Category: anticholinergics

Ganglionic blockers versus depolarising NMBAs

High-dose nicotine induces depolarising blockade and subsequent secondary non-depolarising blockade at autonomic ganglia. Meanwhile, depolarising NMBAs induce depolarising block consisting of Phase I and Phase II. Is it the same thing?

Yes, they are essentially the same mechanisms as far as the nicotinic receptors go. It is primarily a difference in terminology. Although secondary non-depolarising block is a more scientifically descriptive term than Phase II, the depolarising NMBAs are already called “depolarising” to contrast with the non-depolarising NMBAs (direct nicotinic receptor antagonists). It would therefore be confusing to say that depolarising NMBAs have a secondary non-depolarising block. Hence, the common usage of the Phase I and Phase II terminology.

Depolarising versus non-depolarising NMBAs

What is the difference between a depolarising and a non-depolarising NMBA? Do both result in flaccid paralysis?

Depolarising neuromuscular blocking agents (NMBAs) are potent agonists at nicotinic receptors that cause depolarising block (and necessarily also the secondary desensitising/non-depolarising block). In contrast, non-depolarising NMBAs are direct competitive nicotinic receptor antagonists.

An important difference is that non-depolarising NMBAs can be reversed by increasing acetylcholine (ACh) levels by using an acetylcholinesterase inhibitor such as neostigmine. Depolarising NMBAs cannot be reversed in the same way since increasing ACh availability just causes more depolarizing block (and inevitably secondary desensitising/non-depolarising block).

As depolarising NMBAs initially cause activation, they will cause twitching/fasciculation followed by rigid paralysis on onset (although this phase is over quickly) before switching to flaccid paralysis. In contrast, non-depolarising NMBAs will go straight to progressive flaccid paralysis.

Can ipratropium produce bradycardia not tachycardia?

Ipratropium is a muscarinic antagonist used as a bronchodilator in the treatment of chronic obstructive pulmonary disease and asthma. Parasympathetic nervous system activation of M2 receptors in the heart slows the heart but the adverse effects of the muscarinic receptor antagonist, ipratropium, reported by patients can include bradycardia (slowing of the heart). How is this possible?

The parasympathetic nervous innervation of the heart releases acetylcholine, which acts at M2 receptors to slow the heart rate. Thus, muscarinic acetylcholine receptors antagonists, such as atropine, are expected to induce tachycardia (increase the heart rate).  Indeed, they do this at high doses. However, there is a balance between the sympathetic and parasympathetic branches of our autonomic nervous system. If we block the parasympathetic nervous system with a muscarinic receptor antagonist, such as atropine, our body tries to compensate by down-regulating the sympathetic nervous system.  With low doses of muscarinic receptor antagonists, this compensatory down-regulation of the sympathetic nervous system can be sufficient or even overshoot resulting in bradycardia. However, at higher doses of muscarinic receptor antagonists, the compensatory effect is no longer enough, and the parasympatholytic tachycardia dominates.

When delivered by inhalation for the relief of bronchoconstriction, very little ipratropium escapes into the systemic circulation. Thus, the doses reaching the heart are low doses. The compensatory mechanism is in action, and we may see compensatory bradycardia rather than tachycardia. In fact, in normal clinical use, so little inhaled ipratropium escapes into the systemic circulation that even bradycardia is a rare side effect. Of course, in patients with other risk factors, at higher doses, or if administered orally, we need to look out for the risk of tachycardia.

Why is succinylcholine considered an “indirect” anticholinergic?

Succinylcholine is a direct nicotinic receptor agonist but is used clinically as an indirect anticholinergic. 

Succinylcholine (suxamethonium) is a highly potent agonist at the neuromuscular junction (NMJ) nicotinic acetylcholine receptors.  It is a direct cholinergic agonist in that it binds to the same binding site as the endogenous transmitter acetylcholine and activates the receptor in the same manner as acetylcholine. In contrast, non-depolarising neuromuscular blocking agents (NMBAs), such as pancuronium, are direct antagonists at NMJ nicotinic acetylcholine receptors. NMBAs are direct anticholinergics and can be used to produce paralysis when required under surgical anaesthesia.

In the context of autonomic pharmacology, indirect agonist effects are any effects mimicking the effect of the endogenous transmitter and other direct agonists not caused by direct agonism at the receptor. Conversely, indirect antagonist effects are any effects mimicking the effect of direct antagonists not caused by direct antagonism at the receptor.

Although it is a direct agonist of nicotinic acetylcholine receptors, clinically succinylcholine is used as an indirect anticholinergic to block the action of nicotinic acetylcholine receptors at the NMJ causing paralysis when required under surgical anaesthesia. The paralysis is caused because succinylcholine activates the nicotinic acetylcholine receptors so intensely that depolarising block occurs (Phase I) followed by desensitising block (Phase II).  The clinically desired paralysis mimics the direct anticholinergic effect of the NMBAs but is produced indirectly via the depolarising block and desensitising block secondary to direct agonism at the receptor. Therefore, succinylcholine is an indirect anticholinergic.

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.

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