Acetylcholine: Neurotransmitter and Significance

Acetylcholine is one of the most important endogenous neurotransmitters in the body. It is synthesized in the cytoplasm of cholinergic neurons from choline and acetyl coenzyme A by the enzyme choline acetyltransferase and stored in synaptic vesicles. Acetylcholine transmits signals at the motor end plate between nerve and skeletal muscle, in the autonomic nervous system between pre and postganglionic fibers, and at parasympathetic target organs. In the central nervous system, it is involved in attention, learning, memory, and the sleep wake cycle.

As a pharmaceutical agent, acetylcholine (brand name Miochol E) is approved for intraocular use in ophthalmology to produce rapid pupil constriction following procedures such as cataract surgery. However, acetylcholine is therapeutically more important indirectly: many medications act on the cholinergic system by inhibiting degradation (acetylcholinesterase inhibitors such as donepezil, rivastigmine, pyridostigmine, neostigmine, physostigmine), stimulating receptors (muscarinic, nicotinic agonists), or blocking receptors (anticholinergic agents such as atropine, scopolamine, tiotropium, trospium).

Mechanism of Action

Acetylcholine binds to two major receptor groups. Nicotinic receptors (nAChR) are ligand gated ion channels that allow sodium influx upon binding, thereby depolarizing the postsynaptic membrane. They are located at the motor end plate (muscle type) as well as at autonomic ganglia and in the brain (neuronal type). Activation leads to muscle contraction or synaptic transmission in autonomic relay stations.

Muscarinic receptors (M1 to M5) are G protein coupled. They control a variety of parasympathetic responses: M1 mainly in the central nervous system and at gastric parietal cells, M2 at the heart with heart rate reduction, M3 at smooth muscle, glands, and endothelium with bronchoconstriction, increased secretion, and vasodilation, M4 and M5 primarily in the brain. The diversity of receptors explains the broad spectrum of cholinergic medications.

Acetylcholine itself has a very short half life. It is rapidly broken down in the synaptic cleft by acetylcholinesterase into choline and acetate. Choline is taken back into the neuron via a transporter and is available for resynthesis. This rapid inactivation protects against excessive stimulation and is the target of many medications.

Areas of Application

• Intraocular use (Miochol E) for pupil constriction in eye surgery, such as after cataract surgery or iridectomy procedures
• Scientific diagnostics in research on synapses and neurotransmission

Direct therapeutic applications outside these areas are rare. The clinical significance of acetylcholine unfolds rather indirectly through medications that influence the cholinergic system:

• Acetylcholinesterase inhibitors in Alzheimer type dementia (donepezil, rivastigmine, galantamine), in myasthenia gravis (pyridostigmine, neostigmine), and in emergency situations (physostigmine as an antidote in anticholinergic syndrome)
• Muscarinic receptor antagonists in chronic obstructive pulmonary disease (tiotropium, glycopyrronium, aclidinium), in overactive bladder (trospium, solifenacin, oxybutynin), in motion sickness (scopolamine), in anesthesia (atropine)
• Nicotinic receptor antagonists as muscle relaxants in anesthesia (rocuronium, vecuronium, cisatracurium, succinylcholine)

Dosage and Administration

Miochol E intraocular: 0.5 to 2 ml of a 1 percent solution, freshly prepared, slowly instilled intraocularly. Administration is performed by ophthalmic surgical personnel in an operative setting. Acetylcholine is not stable in solution and must be prepared immediately before use.

Systemic administration: not indicated. Acetylcholine would be immediately degraded intravenously and would additionally have an extremely broad adverse effect profile with bradycardia, bronchospasm, salivation, sweating, and hypotension.

In practice the dosage of indirect cholinergic agents is more important. Examples: donepezil for dementia 5 to 10 mg daily, pyridostigmine for myasthenia gravis titrated individually (often 30 to 60 mg four times daily), tiotropium 2.5 or 5 microg inhaled once daily.

Adverse Effects

Direct application to the eye: brief increase in tear production, transient accommodation spasm, mild corneal irritation. Systemic effects are unusual due to minimal absorption.

With systemic cholinergic activation (such as from overdose of acetylcholinesterase inhibitors or poisoning with organophosphates) a cholinergic syndrome develops with salivation, tearing, sweating, abdominal cramps, diarrhea, vomiting, bradycardia, bronchospasm, pupil constriction, and muscle fasciculations. Treatment with atropine as a muscarinic antagonist and pralidoxime in organophosphate poisoning.

Drug Interactions

• Acetylcholinesterase inhibitors increase the concentration of acetylcholine at the receptor and can be problematic in combination with cholinergic agents or in patients with asthma, bradycardia, gastric ulcer, and narrow angle glaucoma.
• Anticholinergic medications (tricyclic antidepressants, some antipsychotics, first generation antihistamines, antispasmodics) counteract the cholinergic effect, which is counterproductive in dementia therapy and increases the risk of delirium and falls.
• Beta blockers enhance cardiac cholinergic effects with additional bradycardia.
• Suxamethonium (succinylcholine) acts agonistically at nicotinic receptors; its degradation is via pseudocholinesterase and can be prolonged if this enzyme is inhibited.

Special Notes

Pregnancy and breastfeeding: intraocular administration with minimal systemic burden is generally unproblematic; individual assessment by the treating physician.

Preexisting conditions: caution with manifest asthma, severe bradycardia, narrow angle glaucoma in treatment with other agents, or gastric ulcer with systemic cholinergic activation. Intraocular acetylcholine administration is largely independent of these.

Cholinergic syndrome: systemic cholinergic enhancement can be life threatening. In emergency medicine, atropine is the antidote in muscarinic crisis. In organophosphate poisoning, additionally pralidoxime and diazepam for seizures.

Diagnostic significance: the Tensilon test with edrophonium was formerly standard diagnosis in myasthenia gravis. Today antibody diagnostics and electrophysiology are preferred.

Lifestyle and learning: central cholinergic activity is reduced by sleep deprivation and chronic stress, which manifests as reduced concentration ability. Anticholinergic medications in elderly people must be critically reviewed because they can enhance cognitive deficits.

You May Also Be Interested In

• Donepezil, acetylcholinesterase inhibitor in dementia therapy
• Rivastigmine, dual inhibitor of acetylcholinesterase and butyrylcholinesterase
• Pyridostigmine, peripheral acetylcholinesterase inhibitor in myasthenia gravis
• Scopolamine, anticholinergic agent for motion sickness
• Trospium, peripherally acting anticholinergic in overactive bladder

Frequently Asked Questions

Sources

• Gelbe Liste, active ingredient and receptor database
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines on dementia and myasthenia gravis
• EMA, European Medicines Agency