5.8
Diretti Agonisti Colinergici: Farmacocinetica.
Gli agonisti colinergici diretti, come gli esteri di colina sintetica e gli alcaloidi di origine naturale, esercitano i loro effetti potenziando l'azi…
Ricordiamo che gli agonisti colinergici ad azione diretta imitano le azioni dell'ACh e sono classificati come esteri di colina e alcaloidi.
Gli esteri della colina, tra cui l'ACh e i suoi derivati sintetici, essendo ammine quaternarie, sono di natura idrofila. Quindi, hanno uno scarso assorbimento orale e non riescono a superare la barriera emato-encefalica o BEE.
ACh, l'estere endogeno della colina, viene rapidamente inattivato dall'AChE e idrolizzato in colina e acetato. Di conseguenza, una dose endovenosa più elevata è essenziale per indurre la sua azione farmacologica.
Gli esteri sintetici della colina sono relativamente più stabili e resistenti all'idrolisi da parte degli AChE, correlando la loro maggiore durata d'azione.
In generale, gli esteri di colina sono agenti a breve durata d'azione in quanto vengono rapidamente eliminati attraverso le urine.
Gli alcaloidi presenti in natura sono ammine terziarie, ad eccezione della muscarina. Quindi, vengono prontamente assorbiti dal sito di somministrazione, possono attraversare la BBB e vengono eliminati per via renale.
L'acidificazione delle urine può accelerare la clearance degli alcaloidi. Poiché la protonazione delle ammine terziarie riduce la loro lipofilia, l'acidificazione favorisce una rapida eliminazione renale.
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Q1: Why do choline esters have poor oral absorption?
Choline esters, including acetylcholine and its synthetic derivatives, are quaternary amines with a positively charged onium group, making them hydrophilic. This hydrophilic nature prevents them from crossing cell membranes efficiently, resulting in poor oral absorption and inability to penetrate the blood-brain barrier.
Q2: How does the structure of alkaloids differ from choline esters in terms of absorption?
Naturally occurring alkaloids are tertiary amines, except muscarine, making them lipophilic and readily absorbed from administration sites. Unlike hydrophilic choline esters, alkaloids can cross the blood-brain barrier and are eliminated primarily through renal excretion, allowing for systemic distribution and broader therapeutic reach.
Q3: Why is acetylcholine rapidly inactivated in the body?
Acetylcholine, the endogenous choline ester, is rapidly inactivated by acetylcholinesterase enzymes and hydrolyzed into choline and acetate. This rapid breakdown necessitates higher intravenous doses to achieve pharmacological effects and explains why synthetic choline esters, which are more resistant to hydrolysis, have longer durations of action.
Q4: What is the primary route of elimination for direct-acting cholinergic agonists?
Renal excretion is the main elimination route for both choline esters and alkaloids. Acidification of urine accelerates clearance of alkaloids by reducing their lipophilicity through protonation of tertiary amines, promoting rapid renal elimination and significantly shortening drug duration in the body.
Q5: How are direct-acting cholinergic agonists administered therapeutically?
Administration routes vary by drug and therapeutic goal. Acetylcholine is given as ophthalmic drops during eye surgery for miosis, carbachol is topically applied as eye drops for glaucoma, pilocarpine is delivered via ocular insert, and bethanechol is taken orally multiple times daily for postoperative urinary retention affecting the urinary and gastrointestinal tracts.
Q6: Why are synthetic choline esters more stable than acetylcholine?
Synthetic choline esters are relatively resistant to hydrolysis by acetylcholinesterase compared to endogenous acetylcholine. This increased stability correlates with their longer duration of action, though they remain short-acting agents overall due to rapid renal elimination and their hydrophilic nature limiting tissue penetration.
Q7: What makes muscarine structurally unique among alkaloid cholinergic agonists?
Muscarine is the only naturally occurring alkaloid that is a quaternary amine rather than a tertiary amine. This quaternary structure makes it poorly absorbed and hydrophilic, preventing blood-brain barrier penetration, yet it induces toxic effects in the central nervous system through its direct acting cholinergic agonists pharmacological actions.