14. Cholinergic agonists and cholinesterase inhibitors

Last updated on January 10, 2019 at 19:20

Direct-acting cholinergic agonists Acetylcholinesterase inhibitors (indirect-acting cholinergic agonists) Chemical weapons, insecticides (irreversible acetylcholinesterase inhibitors) Acetylcholinesterase reactivator
Acetylcholine Demecarium Echothiophate Pralidoxime
Bethanechol Edrophonium Hexaethyl tetraphosphate
Muscarine Neostigmine Malathion
Nicotine Physostigmine Parathion
Pilocarpine Pyridostigmine
Direct-acting cholinergic agonists

These drugs directly activate acetylcholine receptors to mimic many of the physiological effects that result from stimulation of the parasympathetic nervous system. Because they mimic the parasympathetic nervous system are they called direct parasympathomimetics. The muscarinic effects are the most important.

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

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. It’s not used clinically. It is a cause for mushroom poisoning, however.

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.

Bethanechol is a choline ester with a quaternary ammonium group that has a similar structure as acetylcholine. 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. Bethanechol is used to treat supraventricular arrythmia, non-obstructive ileus, atonic bladder and congenital megacolon. Bethanechol has no activity on nicotinic receptors, just muscarinic receptors.

Pilocarpine is a tertiary amine that is well absorbed from the GI tract and readily enters the CNS. It is used topically for glaucoma, because of the reduction of intraocular pressure. It’s also used to treat Sjogren syndrome-associated dry mouth. Like bethanechol, it has activity only on muscarinic receptors.

Muscarinic receptor agonists have the following effects:

  • Contraction of the ciliary muscle and iris sphincter to cause miosis and accommodation, 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. Also, sphincter relaxation.
  • Increased salivation and acid secretion
  • Bronchoconstriction and increased bronchial secretion
  • Contraction of detrusor muscle, and relaxation of internal urethral sphincter

Here are some mneumonics I came up with:

  • Muscarine – M for mushroom – muscarine comes from mushrooms
  • Bethanechol – EC for Ester of Choline – Bethanechol is a choline ester
  • Bethanechol – Col for megacolon – Can treat congenital megacolon
  • Pilocarpine – Pilo reminds you of pilots, who have good eyes – Pilocarpine can treat glaucoma
  • Muscarinic receptor reminds you of muscle – miosis reminds you of myoglobin, found in muscle – Muscarinic activation causes miosis
  • Bethanechol reminds you of Beth – a name with four letters – Bethanechol is a quaternary compound
Acetylcholinesterase inhibitors

These drugs inhibit acetylcholinesterase, the enzyme that usually breaks down Ach in the synaptic cleft. These drugs 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. They are therefore called indirect parasympathomimetics.

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, skin, GI tract, liver, brain, and can break down other choline esters, not just Ach. The acetylcholinesterase inhibitors block both enzymes.

Edrophonium contains a quaternary ammonium, meaning it doesn’t cross the blood-brain barrier. It reversibly inhibits acetylcholinesterase and has a short duration of action, 2-10 minutes. It is used in the diagnosis of myasthenia gravis.

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.

Another hint: Not all quaternary compounds end with -ium… 🤷‍♂️🙄

Demecarium, neostigmine and pyridostigmine also reversibly inhibit acetylcholinesterase, but they have intermediate duration of action, ½ – 6 hours. They are quaternary amines, meaning that they don’t cross the BBB. Their clinical uses are:

  • Glaucoma,
  • Bladder atonia
  • Non-obstructive ileus
  • Myasthenia gravis
  • Reversing the action of tubocurarine
  • Atropine intoxication

Physostigmine is a tertiary compound, so it can cross the BBB and therefore be used to treat Alzheimer’s disease.

Echothiopate is an organic phosphate that is an irreversible acetylcholinesterase inhibitor, meaning that it permanently inactivates acetylcholinesterase enzymes by phosphorylation. The effects of echothiopate therefore last for days, as the body must synthesize new acetylcholinesterase molecules. It is used to treat glaucoma.

Many chemical warfare weapons and pesticides are also organic phosphates and irreversible acetylcholinesterase inhibitors. They are also organic phosphates and the ones we must know are hexaethyl tetraphosphate, malathion and parathion.

A drug called pralidoxime removes the phosphate group from the acetylcholinesterase molecules, causing them to regain their function. Pralidoxime is therefore an antidote for organophosphate 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.

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13. Pharmacokinetics: zero and first order elimination, volume of distribution, clearance, elimination half-life, oral bioavailability, loading dose, maintenance dose

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15. Muscarinic receptor antagonists

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