5.8
Direkt wirkende cholinerge Agonisten: Pharmakokinetik
Direkt wirkende cholinerge Agonisten, wie synthetische Cholinester und natürlich vorkommende Alkaloide, entfalten ihre Wirkung durch die Verstärkung d…
Denken Sie daran, dass direkt wirkende cholinerge Agonisten die Wirkung von ACh nachahmen und als Cholinester und Alkaloide kategorisiert werden.
Cholinester – einschließlich ACh und seiner synthetischen Derivate – sind als quartäre Amine von Natur aus hydrophil. Sie haben also eine schlechte orale Absorption und überwinden die Blut-Hirn-Schranke oder BHS nicht.
ACh – der endogene Cholinester – wird durch AChE schnell inaktiviert und zu Cholin und Acetat hydrolysiert. Infolgedessen ist eine höhere i.v. Dosis unerlässlich, um seine pharmakologische Wirkung zu induzieren.
Synthetische Cholinester sind relativ stabiler und resistenter gegen Hydrolyse durch AChE, was mit ihrer längeren Wirkungsdauer korreliert.
Generell sind Cholinester kurzwirksame Mittel, da sie schnell über den Urin ausgeschieden werden.
Bei den natürlich vorkommenden Alkaloiden handelt es sich um tertiäre Amine, mit Ausnahme von Muskarin. So werden sie leicht von der Verabreichungsstelle resorbiert, können die BHS passieren und werden über die Niere ausgeschieden.
Eine Ansäuerung des Urins kann die Beseitigung von Alkaloiden beschleunigen. Da die Protonierung von tertiären Aminen deren Lipophilie verringert, fördert die Ansäuerung eine schnelle renale Ausscheidung.
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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.