Nicotinic receptor antagonists
Nicotinic antagonists inhibit the effects of acetylcholine on nicotinic receptors. According to their dominant effects, we distinguish the antagonists acting on the autonomic nervous system which are called ganglionic blocking agents, and those acting on neuromuscular junction which are called neuromuscular blocking agents.
Ganglionic blocking agents
The term ganglionic blocking agents or ganglioplegic agents indicates the drugs which inhibit synaptic transmission in autonomic ganglia. They reduce or suppress both sympathetic and the parasympathetic effects on organs receiving an autonomic innervation. They inhibit the nicotinic postsynaptic receptors without preliminary stimulation, contrary to nicotine which stimulates them in moderate dose and inhibits them in very high dose.
After administration of ganglioplegic agents in sufficient dose, the stimulation of sympathetic and parasympathetic preganglionic fibers is inactive whereas the stimulation of postganglionic fibers induces a response of the effector.
Vessels (arteries, veins)
Decrease of tone and motility
Retention of urine
Effect of a ganglioplegic agent such as penthonium
The effects observed on the various organs depend on the prevalence of the sympathetic or parasympathetic effect:
- If the sympathetic tone prevails over the parasympathetic tone, the suppression of the two influences will appear by effects of parasympathetic type;
- Conversely, if the parasympathetic tone prevails on the sympathetic tone, the suppression of the two influences results in effects of sympathetic type.
Ganglionic blocking agents such as penthonium are not used any more in therapeutics because of their lack of specificity, they inhibit at the same time the sympathetic and the parasympathetic effects.
Neuromuscular blocking agents
Neuromuscular blocking agents are divided into two types: acethylcholine competitive antagonists such as tubocurarine which inhibit nicotinic receptors and depolarizing antagonists such as suxamethonium which acts as an acetylcholine excess.
Acetylcholine competitive antagonists
Acetylcholine competitive antagonists, also called competitive blocking agents, have a great affinity for the postsynaptic nicotinic receptors and antagonize acetylcholine effects: they inhibit opening of cation channel-receptors and synaptic transmission . However an acetylcholine excess tends competitively to shift these antagonists from acetylcholine receptors and to restore transmission. Every compound able to increase the acetylcholine concentration has an opposite effect to the competitive antagonists.
The mechanism of action of the D-tubocurarine was shown in experiments as follows:
- When D-tubocurarine is applied on the neuromuscular junction of an isolated muscular fiber, the following facts are observed:
- D-tubocurarine has no action, it gives neither contraction nor depolarization.
- It inhibits muscular contraction induced by stimulation of the motor nerve or by the application of acetylcholine.
- It reduces amplitude and duration of the end-plate potential elicited by stimulation of the nerve or application of acetylcholine.
- The application of an acetylcholine excess or an anticholinesterase agent reduces the effects of tubocurarine.
- When D-tubocurarine is applied apart from the neuromuscular junction, on the nerve or the muscle, it is without action, even in large dose.
The consequence of the inhibition of the neuromuscular transmission is muscular relaxation and then paralysis beginning by the muscles of the face, reaching the muscles of limbs and trunk, and finally the diaphragm. In absence of artificial respiration, diaphragm paralysis causes death by anoxia.
Recovery, i.e. the disappearance of the effects of the D-tubocurarine, starts with the muscles of the face and the diaphragm then successively with the muscles of legs, arms, trunk, pharynx.
D-tubocurarine does not induce loss of consciousness, nor memory disturbances, nor analgesia, because it does not cross the blood-brain barrier.
D-tubocurarine does not have a notable ganglionic blocking effect. It modifies little heart rate and arterial pressure. However, a fast injection of a high dose can cause a fall of blood pressure whose mechanism is not entirely elucidated: decrease of venous return, consecutive to the muscular relaxation, and release of histamine which it elicits, could induce it.
D-tubocurarine is not used any more because the new marketed products are more interesting. Their effect appears more quickly after their administration and ceases more frankly after their discontinuation than that of the D-tubocurarine. Their kinetics of action tends to approach that of suxamethonium. They are less ganglionic blocking agents and less histamine liberators.
The drugs used currently are pancuronium, vecuronium, tracrium, rocuronium, mivacurium and cisatracurium.
Mivacurium has the particularity to be inactivated by the pseudocholinesterases and, when these last are defective, its duration of action is greatly increased.
Certain drugs are likely to modify the activity of acetylcholine competitive antagonists:
- by antagonism: anticholinesterases, neostigmine for example
- by synergy: ganglionic blocking agents, certain antibiotics such as aminoglycosides (streptomycin, neomycin, kanamycin), polypeptides (polymyxine, colimycine and tetracyclines), magnesium and general volatile anesthetics such as halothane and forane.
The only drug of this group used clinically is suxamethonium, also called succinylcholine. Suxamethonium is a cholinomimetic agent but, supplied in excess, it has a cholinolytic effect and inhibits synaptic transmission.
Suxamethonium, after a transient initial stimulation producing fasciculations, inhibits the neuromuscular transmission as would do an acetylcholine excess. Inhibition results from a desensitization of the receptors to the effect of acetylcholine.
Muscle relaxation induced by suxamethonium is characterized primarily by its brevity: in human beings after a single administration by intravenous route, the muscular resolution, often preceded by fasciculations and muscular contractions, appears in less than one minute and disappears in less than three minutes. If one wishes to obtain a longer curarization, it should be administered in intravenous perfusion.
This brevity of action of the suxamethonium is the consequence of its hydrolysis by serum cholinesterases to give choline and succinyl-mono-choline which itself is hydrolyzed to choline and succinic acid.
In certain individuals, there is a deficiency of cholinesterasic activity and the hydrolysis of the suxamethonium is done extremely slowly, which causes a longer duration of action and the possibility of accidents during its use in anesthesiology. In the event of accident of this type, there is no antidote. One can supply enzyme by a transfusion of total blood or plasma.
There is no antagonist to suxamethonium but there are drugs which reinforce its action: anticholinesterases and drugs such as procaine which are also hydrolyzed by the pseudocholinesterases.
The principal undesirable effects observed with suxamethonium result from a stimulation of acetylcholine receptors: muscarinic stimulation can cause bradycardia, hypotension, bronchospasm, whereas stimulation of the nicotinic receptors can give tachycardia and hypertension. One can also observe an hyperkalemia by potassium leakage into the plasma.
Neuromuscular blocking agents are usually used in surgery, orthopedy, endoscopy (intubation, etc) and to prevent traumatisms during electroconvulsive therapy and tetanus.
Any skeletal muscle even in a resting state is subjected to a tension called muscular tone. This muscular tension which is awkward during surgical operations can be reduced or be removed temporarily by the administration of inhibitors of the neuromuscular transmission which withdraw the skeletal muscle from the influence of its motor nerve. Approximately 95% of anesthetized patients receive inhibitors of neuromuscular transmission. The principal cause of death after anesthesia is respiratory depression which can be elicited by neuromuscular blocking agents.
- The absence of equipment for artificial ventilation and especially the absence of a qualified anesthesiologist are absolute contraindications to the use of neuromuscular blocking agents.
- Patients, with myasthenia or treated by drugs likely to reinforce the action of muscle relaxants, require precautions for use of neuromuscular blocking agents.
A return of curarization, due for example to the diffusion of an antibiotic such as gentamycine, can have serious consequences when it occurs after cessation of the assisted respiration.
The antidote to an excessive curarization provoked by acetylcholine competitive antagonists is prostigmine.