NEUROMUSCULAR TRANSMISSION

PHARMACOLOGY OF NEUROMUSCULAR TRANSMISSION

 

I. Introduction and History

A. There are two general classes of neuromuscular blocking drugs. They are the competitive, and the depolarizing blockers. The prototype of the competitive blockers is curare.

B. Although the South American arrow poisons have fascinated scientists since the 1500s, the modern clinical use of curare dates to 1932 when it was first used in patients with tetanus. Its first trial for muscular relaxation in general anesthesia occurred in 1942. 

II. Pharmacology of Competitive Neuromuscular blockers

A. Examples

1. d-tubocurarine, metocurine, pancuronium

a. Long lasting duration of blockade

2. Vecuronium, atracurium, rocuronium

a. Intermediate duration

3. Mivacurium

a. Short acting 

B. Actions on skeletal muscles:

1. After I.V. injection, the onset of effects is rapid. Motor weakness rapidly progresses to flaccid paralysis. Small muscles such as those of the fingers and extraocular muscles of the eyes are effected before those of the limbs, neck, and trunk. Subsequently, the intercostal muscles and finally the diaphragm is paralyzed. Recovery of function occurs in the reverse order, with the diaphragm recovering first. Death is due to paralysis of the muscles of respiration.

C. CNS effects

1. Almost all contain a quaternary nitrogen therefore they do not cross the blood brain barrier.

D. Effects on Autonomic Ganglia

1. Although tubocurarine is more potent at Nm receptors than at Nn receptors of ganglia, some degree of nicotinic receptor blockade is probably produced at autonomic ganglia and the adrenal medulla by usual clinical doses. The net result is hypotension and tachycardia. One also sees a decrease in the tone and motility of the GI tract.Vecuronium, Atracurium, Rocuronium cause considerably less ganglionic blockade.

E. Effects on Histamine release

1. Tubocurarine, Atracurium, and Metocurine cause the release of histamine with resulting hypotension, bronchospasm, and excessive bronchial and salivary secretions.Vecuronium causes less release of histamine, while Pancuronium causes essentially no release of histamine.

F. Drug Interactions with Competitive Neuromuscular Blockers

1. Synergistic potentiation occurs with a variety of inhalation anesthetic agents such as halothane, enflurane, isoflurane. Aminoglycoside antibiotics (...mycins) inhibit release of ACh and thereby potentiate the Nm blockers. Tetracyclines also produce some neuromuscular blockade, possibly by chelating Ca++.

2. Anticholinesterases such as neostigmine, pyridostigmine, and edrophonium will antagonize the effects of the competitive neuromuscular blockers.

G. Pharmacokinetics

1. Tubocurarine and metocurine, pancuronium are excreted primarily by the kidneys.

2. Atracurium and Mivacurium are metabolized by plasma esterases (accounting for briefer duration of action).

3. Vecuronium and Rocuronium are metabolized by the liver.

4. Because of their ionized structures, they are poorly absorbed orally, and are given i.v.

H. Toxicity

1. Prolonged apnea

2. Hypotension (ganglionic blockade, inhibition of release of catecholamines from medulla, release of histamine):

3. Bronchospasm and increased secretions due to histamine release. 

III. Pharmacology of Depolarizing Neuromuscular Blockers 

A. Mechanisms of action and effects on skeletal muscle

1. The depolarizing blockers succinylcholine and decamethonium (C-10 no longer available in the USA) block transmission by causing prolonged depolarization of the end plate at the neuromuscular junction. This is manifested as an initial series of twitches (fasciculations), followed by flaccid paralysis. This is referred to as phase one blockade.

a. Phase 1 blockade is potentiated by anticholinesterases and antagonized by competitive blockers.

2. If the duration of blockade is prolonged however, or if the concentration of the blocker is excessive, then phase two blockade occurs in which the pharmacological characteristic is that of a competitive inhibition.

a. Phase 2 blockade is antagonized by anticholinesterases, and potentiated by competitive blockers.

B. Effects on the CNS

1. Both compounds contain quaternary nitrogens and therefore do not cross the BBB.

C. Effects on autonomic ganglia are relatively rare.

D. Histamine is released by succinylcholine, but not by decamethonium.

E. Drug interactions

1. Potentiation of the neuromuscular blockade caused by the aminoglycoside antibiotics (mycins), and tetracyclines.

2. Do not potentiate the effects of the halogenated hydrocarbon anesthetics (halothane et al).(Mechanism unclear).

3. Phase 1 block potentiated by anticholinesterases and antagonized by competitive blockers.

4. Phase 2 block antagonized by anticholinesterases and potentiated by competitive blockers.

5. Lithium in therapeutic concentrations used in the treatment of manic disorders can slow the onset and increase the duration of action of succinylcholine. 

F. Pharmacokinetics

1. Succinylcholine is a structural analogue of ACh which is metabolized rapidly by plasma esterases. Thus it has an ultrashort duration of action. Some patients who have a prolonged response to the action of succinylcholine have a genetic deficiency in plasma cholinesterase. Procaine type local anesthetics are also metabolized by plasma cholinesterases, and will competitively inhibit the metabolism of succinylcholine, resulting in a prolonged duration of action.

2. Decamethonium is excreted directly by the kidney.

3. Because of their ionized structure, they are poorly absorbed orally, and are given i.v.

G. Toxicity

1. Prolonged apnea

2. Malignant hyperthermia can occur when patients are receiving halothane and succinylcholine. It is one of the main causes of death due to anesthesia.

a. In vitro tests are available to evaluate susceptibility to malignant hyperthermia and results in a prediction of susceptible, normal, or equivocal. Malignant hyperthermia is treated by rapid cooling, inhalation of O₂, and treatment with Dantrolene. This drug blocks release of Ca++ from the sarcoplasmic reticulum and reduces muscle tone and heat production.

3. During prolonged depolarization, muscle cells may lose significant quantities of K+. In patients in whom there has been extensive injury to soft tissues the efflus of K+ following continued administration of succinylcholine can be life threatening due to hyperkalemia.

a. Administration of succinylcholine is contraindicated or very dangerous because of life threatening hyperkalemia in such conditions as burns, trauma, spinal cord injuries with paraplegia or quadriplegia, and muscular dystrophies. In these cases, competitive neuromuscular blockers should be used. 

IV. Therapeutic Uses of Neuromuscular Blockers 

A. Mainly as adjuvants to surgical anesthesia to cause muscle relaxation.

B. In orthopedics to facilitate correction of dislocations and alignment of fractures.

C. To facilitate endotracheal intubation

D. To prevent trauma in electroconvulsive shock therapy

E. In treatment of severe cases of tetanus