14. Cholinergic agonists and cholinesterase inhibitors

Last updated on October 17, 2019 at 19:35

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

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.

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 (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. It has no clinical use. 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.

There is significant overlap in the indications of all drugs which increase cholinergic transmission, as they have very similar effects on the body. For this reason there is a difference between what the drugs _are_ used for and what they _could_ be used for. If you get a question like whether bethanechol could treat glaucoma, answer yes.

Muscarinic receptor agonists 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 gastric acid secretion.

Bronchoconstriction and increased bronchial secretion.

Contraction of detrusor muscle, and relaxation of internal urethral sphincter, easing urination.

Direct-acting cholinergic agonists
  • Bethanechol
  • Carbachol
  • Pilocarpine

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.

Indications:

Bethanechol and carbachol are used to treat non-obstructive ileus and urinary retention.

Pilocarpine is used to treat glaucoma and to induce sweat, tear and saliva production in Sjögren syndrome.

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.

Acetylcholinesterase inhibitors

These drugs are also called indirect parasympathomimetics. The important drugs here are:

  • Short acting drugs
    • Edrophonium
  • Medium duration drugs
    • Neostigmine
    • Pyridostigmine
    • Physostigmine
  • Long acting drugs
    • Donepezil
    • Rivastigmine
    • Galantamine

Indications:

Myasthenia gravis, glaucoma, postoperative ileus and urinary retention.

Donepezil, rivastigmine and galantamine can be used in Alzheimer disease.

Physostigmine can be used as an antidote for atropine overdose.

Edrophonium was used to diagnose myasthenia gravis in the past.

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, ½ – 6 hours.

Physostigmine is a tertiary compound, so it can cross the BBB. It has an intermediate duration of action.

Donepezil, rivastigmine and galantamine all cross the BBB so they can act on the CNS in Alzheimer disease.

Irreversible acetylcholinesterase inhibitors and organic phosphates

The only clinically used irreversible acetylcholinesterase inhibitor is echothiophate.

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 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 organic phosphate 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.


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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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