5.8: Direct-Acting Cholinergic Agonists: Pharmacokinetics

Direct-acting cholinergic agonists, such as synthetic choline esters and naturally occurring alkaloids, exert their effects by enhancing the actions of acetylcholine and stimulating the parasympathetic nervous system. Synthetic choline esters share structural similarities with acetylcholine. For example, they have a positively charged quaternary ammonium or onium group, contributing to their hydrophilic characteristics. As a result, they are poorly absorbed in the body through oral administration and unable to cross the blood-brain barrier. In contrast, alkaloids are tertiary amines readily absorbed into the body and can cross the blood-brain barrier. Notably, the quaternary amine-containing alkaloid muscarine is poorly absorbed and induces toxic effects in the central nervous system.

The pharmacokinetics of direct-acting cholinergic drugs play a crucial role in their therapeutic application. Acetylcholine is used as a pharmacological agent during eye surgeries to induce miosis, and it is administered as ophthalmic or eye drops. Similarly, carbachol is topically applied as an eye drop in the treatment of glaucoma. In addition, pilocarpine, another alkaloid, is delivered to the eye through an ocular insert to induce miosis. Bethanechol has limited absorption and is taken orally multiple times daily; it primarily acts on the urinary and gastrointestinal tracts, commonly used for postoperative urinary retention. Renal excretion is the main route of elimination for choline esters and alkaloids. Carbachol, bethanechol, muscarine, and pilocarpine are not hydrolyzed by acetylcholinesterase, and their removal from the body is expedited by acidifying the urine.

Recall that direct-acting cholinergic agonists mimic the actions of ACh and are categorized as choline esters and alkaloids.

Choline esters—including ACh and its synthetic derivatives—being quaternary amines, are hydrophilic in nature. So, they have poor oral absorption and fail to cross the blood-brain barrier or BBB.

ACh—the endogenous choline ester, is rapidly inactivated by AChEs and hydrolyzed into choline and acetate. As a result, a higher IV dose is essential to induce its pharmacological action.

Synthetic choline esters are relatively more stable and resistant to hydrolysis by AChEs, correlating with their longer duration of action.

In general, choline esters are short-acting agents as they are rapidly eliminated via the urine.

The naturally occurring alkaloids are tertiary amines, except muscarine. So, they are readily absorbed from the site of administration, can cross the BBB, and are eliminated via the renal route.

Acidification of the urine can accelerate the clearance of alkaloids. As protonation of tertiary amines reduces their lipophilicity, acidification promotes rapid renal elimination.