cholinergic pharmacology

Category: cholinergic pharmacology (page 1 of 2)

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

Ganglionic blockers versus depolarising NMBAs

May 5, 2021 / phcdgs / 0 Comments

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

May 5, 2021 / phcdgs / 0 Comments

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.

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.

Does nicotine cause sweating?

October 25, 2017 / phcdgs / 0 Comments

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.

Image 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?

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.

Can ipratropium produce bradycardia not tachycardia?

February 25, 2017 / phcdgs / 0 Comments

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.