Drugs affecting cholinergic neurotransmission

Drugs affecting cholinergic neurotransmission

Drugs affecting synthesis, storage or release of acetylcholine

Synthesis of acetylcholine is dependent on uptake of its immediate precursor, choline which is then metabolized to acetylcholine via a single step catalyzed by choline acetyltransferase (CAT).  Hemicholinium competes with choline for the choline transporter, resulting in inhibition of acetylcholine synthesis. Once synthesized, acetylcholine is taken up via a specific active transport mechanism and stored within synaptic vesicles.  This transport is inhibited by vesamicol.  Both hemicholinium and vesamicol lead to depletion of acetylcholine levels within the nerve terminal, and while not useful as therapeutics, have been used as experimental tools to study the physiological roles of cholinergic nerves. 

Exocytotic release of acetylcholine is triggered by an action potential arriving at the nerve terminal leading to an influx of Ca2+.  This release is inhibited by the neurotoxins, botulinum toxin and β-bungarotoxin.  Botulinum toxin acts to inhibit the docking of the synaptic vesicle with the membrane of nerve terminal and therefore interferes with the release of acetylcholine from all cholinergic nerves.  Some selectivity can be achieved by administering via local injection to the required site of action.  Botulinum toxin (Botox) injections cause localized effects, including muscle paralysis to reduce wrinkles and decreased sweating in conditions such as hyperhidrosis.  

Drugs affecting the termination of action of acetylcholine

The action of acetylcholine is terminated rapidly due to its metabolism by acetylcholinesterase (AChE) enzymes present within cholinergic neuroeffector and synaptic junctions.  AChE is also present in cholinergic nerve terminals and a related enzyme, butyrylcholinesterase (BuChE, or pseudocholinesterase) is found within the plasma. While AChE is quite specific for acetylcholine, BuChE has broader substrate specificity and is involved in the metabolism of some therapeutics, including suxamethonium.  Genetic variants of BuChE, associated with decreased enzymic activity, are associated with clinically relevant increases in the duration of activity of these drugs.

Inhibition of cholinesterase enzymes accounts for the effects organophosphate nerve gases (e.g. sarin) and insecticides (e.g. malathion).  The symptoms of organophosphate poisoning include over activity of the parasympathetic nervous system (“DUMBBELS”*); stimulation followed by inhibition of nicotinic receptors at autonomic ganglia and on the skeletal muscle; and stimulation of cholinergic receptors in the CNS.

*DUMBBELLS: Diarrhoea, Urination, Miosis, Bradycardia,Bronchoconstriction, Emesis, Lacrimation, Salivation

Cholinesterase inhibitors (or anticholinesterases) used therapeutically are classified according to their duration of action and may be long acting and irreversible (e.g. ecothiopate), medium-duration (e.g. physostigmine) or short-acting (e.g. edrophonium). Therapeutic uses of anticholinesterases include:

  • the diagnosis (e.g. edrophonium) and treatment (e.g. neostigmine; physostigmine; pyridostigmine) of myasthenia gravis, an autoimmune disease associated with a reduced number of functional skeletal muscle nicotinic receptors
  • slowing the progression of Alzheimer’s disease, a neurodegenerative condition associated with a loss of cholinergic neurons in the CNS (e.g. donepezil, rivastigmine)
  • the treatment of glaucoma (e.g. ecothiopate, physostigmine )

Anticholinesterases and anticholinergic drugs (Nair & Hunter, 2004)

A good review of the actions of anticholinesterases; their mechanisms of action, effects and therapeutic uses.  It also includes information about specific anticholinesterases in use.

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