Chemistry of Indirect Acting Cholinergic Agonists

Indirect Acting Cholinergic Agonists (Cholinesterase Inhibitors)

• Acetylcholine action is terminated by hydrolysis via acetylcholinesterase in cholinergic synapses.
• Indirect acting cholinergic agonists inhibit acetylcholinesterase.

Chemistry

• Cholinesterase inhibitors are categorized into three chemical groups:
  • Simple alcohols (e.g., edrophonium): Reversibly bind electrostatically to the cholinesterase active site, preventing access of acetylcholine. The enzyme-inhibitor complex is short-lived (2-10 minutes).
  • Carbamic acid esters of alcohols (carbamates, e.g., neostigmine, physostigmine, pyridostigmine): Bind to the active site and undergo hydrolysis, then form a covalent bond with the enzyme, inhibiting enzyme activity for 30 minutes to 6 hours.
  • Organic derivatives of phosphoric acid (organophosphates, e.g., echothiophate, malathion, parathion, soman): Undergo initial binding and hydrolysis, resulting in a phosphorylated active site. The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes at a very slow rate (hundreds of hours). The complex can undergo aging, further strengthening the bond.

Pharmacokinetics

• Quaternary carbamates (e.g., neostigmine) are poorly absorbed from skin, eyes, and lungs due to poor lipid solubility.
• Tertiary amines (e.g., physostigmine) are well absorbed and can be used topically in the eye. Physostigmine crosses the blood-brain barrier (BBB) and is more toxic than quaternary carbamates.
• Organophosphates (except echothiophate) are well absorbed from skin, lungs, gut, and conjunctiva. They penetrate the CNS. They are dangerous to humans and effective insecticides.

Mechanism of Action

• Edrophonium (simple alcohol): Reversibly binds electrostatically and via hydrogen bonds to the active site of cholinesterase enzyme, preventing access of acetylcholine.
• Carbamate esters: Bind to the active site, undergo hydrolysis, and then form a covalent bond with the enzyme, inhibiting enzyme activity.
• Organophosphates: Undergo initial binding and hydrolysis, resulting in a phosphorylated active site. The covalent phosphorus-enzyme bond is very stable and hydrolyzes slowly. The complex can undergo aging, further strengthening the bond. Pralidoxime is able to break the phosphorus-enzyme bond if given before aging has occurred.

Organ System Effects

• CNS: High doses of lipid-soluble agents can cause convulsions, coma, and respiratory arrest.
• Eye, Gastrointestinal (GI) Tract, Respiratory Tract, and Urinary Tract: Effects similar to direct-acting cholinergic agonists.
• Cardiovascular System (CVS): Bradycardia and reduced cardiac output.
• Neuromuscular Junction: Low concentrations increase the strength of contraction of weakened muscles (e.g., myasthenia gravis). High concentrations can lead to fasciculation of muscle fibers and neuromuscular blockade.

Clinical Uses

• Eye: Useful in glaucoma (increased intraocular pressure) by causing contraction of the ciliary body, facilitating outflow of aqueous humor. Physostigmine is commonly used.
• Gastrointestinal (GI) and Urinary Tract: Neostigmine can be used to increase smooth muscle activity in conditions like paralytic ileus, congenital megacolon, reflux esophagitis, and urinary retention.
• Neuromuscular Junction: Cholinesterase inhibitors (e.g., pyridostigmine) are useful for managing myasthenia gravis. Edrophonium can diagnose myasthenia gravis by observing improved muscle strength, and it can also be used to reverse post-surgical neuromuscular blockade.

Toxicity

• Overdose (e.g., organophosphate poisoning): Muscarinic effects such as nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, and bronchoconstriction. These effects are blocked by atropine.
• Atropine (anticholinergic) overdose: Can manifest as dry mouth, mydriasis (pupil dilation), tachycardia, hot and flushed skin, agitation, and delirium.

Other Notes

• Anticholinergics (also known as antimuscarinics or parasympatholytics) are divided into muscarinic and nicotinic subgroups.
• Atropine (hyoscyamine) is the prototype drug found in the plant Atropa belladonna. Other examples include scopolamine and homatropine.
• Atropine is well absorbed from the gut and conjunctiva, widely distributed in the body including the CNS, and approximately 50% is excreted unchanged in the urine.
• Atropine causes a reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors.
• Clinical uses of anticholinergics include CNS disorders (e.g., Parkinson's disease, motion sickness), eye conditions, respiratory disorders (e.g., asthma, COPD), and cholinergic excess (e.g., organophosphate poisoning).

This quiz explores the chemistry and mechanisms of indirect acting cholinergic agonists, specifically cholinesterase inhibitors. Understand the classifications, actions and duration of different chemical groups of these inhibitors including simple alcohols and organophosphates.