anticholinesterases

Category: anticholinesterases

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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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.

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.