Tubocurarine

UNDER REVIEW (September 2016)

Mechanism of Action:

Tubocurarine is a plant alkaloid that, although not used clinically in the modern era is a prototype for other drugs that block the neuromuscular junction. It is a slow onset, long-acting, non-depolarizing blocker. It is a competitive antagonist of acetylcholine (ACh) acting at nicotinic acetylcholine receptors (nAChR). It blocks postsynaptic nAChRs, preventing action potential transmission and thus causing skeletal muscle relaxation. This sort of block can be overcome by increasing the relative concentration of ACh (e.g. by administration of an anti-cholinesterase such as neostigmine). Atracurium is another neuromuscular blocking drug that binds to the same site as ACh preventing the activation of the receptor-channel complex.

Lecture and CAL materials:

Neostigmine

UNDER REVIEW (September 2016)

Mechanism of Action:

Neostigmine is a reversible, medium-acting anticholinesterase drug (therapeutic effect up to 4 hours). Anticholinesterases competitively inhibit the action of acetylcholinesterase (AChE), which destroys the neurotransmitter acetylcholine following its release from cholinergic nerve endings. By interfering with the breakdown of acetylcholine, neostigmine indirectly (via action of ACh) stimulates both nicotinic and muscarinic receptors. Because neostigmine increases the effective concentration of acetylcholine, it causes such body changes as contraction of the pupils, increased activity of intestinal muscles, and increased secretion by the salivary and sweat glands. Neostigmine is a parasympathomimetic, ie it mimics the effects of stimulation of the parasympathetic nervous system.

Lecture and CAL materials:

Atracurium

UNDER REVIEW (September 2016)

Mechanism of Action:

Atracurium is a non-depolarizing competitive antagonist acting at the nicotinic ACh receptor (nAChR) on skeletal muscle to cause muscle relaxation. Atracurium binds to the same receptor site as ACh on the muscle end plate, preventing the activation of the receptor-channel complex. It belongs to the non-depolarising class of neuromuscular-blocking drugs (the other class being depolarizing drugs such as suxamethonium – see separate eDrug entry). ACh is released in response to the arrival of an action potential at the nerve ending. The amount of ACh released by the nerve ending and the amount needed to initiate an action potential at the muscle fibre is redundant by several folds. Hence, blocking just a few receptor sites at the muscle end plate will be compensated by the copious amount of ACh activating the remaining receptors. For atracurium to be effective, it needs to block 70-80% of nACHRs at any one muscle fibre. A small muscle end plate potential may still be recorded at the muscle fibre from the remaining nAChRs but this does not exceed the threshold potential required to initiate an action potential at the muscle fibre (all-or-nothing principle of transmission). The degree of muscle relaxation represents the proportion of muscle fibres failing to respond to a nerve action potential. This sort of block can be overcome by increasing the relative concentration of ACh by administration of an anti-cholinesterase drug such as neostigmine (see separate eDrug entry). High levels of ACh will effectively compete with atracurium to occupy nAChR sites on the muscle end plate. Atracurium is designed to spontaneously degrade at physiological plasma pH. It subsequently has a short duration of action and is independent of renal and hepatic function.

Lecture and CAL materials:

Suxamethonium

Mechanism of Action:

Suxamethonium acts on the neuromuscular junction, as a depolarizing blocker. Compared to non-depolarizing blockers (e.g. atracurium), which are competitive antagonists of acetylcholine (ACh) at the nicotinic receptor (nAChR) in skeletal muscle, non-depolarizing blockers are agonists that activate the nAChR. Suxamethonium causes sustained depolarization at the endplate which prevents normal neuromuscular transmission. Suxamethonium consists of 2 ACh molecules linked by acetyl groups and is broken down by enzyme cholinesterase (AChE). Therefore the duration of action is prolonged in those who have low enzyme levels (genetic variation) or take anticholinesterase drugs.

Lecture and CAL materials: