Anesthesia Pharmacology: Depolarizing Agents and Neuromuscular Blockers

MOA of Depolarizing Agents

• Depolarizing agents activate the Ach receptor on the motor end plate, causing voluntary muscle contraction initially, but leading to depolarization block and eventually competitive block (dual block) with prolonged administration.
• This results in desensitization of the receptor to Ach.

Pharmacokinetics of Neuromuscular Blockers

• All neuromuscular blockers are quaternary compounds and are not absorbed orally.
• They are practically always given IV.
• Redistribution plays a significant role in the termination of action of a single dose.
• These drugs do not cross the placenta or penetrate the brain.
• Drugs excreted by the kidney have a longer half-life (e.g., d-tubocurarine, pancuronium), while those eliminated by the liver have a shorter duration of action (e.g., vecuronium).

Succinylcholine

• Advantages:
  • Most commonly used skeletal muscle relaxant for endotracheal intubation.
  • Provides good intubation conditions, including relaxed jaw, separated vocal cords, and immobility.
  • Quick onset of action (1-2 minutes).
  • Can be used as a continuous infusion occasionally.
• Disadvantages:
  • Unpredictable BP, HR, and arrhythmias.
  • Fasciculations.
  • Muscle pain.
  • Increased intraocular pressure.
  • Increased intracranial pressure.
  • Hyperkalemia.
  • Not indicated for use below 8 years of age.
  • May cause malignant hyperthermia.

Pancuronium

• Steroid compound that is 5 times more potent.
• No cardiac or respiratory toxicity (little ganglion block).
• Low histamine release – no bronchospasm or flushing.
• Long duration of action, requiring reversal.
• Preferred only for long surgeries.

Vecuronium

• Congener of pancuronium.
• Slow onset but prolonged action.
• CVS stability – no histamine release.
• Spontaneous and quick recovery.
• Most commonly used.

Rocuronium

• Non-depolarizing agent.
• Rapid and immediate action.
• Alternative to succinylcholine for tracheal intubation.
• Also used as a maintenance relaxant, with no reversal required.
• Rapid intubation condition in 60-90 seconds.
• Also used in ICU for mechanical ventilation.

Atracurium

• Competitive blocker, less potent than pancuronium.
• Reversal not required.
• Non-enzymatic spontaneous degradation in addition to cholinesterase.
• Preferred in elderly and neonates.

Other Actions of NM Blockers

• Autonomic ganglia:
  • Partial blockade of ganglia.
  • Results in fall in BP and tachycardia.
• Histamine release:
  • Hypotension.
  • Bronchospasm, excess bronchial and salivary secretion.
• CVS:
  • Fall in BP due to ganglion blockade, histamine release, and reduced venous return.
• GIT:
  • Paralytic ileus.

Interactions of NMB

• Thiopentone sodium – same syringe.
• General anesthetics – potentiate blockers.
• Anticholinesterases – neostigmine.
• Antibiotics – aminoglycosides.
• Calcium channel blockers – potentiate blockers (verapamil) – both competitive and non-competitive.
• Diuretics – hypokalemia: enhances competitive block.

Uses of Neuromuscular Blocking Drugs

• Adjuvant to general anesthesia.
• Assisted ventilation.
• Convulsion and trauma from electroconvulsive therapy.
• Status epilepticus.

Directly Acting Relaxants

• Dantrolene:
  • Different from neuromuscular blockers, with no action on NM transmission.
  • MOA – Ryanodine receptors calcium channels – prevents depolarization – no intracellular release of Ca++.
  • Reduces actin-myosin interaction; weakens skeletal muscle contraction.
  • Absorbed orally, penetrates brain, and produces sedation, metabolized in liver, excreted in kidney.

Other CNS Depressants

• Barbiturates.
• Benzodiazepines.
• Gama hydroxybutyric acid (GHB).

Skeletal Muscle Relaxants

• Drugs that act:
  • Peripherally at NMJ or muscle fiber itself.
  • In the cerebrospinal axis to reduce muscle tone or cause muscle paralysis.

Classification of SMRs

• A. Neuromuscular blockers:
  • Non-depolarizing (competitive) blockers:
    • Long acting: d-Tubocurarine, pancuronium, Doxacurium, etc.
    • Intermediate acting: Vecuronium, Atracurium, Rapacuronium, Cisatracurium.
    • Short acting: Mivacurium.
  • Depolarizing blockers: Succinylcholine (Suxamethonium), Decamethonium.
• B. Directly acting: Dantrolene, quinine.
• C. Centrally acting:
  • 1. Mephesin congeners (e.g., mephensin, chlormezanone).
  • 2. Benzodiazepines (e.g., Diazepam).
  • 3. GABA derivatives (e.g., Baclofen).
  • 4. Central alpha 2 agonist (e.g., tizanidine).