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6 Drugs acting at the neuromuscular junction

Action potentials are conducted along the motor nerves to their terminals (upper figure, ) where the depolarization initiates an influx of Ca²⁺ ions and the release of acetylcholine (ACh) by a process of exocytosis (). The ACh diffuses across the junctional cleft and binds to receptors located on the surface of the muscle fibre membrane at the motor endplate. The reversible combination of ACh and receptors (lower figure, ) triggers the opening of cation‐selective channels in the endplate membrane, allowing an influx of Na⁺ ions and a lesser efflux of K⁺ ions. The resulting depolarization, which is called an endplate potential (EPP), depolarizes the adjacent muscle fibre membrane. If large enough, this depolarization results in an action potential and muscle contraction. The ACh released into the synaptic cleft is rapidly hydrolysed by an enzyme, acetylcholinesterase (), which is present in the endplate membrane close to the receptors.

Neuromuscular transmission can be increased by anticholinesterase drugs (bottom left), which inhibit acetylcholinesterase and slow down the hydrolysis of ACh in the synaptic cleft (see also Chapter 8). Neostigmine and pyridostigmine are used in the treatment of myasthenia gravis and to reverse competitive neuromuscular blockade after surgery. Overdosage of anticholinesterase results in excess ACh and a depolarization block of motor endplates (‘cholinergic crisis’). The muscarinic effects of ACh (see Chapter 7) are also potentiated by anticholinesterases, but are blocked with atropine. Edrophonium has a very short action and is only used to diagnose myasthenia gravis.

Neuromuscular blocking drugs (right) are used by anaesthetists to relax skeletal muscles during surgical operations and to prevent muscle contractions during electroconvulsive therapy (ECT). Most of the clinically useful neuromuscular blocking drugs compete with ACh for the receptor but do not initiate ion channel opening. These competitive antagonists reduce the endplate depolarizations produced by ACh to a size that is below the threshold for muscle action potential generation and so cause a flaccid paralysis. Depolarizing blockers also act on ACh receptors, but trigger the opening of the ion channels. They are not reversed by anticholinesterases. Suxamethonium is the only drug of this type used clinically.

Some agents (top left) act presynaptically and block neuromuscular transmission by preventing the release of ACh.

Acetylcholine (ACh)

ACh is synthesized in motor neurone terminals from choline and acetyl coenzyme‐A by the enzyme choline acetyltransferase. The choline is taken up into the nerve endings from the extracellular fluid by a special choline carrier located in the terminal membrane.

Exocytosis

ACh is stored in nerve terminals in the cytoplasm and within synaptic vesicles. When an action potential invades the terminal, Ca²⁺ ions enter and bind to synaptotagmin on the vesicle membrane. This results in the association of a second vesicle‐bound protein, synaptobrevin, with synaptotaxin, a protein on the inner surface of the plasma membrane. This association results in fusion with the presynaptic membrane. Several hundred ‘packets’ or ‘quanta’ of ACh are released in about a millisecond. This is called quantal release and is very sensitive to the extracellular Ca²⁺ ion concentration. Divalent ions, such as Mg²⁺, antagonize Ca²⁺ influx and inhibit transmitter release.

ACh receptor

This can be activated by nicotine and, for this reason, is called a nicotinic receptor.^* The receptor–channel complex is pentameric and is constructed from four different protein subunits (ααβγε in the adult) that span the membrane and are arranged to form a central pore (channel) through which cations (mainly Na⁺) flow. ACh molecules bind to the two α‐subunits, inducing a conformational change that opens the channel for about 1 ms.

Myasthenia gravis

Myasthenia gravis is an autoimmune disease in which neuromuscular transmission is defective. Circulating heterogeneous immunoglobulin G (IgG) antibodies cause a loss of functional ACh receptors in skeletal muscle. Symptomatic relief to counter the loss of receptors is obtained by the use of an anticholinesterase, usually pyridostigmine. Immunological treatment includes the administration of prednisolone or azathioprine (Chapter 45). Plasmapheresis, in which blood is removed and the cells returned, may improve motor function, presumably by reducing the level of immune complexes. Thymectomy may be curative.

Presynaptic agents

Drugs inhibiting ACh release

Botulinum toxin is produced by Clostridium botulinum (an anaerobic bacillus, see Chapter 37). The exotoxin is extraordinarily potent and prevents ACh release by enzymatically cleaving the proteins (e.g. synaptobrevin) required for docking of vesicles within the presynaptic membrane. C. botulinum is very rarely responsible for serious food poisoning in which the victims exhibit progressive parasympathetic and motor paralysis. Botulinum toxin type A is used in the treatment of certain dystonias, such as blepharospasm (spasmodic eye closure), hemifacial spasm and spasmodic torticollis. In these conditions, low doses of toxin are injected into the appropriate muscle to produce paralysis that persists for about 12 weeks. Botulinum toxin is used to treat urinary incontinence in patients with spinal cord injury in patients with MS. Injected directly into the bladder, the toxin increases storage capacity and decreases incontinence.

Competitive neuromuscular blocking drugs

In general, the competitive neuromuscular blocking drugs are bulky, rigid molecules and most have two quaternary N atoms. Neuromuscular blocking drugs are given by intravenous injection and are distributed in the extracellular fluid. They do not pass the blood–brain barrier or the placenta. The choice of a particular drug is often determined by the side‐effects produced. These include histamine release, vagal blockade, ganglion blockade and sympathomimetic actions. The onset of action and the duration of action of neuromuscular blocking drugs depend on the dose, but also on other factors (e.g. prior use of suxamethonium, anaesthetic agent used).

Pancuronium is an aminosteroid neuromuscular blocking drug with a relatively long duration of action. It does not block ganglia or cause histamine release. However, it has a dose‐related atropine‐like effect on the heart that can produce tachycardia.

Vecuronium and atracurium are commonly used agents. Vecuronium has no cardiovascular effects. It depends on hepatic inactivation and recovery can occur within 20–30 min, making it an attractive drug for short procedures. Atracurium has a duration of action of 15–30 min. It is only stable when kept cold and at low pH. At body pH and temperature, it decomposes spontaneously in plasma and therefore does not depend on renal or hepatic function for its elimination. It is the drug of choice in patients with severe renal or hepatic disease. Atracurium may cause histamine release with flushing and hypotension. Cisatracurium is an isomer of atracurium. Its main advantage is that it does not cause histamine release and its associated cardiovascular effects.

Rocuronium has an intermediate duration of action of about 30 min, but with a rapid onset of action (1–2 min) comparable with that of suxamethonium (1–1.5 min). It has minimal cardiovascular effects.

Reversal of neuromuscular blockade Neostigmine IV quickly reverses the action of competitive neuromuscular blockers. Atropine or glycopyrronium is given first to prevent parasympathetic effects. Sugammadex binds to the steroidal drugs vecuronium and rocuronium forming an inactive complex.

Depolarizing neuromuscular blocking drugs

Suxamethonium (succinylcholine) is used because of its rapid onset and very short duration of action (2–6 min). The drug is normally hydrolysed rapidly by plasma pseudocholinesterase, but a few people (about 1 in 3000) inherit an atypical form of the enzyme and, in such individuals, the neuromuscular block may last for hours. Suxamethonium depolarizes the endplate and, because the drug does not dissociate rapidly from the receptors, a prolonged receptor activation is produced. The resulting endplate depolarization initially causes a brief train of muscle action potentials and muscle fibre twitches. Neuromuscular block then occurs as a result of several factors which include: (i) inactivation of the voltage‐sensitive Na⁺ channels in the surrounding muscle fibre membrane, so that action potentials are no longer generated; and (ii) transformation of the activated receptors to a ‘desensitized’ state, unresponsive to ACh. The main disadvantage of suxamethonium is that the initial asynchronous muscle fibre twitches cause damage, which often results in muscle pains the next day. The damage also causes potassium release. Repeated doses of suxamethonium may cause bradycardia in the absence of atropine (a muscarinic effect).

Note

1 * Pentameric nicotinic receptors also occur in autonomic ganglia and the brain. They have variants of the α‐ and β‐subunit and a different pharmacology.