (spontaneous recovery in hours). Irreversible = phosphorylation with aging (days to weeks, only new enzyme synthesis restores function).
3. OP poisoning - Atropine is DOC for muscarinic effects; Pralidoxime is the specific antidote (must give before aging); airway management is the immediate priority; avoid succinylcholine.
4. MG treatment - Pyridostigmine is drug of choice (oral, sustained release at night). Steroids for immunosuppression. Thymectomy for thymoma or refractory disease. Plasmapheresis/IVIG for crisis.
5. Tropicamide = short duration (4-6 hours) = adult fundoscopy. Atropine/Cyclopentolate = prolonged cycloplegia = children's refraction + uveitis.
6. Glycopyrrolate = quaternary amine atropine substitute = does NOT cross BBB = no CNS effects = preferred pre-anaesthetic antisialagogue when tachycardia/CNS effects are undesirable.