Channel Block

Local anesthetics and calcium-entry blockers block the flow of sodium or calcium through their respective channels, explaining the term channel-blocking drugs. Similarly, a block to the flow of ions can occur at the acetylcholine receptor with concentrations of drugs used clinically and may contribute to some of the phenomena and drug interactions seen at the receptor. Two major types, closed channel and open channel block, can occur.^{[57] [58]} In a closed channel block, certain drugs can occupy the mouth of the channel, preventing ions from passing through the channel to depolarize the end plate. The process can take

TABLE 22-1 -- Drugs that can cause or promote desensitization of nicotinic cholinergic receptors

Volatile anesthetics

Halothane

Methoxyflurane

Isoflurane

Antibiotics

Polymyxin B

Cocaine

Alcohols

Ethanol

Butanol

Propanol

Octanol

Barbiturates

Thiopental

Pentobarbital

Agonists

Acetylcholine

Decamethonium

Carbachol

Succinylcholine

Acetylcholinesterase inhibitors

Neostigmine

Pyridostigmine

Difluorophosphate (DFP)

Local anesthetics

Dibucaine

Lidocaine

Prilocaine

Etidocaine

Phenothiazines

Chlorpromazine

Trifluoperazine

Prochlorperazine

Phencyclidine

Ca2+ channel blockers

Verapamil

place even when the channel is not open. In an open channel block, a drug molecule enters a channel that has been opened by reaction with acetylcholine but does not necessarily penetrate all the way through. Open channel blockade is a use-dependent block, which means that molecules can enter the channel only when it is open. In open and closed channel blocks, the normal flow of ions through receptor is impaired, resulting in prevention of depolarization of the end plate and a weaker or blocked neuromuscular transmission. However, because the action is not at the acetylcholine recognition site, it is not a competitive antagonism of acetylcholine and is not relieved by anticholinesterases that increase concentrations of acetylcholine. Increasing the concentration of acetylcholine may cause the channels to open more often and thereby become more susceptible to blockade by use-dependent compounds. There is evidence that neostigmine and related cholinesterase inhibitors can act as channel-blocking drugs.^[57]

Channel blockade is believed to play a role in some of the antibiotics, cocaine, quinidine, piperocaine, tricyclic antidepressants, naltrexone, naloxone, and histrionicotoxin-induced alterations in neuromuscular function. Muscle relaxants, in contrast, can bind to the acetylcholine recognition site of the receptor and occupy the channel. Pancuronium preferentially binds to the recognition site. Gallamine seems to act equally at the two sites. Tubocurarine is in between; at low doses, those that produce minimal blockage of transmission clinically, the drug is essentially a pure antagonist at the recognition site; at larger doses, it also enters and blocks channels. Decamethonium and succinylcholine as agonists can open channels and, as slender molecules, also enter and block them. Decamethonium and some other long, thin molecules can penetrate all the way through the open channel and enter the muscle cytoplasm. Whether prolonged administration of nondepolarizers, as in the intensive care situation, can result in entry of the relaxant, occupation of the channel, and entry of drug into the cytosol is unknown. This effect may partially explain the muscle weakness associated with relaxant therapy in the intensive care unit.