Category: MDG5238 (page 3 of 4)

Does nicotine cause sweating?

The eccrine sweat glands express muscarinic M3 cholinergic receptors. In an exception to the usual rule that the postganglionic neurotransmitter for the sympathetic nervous system is noradrenaline or adrenaline, the sympathetic nervous system innervates the eccrine sweat glands with cholinergic nerve fibres.  Thus, sweating associated with the fight-or-flight response is a sympathetic nervous system response mediated by cholinergic activation of M3 receptors.

But does nicotine not also cause sweating? Nicotine can contribute to sweating in a number of ways. The preganglionic nerve fibres of both the sympathetic and parasympathetic nervous system are cholinergic release acetylcholine to activate nicotinic cholinergic receptors on the ganglionic neurones. Thus nicotine can directly activate the ganglionic neurones triggering activation of the cholinergic postganglionic sympathetic nervous system innervation of the eccrine sweat glands.

The nerve terminals innervating the sweat glands also have presynaptic nicotinic receptors. Application of acetylcholine or nicotine to the skin will activate these nerve terminals triggering action potentials to branches of the nerve innervating adjacent sweat glands to release acetylcholine and activate postsynaptic M3 receptors on these sweat glands.  This is referred to as the sudomotor axon reflex.

sudomotorImage credit: http://www.medicavisie.eu/de/technologien/#sudomotor

Note that to acheive activation of nicotinic receptors exposure to nicotine has to be at a low dose and for a short duration. High doses of nicotine or prolonged exposure to nicotine can lead to depolarising and desensitising block of nicotinic receptor neurotransmission.

How long is the window before ageing of acetylcholinesterase after organophosphate poisoning?

Organophosphates essentially irreversibly inhibit acetylcholinesterase by leaving a phosphate group bound to the enzyme. Oximes, such as pralidoxime, reversibly bind to acetylcholinesterase and have high affinity for binding to phosphate groups. They can, therefore, bind to acetylcholinesterase, pick up the phosphate group inhibiting the acetylcholinesterase, and take the phosphate group with them when they leave the acetylcholinesterase. Thus pralidoxime can be used to regenerate acetylcholinesterase after organophosphate poisoning.

A limitation of pralidoxime is that it is only effective in a limited time window before ageing of the organophosphate inhibition of acetylcholinesterase occurs. Pralidoxime itself binds to and competitively inhibits acetylcholinesterase. Therefore, if pralidoxime is administered after all the organophosphate-inhibited acetylcholinesterase has already aged, pralidoxime will just make the anticholinesterase poisoning worse. It is therefore important to administer pralidoxime in the appropriate time window.

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How can I remember the adverse effects of over-activation of the parasympathetic nervous system?

The adverse effects of over-activation of the parasympathetic nervous system, for example by poisoning with an acetylcholinesterase inhibitor, can be remembered by the following mnemonic, SLUDGE/BBB:

Salivation
Lacrimation
Urination or urinary incontinence
Defecation or diarrhoea
Gastrointestinal distress
Emesis
/
Bradycardia
Bronchoconstriction
Bronchorrhoea

Alternatively, you can use the mnemonic, DUMBELS:

Defecation or diarrhoea
Urination or urinary incontinence
Miosis
Bradycardia / Bronchoconstriction / Bronchorrhoea
Emesis
Lacrimation
Salivation

Why does it matter that neostigmine is resistant to hydration or hydrolysis?

Why do we say that neostigmine inhibition of acetylcholinesterase is resistant to hydration or hydrolysis? Why do some textbooks say resistant to hydration, while others say resistant to hydrolysis? Are hydration and hydrolysis the same thing? 

Neostigmine is an example of a carbamate anticholinesterase.  It inhibits the breakdown of acetylcholine by acetylcholinesterase and so increases the availability of synaptic acetylcholine wherever it is release.  Clinically it is used to reverse non-depolarizing neuromuscular blockade (e.g. coming out of surgical anaesthesia) and in the treatment of myasthenia gravis.  It is also sometimes used to increase gastrointestinal motility on postoperative or neurogenic ileus and in the treatment of urinary retention secondary to bladder atony.

Acetylcholinesterase works by rapidly hydrolyzing acetylcholine (which is an ester of acetic acid and choline) to acetic acid and choline. Carbamate esters competitively inhibit acetylcholinesterase by occupying the active site on the enzyme and taking much longer to be hydrolyzed.  They work by forming a carbamoylated acetylcholinesterase-drug complex that is resistant to hydration and hence is resistant to hydrolysis.

Hydration and hydrolysis are not the same thing. Hydration is the addition of water (H2O) whereas hydrolysis is the breaking of a bond by reaction with water. However, in the case of the carbamoyl group attached to acetylcholinesterase the hydrolysis is a two-step process: first requiring hydration (addition of the water) before hydrolysis (breaking of the bond between the carbamoyl group and the acetylcholinesterase). Hence, for the carbamate anticholinesterase inhibition of acetylcholinesterase, the resistance to hydrolysis is a consequence of resistance to hydration.

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.

Side effects, adverse effects and contraindications

What is the difference between side effects, adverse effects and contraindications?

The terms “side effects” and “adverse effects” are often used interchangeably.  This may be correct in many contexts, but the two terms do not mean exactly the same thing.

Side effects are effects seen on the side in clinical use. These effects occur at clinical therapeutic doses. Side effects encompass any effects that are not the intended clinical effect of the drug, whether or not these effects are harmful or adverse.

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Alpha adrenoceptor agonists and reflex bradycardia

Phenylephrine and oxymetazoline can increase blood pressure and at the same time cause bradycardia.

Phenylephrine is a selective alpha-1 adrenoceptor agonist while oxymetazoline is a non-selective alpha adrenoceptor agonist. You are likely to most commonly come across phenylephrine and oxymetazoline in their us as nasal decongestants. Acting as agonists at the alpha adrenoceptors on blood vessels, they can vasoconstrict the blood vessels of the nasal mucosa. Phenylephrine can also be administered as eye drops to produce mydriasis (dilation of the pupil) without cycloplegia (paralysis of the ciliary muscle of the eye resulting in loss of accommodation and blurred near vision).  In contrast, muscarinic receptor antagonists, such as cyclopentolate, produce both mydriasis and cycloplegia.

The vasoconstriction caused by the alpha adrenoceptor agonists increases blood pressure. In fact, phenylephrine is also used as a vasopressor to treat hypotension. Our baroreceptors constantly monitor blood pressure and trigger reflex bradycardia as a compensatory measure when they detect increases in blood pressure. Thus phenylephrine and oxymetazoline are associated with increases in blood pressure and reflex bradycardia.

When treating hypotension, phenylephrine is most useful as a choice of drug for hypotensive patients who are tachycardic. Other vasopressors that increase the heart rate and force via beta-1 adrenoceptor activation, such as dopamine, adrenaline and noradrenaline, would be more likely used for hypotensive patients with normal heart rates or bradycardia.

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