Classification of neuromuscular blockers

1. Nondepolarizing (competitive) blockers
   • Natural curare alkaloid: d-Tubocurarine
   • Benzylisoquinoliniums: Atracurium, cisatracurium, mivacurium
   • Aminosteroids: Pancuronium, vecuronium, rocuronium
2. Depolarizing blockers
   • Succinylcholine (suxamethonium)
   • Decamethonium

Curare alkaloids

• It is a nondepolarizing competitive neuromuscular blocker.
• It competes with acetylcholine at nicotinic Nm receptors on the motor end plate.
• Thus, end-plate depolarization and skeletal-muscle contraction do not occur, causing flaccid paralysis.
• The blockade can be reversed by anticholinesterases such as neostigmine, which increase acetylcholine at the neuromuscular junction. Medical Physiology describes d-tubocurarine as a competitive inhibitor at the two ACh-binding sites of muscle nicotinic receptors (p. 358).

• Histamine release causing hypotension, flushing, and bronchospasm
• Ganglion blockade causing hypotension
• Prolonged skeletal-muscle paralysis and respiratory paralysis/apnea
• No analgesia, amnesia, or unconsciousness. Therefore, adequate anesthesia and ventilatory support are required.

• Previously used as an adjunct to general anesthesia to produce skeletal-muscle relaxation during surgery.
• Facilitation of endotracheal intubation and controlled ventilation.
• Historically used for tetanus, severe muscle spasm, and electroconvulsive therapy.
• d-Tubocurarine is now rarely used, having been largely replaced by safer agents such as atracurium, cisatracurium, vecuronium, and rocuronium.

G protein-coupled receptor (GPCR) effector pathways

1. Regulation of adenylyl cyclase-cAMP pathway

• Gs activates adenylyl cyclase, whereas Gi inhibits it.
• Adenylyl cyclase converts ATP to cAMP.
• cAMP activates protein kinase A (PKA), which phosphorylates proteins, producing the cellular response.
• Examples:
  • β1, β2 adrenoceptors, H2 and D1 receptors: Gs → ↑ cAMP
  • α2, M2, D2 receptors: Gi → ↓ cAMP

2. Phospholipase C-IP3-DAG-Ca²⁺ pathway

• Receptors coupled to Gq activate phospholipase C-β (PLC).
• PLC hydrolyses membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into:
  • IP3 (inositol trisphosphate): releases Ca²⁺ from endoplasmic reticulum.
  • DAG (diacylglycerol): activates protein kinase C (PKC), with Ca²⁺ assistance.
• Increased intracellular Ca²⁺ and PKC activation produce responses such as secretion and smooth-muscle contraction.
• Examples: α1 adrenoceptors, M1/M3 muscarinic receptors, H1 histamine receptors, angiotensin AT1 receptors.

3. Direct regulation of ion channels

• The activated Gα or Gβγ subunits directly open or close ion channels, without a second messenger. It is therefore also called the shortcut pathway.
• It can open K⁺ channels, close Ca²⁺ channels, or alter other ionic conductances.
• Examples:
  • M2 muscarinic receptors in the heart open K⁺ channels, causing hyperpolarization and reduced heart rate.
  • Gi-coupled receptors can inhibit voltage-gated Ca²⁺ channels, reducing neurotransmitter release.

1. Adenylyl cyclase → cAMP → PKA
2. PLC → IP3 + DAG → Ca²⁺ + PKC
3. Direct opening/closure of ion channels