Nondepolarizing muscle relaxants

Curare is the term for plant-derived arrow poisons of South American natives. When struck by a curare-tipped arrow, an animal suffers paralysis of skeletal musculature within a short time after the poison spreads through the body; death follows because respiratory muscles fail (respiratory paralysis). Killed game can be eaten without risk because absorption of the poison from the gastrointestinal tract is virtually nil. The curare ingredient of greatest medicinal importance is d-tubocurarine. This compound contains a quaternary nitrogen atom (N) and, at the opposite end of the molecule, a tertiary N that is proto-nated at physiological pH. These two positively charged N atoms are common to all other muscle relaxants. The fixed positive charge of the quaternary N accounts for the poor enteral absorbability.

d-Tubocurarine is given by i.v. injection (average dose approx. 10 mg). It binds to the endplate nicotinic cholino-ceptors without exciting them, acting as a competitive antagonist towards ACh. By preventing the binding of released ACh, it blocks neuromuscular transmission. Muscular paralysis develops within about 4 min. d-Tubocurarine does not penetrate into the CNS. The patient would thus experience motor paralysis and inability to breathe, while remaining fully conscious but incapable of ex-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

pressing anything. For this reason, care must be taken to eliminate consciousness by administration of an appropriate drug (general anesthesia) before using a muscle relaxant. The effect of a single dose lasts about 30 min.

The duration of the effect of d-tubo-curarine can be shortened by administering an acetylcholinesterase inhibitor, such as neostigmine (p. 102). Inhibition of ACh breakdown causes the concentration of ACh released at the endplate to rise. Competitive "displacement" by ACh of d-tubocurarine from the receptor allows transmission to be restored.

Unwanted effects produced by d-tu-bocurarine result from a nonimmune-mediated release of histamine from mast cells, leading to bronchospasm, urticaria, and hypotension. More commonly, a fall in blood pressure can be attributed to ganglionic blockade by d-tu-bocurarine.

Pancuronium is a synthetic compound now frequently used and not likely to cause histamine release or ganglionic blockade. It is approx. 5-fold more potent than d-tubocurarine, with a somewhat longer duration of action. Increased heart rate and blood pressure are attributed to blockade of cardiac M2-cholinoceptors, an effect not shared by newer pancuronium congeners such as vecuronium and pipecuronium.

Other nondepolarizing muscle relaxants include: alcuronium, derived from the alkaloid toxiferin; rocuroni-um, gallamine, mivacurium, and atra-curium. The latter undergoes spontaneous cleavage and does not depend on hepatic or renal elimination.

Muscle Relaxant Curarine

Blockade of ACh receptors No depolarization of endplate

Antidote: cholinesterase inhibitors e.g., neostigmine

Blockade of ACh receptors No depolarization of endplate

Relaxation of skeletal muscles (Respiratory paralysis) -

Artificial ventilation necessary - (plus general anesthesia!)

Antidote: cholinesterase inhibitors e.g., neostigmine

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