parasymapthomimetics

Category: parasymapthomimetics

Why are peripheral effects of AChE inhibitors predominantly parasympathomimetic?

Acetylcholinesterase (AChE) inhibitors will prevent the breakdown of acetylcholine (ACh) and so increase ACh levels. Increased ACh levels at autonomic nervous system ganglia should activate both the sympathetic and parasympathetic nervous systems. However, the adverse effects of AChE inhibitors outside of the CNS are mostly parasympathomimetic. Why do AChE inhibitors not stimulate the sympathetic nervous system as well?

Acetylcholinesterase (AChE) inhibitors increase the concentration of acetylcholine (ACh) at synapses by blocking its breakdown. This will activate both the sympathetic and parasympathetic systems, as the preganglionic neurons in both systems release ACh.

However, the impact of AChE inhibitors is more prominent on the parasympathetic nervous system for several reasons:
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When sympathetic and parasympathetic systems collide: The dominance of excitatory effects

August 30, 2023 / phcdgs / 0 Comments

When the autonomic nervous system ganglia are activated (for example, by low-dose nicotine), both the sympathetic and parasympathetic nervous system innervations of target organs and tissues are simultaneously stimulated. However, the “fright, fight or flight” sympathetic and “rest and digest” parasympathetic nervous systems have opposing effects in most target organs and tissues. So why do the sympathetic and parasympathetic nervous systems not just cancel each other out when activated at the same time?

It is true that in the realm of autonomic nervous system functioning, the sympathetic and parasympathetic systems often represent two sides of the same coin. These systems largely produce opposing effects on the same target organs and tissues. However, what happens when both systems are simultaneously activated? Contrary to intuitive thinking, they don’t simply cancel each other out. Instead, the dominion of activation or excitatory effects takes centre stage.

The Principle of Dominant Excitation: When both the sympathetic and parasympathetic systems are co-activated, it isn’t a zero-sum game. Rather than neutralizing each other, the excitatory effects from each system generally prevail. This principle is observed in a variety of physiological contexts. Continue reading

Neostigmine versus pyridostigmine

February 22, 2020 / phcdgs / 0 Comments

What is the preferred oral acetylcholinesterase inhibitor for myasthenia gravis?

Pyridostigmine is often preferred to neostigmine for myasthenia gravis for three reasons:

(1) The onset of the effect of oral pyridostigmine (approximately 45 minutes) is faster than that for neostigmine (approximately 4 hours). The speedier onset allows for more precise adjustment of the dosing schedule around daily living activities to ensure as much muscle function as possible when required.

(2) The half-life of pyridostigmine (approximately 90 to 110 minutes) is longer than that for neostigmine (approximately 50 to 90 minutes). The difference is not great, but when the patient has to take the drug multiple times in a day, it is an advantage that 3 or 4 times per day is often sufficient with pyridostigmine.

(2) Pyridostigmine is about four times less potent than neostigmine. That is right, being less potent is an advantage because it is easier to titrate the dose to a level that controls the motor symptoms without causing too many adverse effects. This is especially important in the early stages of the disease when the motor symptoms are less pronounced.

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

October 25, 2017 / phcdgs / 0 Comments

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.

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

October 25, 2017 / phcdgs / 5 Comments

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?

March 2, 2017 / phcdgs / 0 Comments

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.

What does “nonselective” muscarinic receptor antagonist mean?

February 25, 2017 / phcdgs / 0 Comments

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: α_1A-, α_1B-, α_1D-, α_2A-, α_2B-, α_2C-, 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 α_1A-, α_1B-, α_1D-, α_2A-, α_2B– and α_2C-adrenoceptors.

Can parasympatholytics cause nausea and vomiting?

February 25, 2017 / phcdgs / 0 Comments

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.

VX Nerve Agent

February 24, 2017 / phcdgs / 0 Comments

VX nerve agent, which has been in the news lately with the killing of Kim Jong-nam, is another example of an organophosphate anticholinesterase.

The newspapers and other media have recently reported that it was the VX nerve agent that was used to kill Kim Jong-nam, the half-brother of North Korea’s leader, in Malaysia. VX nerve agent is an example of an organophosphate anticholinesterase. Other examples of organophosphate anticholinesterases include the chemical weapon sarin and the organophosphate insecticides such as a malathion.

VX (S-2 Diisoprophylaminoethyl methylphosphonothiolate) is one of the most toxic nerve agent known. It is especially insidious as it is a highly viscous, tasteless and odourless liquid that can easily be transferred via clothing to be absorbed into the body by inhalation, ingestion, skin contact, or eye contact.

Although more potent and fast-acting, the effects of VX poisoning would be the same as for any organophosphate anticholinesterase. Inhibition of acetylcholinesterase will result in increased levels of acetylcholine at all cholinergic synapses in the body.

Sympathetic cholinergic innervation of blood vessels? Not in humans.

February 7, 2017 / phcdgs / 0 Comments

Exceptions to the general rule that the sympathetic nervous system is adrenergic include cholinergic innervation of sweat glands expressing M3 receptors and dopaminergic innervation of the renal blood vessels expressing D1 receptors. But what about the arteries of skeletal muscle?

Parasympathetic cholinergic fibres innervate some blood vessels. In arterial blood vessels, the release of acetylcholine activates M3 receptors on the vascular endothelium, which are coupled to formation of nitric oxide (NO) that produces vasodilation (1). However, if the synthesis of NO is inhibited, the activation of M3 and M2 receptors can produce vasoconstriction. In contrast, cerebral arteries express M5 receptors, which produce vasodilation in response to acetylcholine (1).

In cats and dogs, some of the arterial blood vessels in skeletal muscle are innervated by sympathetic cholinergic nerves that release acetylcholine, which acts at M3 receptors to produce vasodilation (1). In these species, the sympathetic nervous system innervation of the arterial blood vessel in skeletal muscle appears to play a role in active hyperaemia, increasing blood flow to the muscle at the start of exercise (1).

In contrast to cats and dogs, humans do not have sympathetic cholinergic innervation of arterial blood vessels in skeletal muscle (1).

Reference:
(1) Richard E Klabunde Cardiovascular Physiology Concepts: Adrenergic and Cholinergic Receptors in Blood Vessels http://www.cvphysiology.com/Blood%20Pressure/BP010b [Accessed 7 Feb 2017]