13. Cholinergic agonists and cholinesterase inhibitors

Overview of drugs

Direct-acting cholinergic agonists	Acetylcholinesterase inhibitors (indirect-acting cholinergic agonists)	Irreversible acetylcholinesterase inhibitors	Acetylcholinesterase reactivator
Bethanechol	Edrophonium	Echothiophate	Pralidoxime
Carbachol	Donepezil	Hexaethyl tetraphosphate
Cevimeline	Galantamine	Malathion
Pilocarpine	Neostigmine	Parathion
	Physostigmine
	Pyridostigmine
	Rivastigmine

Cholinergic transmission

Physiology refresher

Acetylcholine is the molecule that the body synthesized that binds to both muscarinic and nicotinic acetylcholine receptors. It has no clinical uses. It is broken down by acetylcholinesterase and butyrylcholinesterase.

There are two types of cholinesterase: acetylcholinesterase and butyrylcholinesterase (also called pseudocholinesterase). The former is found in the synaptic cleft and only breaks down acetylcholine, while the latter is found in plasma and other organs, and can break down other choline esters (like certain drugs) in addition to Ach. Most importantly it breaks down succinylcholine and procaine.

Muscarine is a molecule that is found in certain mushrooms. It activates muscarinic receptors but not nicotinic receptors and is what gave muscarinic receptors their name. Muscarine has no clinical use. It may be a cause for mushroom poisoning, however. Muscarinic receptors can be blocked by atropine.

Nicotine is found in the nightshade family of plants. It activates nicotinic acetylcholine receptors but not muscarinic receptors. It gave the nicotinic receptors their name. It’s not used clinically either, unless you count smoking. Nicotinic receptors can be blocked by tubocurarine (a poison).

Muscarinic receptor agonists effects

• Contraction of the ciliary muscle and iris sphincter to cause accommodation and miosis, and an increased outflow of aqueous humour into the Schlemm’s canal, resulting in a reduction in intraocular pressure.
• Negative chronotropic and dromotropic effects (but no inotropic effect).
• Vasodilation (by causing endothelial cells to produce NO).
  • The resulting decrease in BP can result in a reflex increase in HR.
• Increased GI tract smooth muscle contraction, leading to increased peristaltic activity.
• Gastrointestinal sphincter relaxation.
• Increased salivation and gastric acid secretion.
• Bronchoconstriction and increased bronchial secretion.
• Contraction of detrusor muscle, and relaxation of internal urethral sphincter, easing urination.

Direct-acting cholinergic agonists

Compounds

• Bethanechol
• Carbachol
• Pilocarpine
• Cevimeline

Mechanism of action

These drugs are acetylcholine receptor agonists (directly bind to and activate acetylcholine receptors), thereby mimicking many of the physiological effects that result from stimulation of the parasympathetic nervous system. Because they mimic the parasympathetic nervous system they are also known as direct parasympathomimetics. The muscarinic effects are the most important.

Indications

Bethanechol can be used to treat paralytic ileus and atonic bladder.

Pilocarpine can be used to treat glaucoma.

Cevimeline can be used to induce sweat, tear and saliva production in Sjögren syndrome.

Carbachol is not used clinically anymore.

Pharmacokinetics

Bethanechol is a choline ester with a quaternary ammonium group. The quaternary ammonium group makes it poorly lipid-soluble and therefore impossible for bethanechol to cross the blood-brain barrier. It is more resistant to hydrolysis by acetylcholinesterase than acetylcholine.

Pilocarpine is a tertiary amine that is well absorbed from the GI tract and readily enters the CNS.

Adverse effects

• Bradycardia
• Hypotension
• Diarrhoea
• Urinary incontinence
• Increased salivation
• Muscle weakness
• Miosis (-> blurred vision)

(Basically the “Muscarinic receptor agonists effects”.)

Acetylcholinesterase inhibitors

Compounds

These drugs are also called indirect parasympathomimetics. These are classified according to their duration of action:

• Short acting drugs (few minutes)
  • Edrophonium
• Medium duration drugs (0,5 – 6 hours)
  • Neostigmine
  • Pyridostigmine
  • Physostigmine
• Long acting drugs
  • Donepezil
  • Rivastigmine
  • Galantamine

Indications

Edrophonium was previously used to diagnose myasthenia gravis (before more modern tests were invented), as administration of edrophonium caused a temporary improvement in the patient’s symptoms.

The medium-duration drugs can be used for:

• Myasthenia gravis (when combined with atropine)
• Glaucoma
• Paralytic ileus
• Atonic bladder
• Reversing tubocurare poisoning
• Treating atropine intoxication

The long-acting drugs can be used to improve Alzheimer disease (slightly)

Mechanism of action

These drugs inhibit acetylcholinesterase, the enzyme that usually breaks down Ach in the synaptic cleft. They therefore indirectly increase the effect of acetylcholine on the receptor by allowing it to bind to the receptor for longer. They have indirect activating effects on both muscarinic and nicotinic receptors and have mostly the same effects as the cholinergic agonists plus nicotinic effects.

In addition to acetylcholinesterase these drugs inhibit butyrylcholinesterase. This means they prolong the effect of other drugs broken down by this enzyme, like procaine and succinylcholine.

Pharmacokinetics

Hint: All drugs ending with -ium are quaternary compounds and therefore don’t cross the blood-brain barrier, and are also poorly absorbed from the GI tract. However, not all quaternary compounds end with -ium.

Edrophonium contains a quaternary ammonium, meaning it doesn’t cross the blood-brain barrier. It has a short duration of action, 2-10 minutes.

Neostigmine and pyridostigmine are also quaternary amines. They have intermediate duration of action, 0,5 – 6 hours.

Donepezil, physostigmine, rivastigmine and galantamine are tertiary amines and therefore cross the BBB.

Adverse effects

Same as direct parasympathomimetics.

Irreversible acetylcholinesterase inhibitors and organophosphates

Compounds

• In clinical use
  • Echothiophate
• Pesticides and chemical warfare weapons
  • Hexaethyl tetraphosphate
  • Malathion
  • Parathion
• Reversible inhibitor
  • Pralidoxime

The only clinically used irreversible acetylcholinesterase inhibitor is echothiophate.

Many chemical warfare weapons and pesticides are also organophosphates and irreversible acetylcholinesterase inhibitors.

A drug called pralidoxime reverses the irreversible inhibition of acetylcholinesterase.

Indications

Echothiophate is used to treat glaucoma.

Pralidoxime is an antidote for organophosphate poisoning.

Mechanism of action

These drugs permanently inactivate acetylcholinesterase enzymes by phosphorylation.

Pralidoxime removes the phosphate group from the acetylcholinesterase molecules, causing them to regain their function.

Pharmacokinetics

Because these drugs and poisons irreversibly inactivate acetylcholinesterase they have a long duration of action (days). Cells must synthesize new molecules of acetylcholinesterase to overcome the effect of the drug, which takes time.

Symptoms of organohosphate poisoning

Organophosphate poisoning causes overstimulation of the neuromuscular junction, a condition called cholinergic crisis. It causes:

• First activation of sympathetic ganglia, later blocking them
• Parasympathetic overactivation
• Depolarization block and paralysis. This paralysis can then extend to the respiratory muscles to cause respiratory depression and eventually coma.
• Convulsions and tremor

Cholinergic crisis is treated with removal of the offending compound and intravenous atropine administration. Pralidoxime can be given within 6 hours of when the crisis starts.