Category: parasympatholytics

What does “nonselective” muscarinic receptor antagonist mean?

In the context of autonomic system pharmacology, you will often come across drugs described as “nonselective muscarinic antagonists” or “nonselective alpha-adrenoceptor antagonists”. What does “nonselective” mean in this context?

The potential confusion here is that you might think that a “nonselective muscarinic antagonist” is a drug that is not selective for muscarinic receptors and so also acts on other types of receptors (for example, adrenoceptors) at therapeutic doses.  This is not what is meant when these phrases are used in the context of autonomic nervous system pharmacology.

There are many subtypes of muscarinic acetylcholine receptors: M1, M2, M3, M4 and M5 receptors. However, most of the muscarinic cholinergic and anticholinergic drugs in current clinical use are nonselective between the muscarinic receptors subtypes. These drugs are selective for muscarinic receptors over other types of receptor, such as nicotinic acetylcholine receptors or adrenoceptors, but are nonselective between the muscarinic receptor subtypes (M1, M2, M3, M4 and M5 receptors). For example, atropine is a nonselective muscarinic acetylcholine receptor antagonist because it blocks all muscarinic receptor subtypes: M1, M2, M3, M4 and M5 receptors.  But atropine is selective for muscarinic acetylcholine receptors over other classes of receptor, such as nicotinic acetylcholine receptors.

Likewise, there are many subtypes of adrenoceptors: α1A-, α1B-, α1D-, α2A-, α2B-, α2C-, β1-, β2– and β3-adrenoceptors. Many of the adrenergic and antiadrenergic drugs in current clinical use target alpha- or beta-adrenoceptors but are nonselective between the subtypes of alpha or beta receptors. For example, oxymetazoline is selective for alpha-adrenoceptors over beta-adrenoceptors but may be described as a nonselective alpha-adrenoceptor agonist because it is largely nonselective between α1A-, α1B-, α1D-, α2A-, α2B– and α2C-adrenoceptors.

How does atropine cause flushing?

Atropine can cause patients to become “as red as a beet” due to superficial vasodilation. How does atropine cause this flushing response? 

At toxic doses, and even occasionally therapeutic doses, atropine can cause dilation of cutaneous blood vessels resulting in an atropine flush. This reaction, making the patient “as red as a beet”, is well recognised as a classical sign of atropine overdose.

Atropine is a muscarinic receptor antagonist. Muscarinic receptors are involved in controlling the dilation of some blood vessels (see Sympathetic cholinergic innervation of blood vessels? Not in humans) but they are not known to be important for control of superficial cutaneous blood vessels.  It has therefore been something of a mystery why atropine should cause flushing. The mechanisms by which atropine causes this “anomalous vascular response” have therefore long been debated.

One hypothesis is that the response is due to the fact that atropine has alpha-adrenoceptor antagonist effects at very high doses (1). Antagonism of alpha adrenoceptors could block alpha-adrenoceptor-mediated vasoconstriction resulting in vasodilation and flushing. However, the more widely accepted explanation in recent years has been that the flushing is secondary to overheating due to block of sweating. Antagonism of M3 receptors on sweat glands will block the sweating response. This will cause overheating and compensatory superficial cutaneous vasodilation to increase heat loss.

Reference:
(1) Chang KC, Hahn KH. (1995) Is alpha-adrenoceptor blockade responsible for atropine flush? Eur J Pharmacol. 1995 Sep 25;284(3):331-4.

Can parasympatholytics cause nausea and vomiting?

Why are nausea and vomiting reported as adverse effects of some parasympatholytics, such as oxybutynin, when nausea and vomiting are known to be parasympathomimetic adverse effects, and muscarinic antagonists can be used to treat nausea and vomiting? 

Parasympathomimetics often cause nausea and vomiting. Increased stimulation of muscarinic receptors in the gastrointestinal tract leads to increased secretion and motility, which can trigger nausea and vomiting.  Perhaps more importantly, activation of muscarinic cholinergic receptors, in particular, M1 receptors, in the vestibular nuclei, the nucleus of the solitary tract and the vomiting centre can directly activate the CNS pathways triggering nausea and vomiting. Hence, muscarinic receptor antagonists, such as scopolamine (hyoscine), can be used to prevent nausea and vomiting.

As muscarinic antagonists can be used to treat nausea and vomiting, it can be confusing that some parasympatholytics, such as oxybutynin, are reported to cause nausea and vomiting.  Oxybutynin is a muscarinic antagonist. It can be used to treat urinary incontinence. Historically it was also important for treatment of peptic ulcers although now it is rarely used for this indication as we have better drugs such as H2 receptor antagonists (for example, cimetidine) and proton pump inhibitors (PPIs)  (for example, omeprazole).  However, the fact that oxybutynin can be used to treat peptic ulcers reminds us that this drug blocks M1 receptors on the enterochromaffin-like cells in the stomach and prevents gastric acid secretion. The nonselective muscarinic antagonism of oxybutynin also blocks secretions and motility all along the gastrointestinal tract. These effects can lead to delayed gastric emptying.  The delayed gastric emptying leads to nausea and vomiting.

© 2024 PharmaNUS

Theme by Anders NorenUp ↑

Skip to toolbar