(USMLE topics) Mechanisms of action of cholinergic agonists and antagonists (anticholinergics): direct and indirect agonists (reversible and irreversible cholinesterase inhibitors), Botox, nicotinic and muscarinic antagonists.
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Acetylcholine is a major neurotransmitter of the nervous system. It is released by motor neurons at neuromuscular junctions to stimulate skeletal muscle contraction. Acetylcholine is also the primary neurotransmitter of the parasympathetic nervous system responsible for the body’s “rest and digest” state. It slows heartbeats, slows respiratory rate, contracts smooth muscles of the gastrointestinal tract and urinary bladder, stimulates various secretions, and constricts pupils. Acetylcholine is also active in several brain regions associated with cognition and movement.
A neuron that uses mainly acetylcholine as neurotransmitter is called a cholinergic neuron.
Acetylcholine is an ester of choline. It is synthesized and stored in the nerve terminal. When a cholinergic neuron is stimulated, acetylcholine is released into the synaptic cleft where it binds to its receptor on the postsynaptic cell, triggering cellular response. Acetylcholine is rapidly cleared from the synapse by the enzyme acetylcholinesterase, which binds to acetylcholine and hydrolyzes it into choline and acetate. The enzyme molecule quickly recycles itself each time, ready for another round of reaction.
There are 2 main types of acetylcholine receptors: muscarinic and nicotinic, each type has several subtypes, or classes. Each receptor class is specific to certain synapses or tissues.
Cholinergic agonists are drugs that mimic or enhance the action of acetylcholine, while cholinergic antagonists are those that inhibit its action. Because action of acetylcholine is widespread, cholinergic drugs may produce lots of side effects when administered systemically. Drugs that target a particular receptor class are more specific and are therefore preferred.
Cholinergic agonists can be direct-acting or indirect-acting:
Direct-acting agonists mimic acetylcholine, they bind to acetylcholine receptor and activate downstream signaling. They are not easily metabolized by acetylcholinesterase and therefore last longer at the synapse. Examples are drugs used as eye drops to constrict pupil and reduce intraocular pressure for treatment of glaucoma. Some agents are used to increase smooth muscle tone in urinary bladder and gastrointestinal tract, or to stimulate saliva secretion to treat dry mouth.
Indirect agonists act by inhibiting the enzyme acetylcholinesterase, thereby increasing the concentration of acetylcholine available at the synapse.
Reversible inhibitors form a transient, reversible complex with the enzyme. They slow down the recycling of the enzyme, making it less available for breaking down acetylcholine. Some of these drugs are used to treat myasthenia gravis, or to reverse the effects of anesthesia. Others are given to boost cholinergic activities in Alzheimer’s brain to compensate for the loss of functioning neurons.
Irreversible cholinesterase inhibitors bind to the enzyme in an irreversible manner and permanently inactivate it. These drugs are very toxic, they are used as insecticides and “nerve gases”.
Cholinergic antagonists inhibit acetylcholine action by several mechanisms:
Botulinum toxin, Botox, is a bacterial toxin. It blocks acetylcholine release by inhibiting exocytosis. Botox is used to treat localized muscle spasms, movement disorders and strabismus. It is given by direct injection into the affected muscle.
Nicotinic antagonists compete with acetylcholine for binding to nicotinic receptor. They are most commonly used to relax skeletal muscles during surgery.
Muscarinic antagonists compete with acetylcholine for binding to muscarinic receptor. They are used to treat bradycardia, diarrhea and bladder spasms, dilate bronchi, reduce secretions, and dilate pupils. Some are used as sedatives and to counteract cholinesterase inhibitors.