Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers.
Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.
Martyn
J A
JA
Department of Anesthesiology, Harvard Medical School, Boston, Massachusetts.
White
D A
DA
Gronert
G A
GA
Jaffe
R S
RS
Ward
J M
JM
D000818:Animals; D002056:Burns / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D009157:Myasthenia Gravis / Q000503:physiopathology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D009125:Muscle Relaxants, Central; D009467:Neuromuscular Depolarizing Agents; D011950:Receptors, Cholinergic