Cholinergic drugs and acetylcholinesterase inhibitors

This chapter is relevant to Section M2(i) of the 2023 CICM Primary Syllabus, which says that we expect the exam candidates to “understand the pharmacology of drugs acting upon the autonomic nervous system”, but really means "know the anticholinergic agents and acetylcholinesterase inhibitors". Only cholinergic and anticholinergic agents are mentioned by name in the syllabus pharmacopea, as it lists only atropine,  glycopyrrolate, neostigmine and organophosphates as The Drugs You Need To Know for this exam. Moreover, observing the past exam papers, a trend is established:

• Question 14 from the second paper of 2018 asked about a classification of anticholinesterase drugs, with examples
• Question 21 from the first paper of 2015 asked for the pharmacodynamic effects and indications for anticholinesterase drugs
• Question 8(p.2) from the first paper of 2008 asked about the management of organophosphate poisoning

As the result, neostigmine and the organophosphates are the stars of the following show.  Management of organophosphate poisoning now seems to have become consigned to the Second Part Exam along with all the other toxicology, but an extensive discussion of oxime pharmacology would surely drain the patience of even the most devoted Second Part exam candidate, and it ended up here,  there being nowhere else to put it. In general it is unfortunate that any discussion of this group of drugs ends up inevitably crossing some fascinating toxicological material, and the returning reader will not be surprised that the authors' best intentions to keep the narrative simple and the language professional would have completely surrendered to the exploration of nerve gas ethnography and the culinary properties of toxic mushrooms.  

In summary,

In terms of reading to recommend, the "Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system" by Wehrwein et al (2016) is probably the best single reference, even though it is massive (because the reasonable person will find it easy to limit themselves to the specific cholinergic section). There is no other generic paper that would cover all the possible drugs that directly or indirectly stimulate the parasympathetic nervous system, and the obsessive pursuit of  exotic fragmentary knowledge had guided the author into such forsaken cavities of deep cholinergic lore as Hayes' Handbook of Pesticide Toxicology and the Nuremberg trials. Some bare minimum of self-editing does mean that the reader was hopefully spared from the worst of the resulting garbage, as most of it was irrelevant even according to the severely corroded attitudes and values of this website, but some may have inevitably spilled into what follows.

What is a "cholinergic” drug?

Oddly, the term is not used as widely as "anticholinergic", and the IUPAC Glossary for Chemists of Terms Used in Toxicology (Duffus, 1993) does not contain this word, even though they have the more unwieldy alternatives "parasympathomimetic" and "cholinomimetic", which are:

"Producing effects resembling those caused by stimulation of the parasympathetic nervous system"

The main reason for this must surely be the relative rarity of agents that produce an agonist effect at these receptors. Consider the extensive range of tropane alkaloids and non-tropane drugs that cause anticholinergic effects (i.e. seemingly everything ever prescribed to the older person) and contrast this with the paltry list of agents that act as direct muscarinic agonists, or therapeutically relevant "indirect cholinomimetics" like acetylcholinesterase inhibitors. This statement is an excellent segue into an attempt to create this paltry list, and to somehow classify it into meaningful categories.

Classification of parasympathomimetic (cholinergic?) agents

Why would anyone even do that? Reader, they made you do it in Question 14 from the second paper of 2018, where the stem asked to "classify anticholinesterase drugs according to chemical interaction with an example of each". Fortunately, it should not be difficult to improve on the performance of that trainee cohort, as "many candidates who scored poorly confused anticholinesterase drugs with anticholinergic drugs". Unfortunately, these agents lack a widely accepted classification system, and for many there is no agreement what to call them, which means any literature search expedition looking for class-level definitions and taxonomies for these agents runs aground fairly early, beached by the frustration of the searcher. The best one can do is divide them into groups according to where in the neurotransmission pathway they act, which could be simplified even further into a binary "direct and indirect" division. However, simplifying classification schema is not what we do here at Deranged Physiology, and so what follows is a mutant version of the classification scheme offered by Wehrwein et al (2016), adjusted to contain only the cholinergic agents:

Some of the agents mentioned in this list will have no further airtime here and were added mainly for completeness or to facilitate an amusing digression in the following text. For example, including latrotoxin from the venom of widow spiders (and allocating an entire classification taxon to include it) was wastefully indulgent and should not be encouraged.  In any case latrotoxin forms membrane pores that flood all presynaptic terminals with calcium, and so facilitates the exocytosis of all neurotransmitters (not just acetylcholine), which means it is not unique to cholinergic transmission and probably does not even belong in the autonomic nervous system section (as the most concerning features of latrodectism are related to the neuromuscular effects). 

In short, the reader preparing for any sort of exams will appreciate the esoterica being ejected from this chapter, or at least confined to clearly bounded stretches of easily skipped text. The list of agents used to compare pharmacological properties will therefore be truncated to only what is commonly seen in human use and abuse:

Drug	Classification	Uses and indications
Nicotine	Nicotinic receptor agonist	Annoying the people who walk past the entrances of hospitals and office buildings; postcoital; establishing a noir vibe;  decreasing the size of a foetus.
Pilocarpine	Muscarinic receptor agonist	Glaucoma
Neostigmine	Acetylcholinesterase inhibitor	Prokinetic
Physostigmine	Acetylcholinesterase inhibitor	Reversal of anticholinergic delirium
Pyridostigmine	Acetylcholinesterase inhibitor	Myasthenia gravis
Rivastigmine	Acetylcholinesterase inhibitor	Dementia
Donepezil	Acetylcholinesterase inhibitor	Dementia
Chlorpyrifos	Acetylcholinesterase inhibitor	Insecticide
Sarin	Acetylcholinesterase inhibitor	Failure of diplomacy

Chlorpyrifos was chosen from among the many possible organophosphate pesticides because it is still occasionally seen in agricultural use in Australia. Incidentally, this Victorian government website was an excellent resource for finding organophosphates which might still be available in this country, though many have been banned or nerfed by the AVPMA. The choice of sarin and nicotine from among the many possible nerve agents was based mostly on their wide cultural footprint, as both are well-known and highly potent neurotoxins with strong government support. In general, including nicotine in this page was entirely worthwhile because there would have been nowhere else to put it, and it would have been a pity to omit it because literally none of the other pharmacologically active agents discussed in Deranged Physiology, apart perhaps from ethyl alcohol, have had the same sort of effect on the health of the human species.  

Which brings the question: if nicotine and its tickling of the nicotinic receptors is so popular, why not muscarine? How have Clitocybe and Inocybe escaped becoming ubiquitous in culture, hanging from the lips of actresses to epitomise cool? Well, the bioavailability of muscarine is fairly low, and where one consumes enough to be awesome, the effects are not exactly sultry or cinematographically attractive (salivation, twitching, sweating, diarrhoea), which has probably limited the popularity of this substance, and reduced the exposure of critical care staff to patients suffering its effects. However, it would not have been appropriate to carry on with the constant use of the term muscarinic without at least once digressing on the topic of muscarine.

Chemistry of cholinergic agents

A group as chemically diverse as this is difficult to characterise in the same way as, for example, neuromuscular junction blockers or local anaesthetics might be characterised. All one may do is offer some chemical tidbit to help the reader anchor each agent in their mind as a representative member of its chemical family. In this fashion:

• Nicotine can be presented as a "natural alkaloid", shivering at the vagueness of the term. Hesse (2002) classified it as one of the "true" alkaloids, as it originates from an amino acid (ornithine). It hard to call it anything else because it is otherwise a somewhat nondescript molecule comprising of two nitrogen-containing rings (a pyridine and a pyrrolidine). It has the odd distinction of being one of the few liquid alkaloids extractable from plants, all the others generally presenting as a solid. 
• Pilocarpine is also an alkaloid, except this one is an imidazole derivative, and is extracted from Pilocarpus pennatifolius, an aromatic evergreen shrub.
• Of the 'stigmines only physostigmine can officially be called an alkaloid as it is extracted from the dried beans of the Physostigma venenosum plant. The rest would have to be called carbamates, specifically aryl carbamates (derived from carbamic acid).  Interestingly, though it might seem sensible and convenient to refer to the group as "the stigmines", it appears the only person in the literature who has done so was Zeev (2006). Of these agents, physostigmine is the original, and the others (neostigmine and pyridostigmine) are quaternary ammonium compounds created to be more water-soluble and therefore unable to penetrate the blood brain barrier.
• Donepezil is specifically designed to penetrate the blood brain barrier, as the main objective of using it is to improve memory in patients with dementia. "Designed" being an operative term here, because it was created by modifying benzyl piperidine (a molecule with some acetylcholinesterase inhibitor activity) until it possessed the specific activity properties that Eisai Co., Ltd were looking for. 
• Chlorpyrifos is a representative member of the organophosphate compounds and is an irreversible  inhibitor of acetylcholinesterase.  There are literally hundreds if not thousands of related compounds and the interested reader who needs to know everything about them is redirected to the excellent chapter by Gupta (2006). They are mostly used as pesticides or antiparasitics, though it appears that most of them are sufficiently toxic to humans that they could just as easily be reclassified as agents of chemical warfare.
• Sarin, and VX for that matter, are these organophosphate compounds that just happen to have the right kind of history and physicochemical characteristics that give them military rather than agricultural market potential.  Sarin is a phosphonofluoridate and VX is an S-substuted phosphonothioate, i.e. esthers of phosphonic acid (H₃PO₃) which incorporate either fluoride or sulfur, made most desirable by the combined properties of high boiling point (158 ºC for sarin) but also high volatility (22g/m³ at 25 ºC for sarin). The ability to persist in an environment while continuously giving off toxic vapour makes them attractive "terrain denial" agents, intended to be left in a place through which enemy thoroughfare will henceforth be impossible.

It would probably be both predictable and undesirable to digress here about the naming of these drugs, but for some people nomenclature may play a role in remembering other details, and so the author will permit himself a departure from what would otherwise be a sober account of chemistry. For the "stigmine" drugs, the stem of the word comes from stigma, a biologist's name for the female sex organs of a flowering plant. Physostigma is so named because of its supposedly hollow stigma, physo  meaning "bubble" or "bladder". Physostigmine was therefore the logical choice for the name of the alkaloid derived from this plant after the botanical source was "discovered" by a Scottish missionary in Nigeria, where the Ibibio had used it for probably thousands of years. This Reverend Thompson, in 1864, wrote of duels where:

"It is customary for the challenger to bite the bean in two, consume his half, and hand the other to his opponent, who is obliged to eat it up."  

The effect was occasionally immediately fatal: the Reverend reported that "one (bean) being halved between a brace of infatuated duellists had cut both off". The effects was clearly pharmacologically very impressive, as some survived purely because "the poison so iritates the stomach and bowels as to be completely ejected". When Aeschlimann & Reinert (1931) explored a series of its chemical relatives, pursuing the possibility that they might all have some similar effect on miosis and peristalsis, the result which Aeschlimann ultimately patented in 1933 was originally referred to as "prostigmine", and appears to have became known as "neostigmine" at some point during the 1940s, though the reasons for this are not clearly articulated anywhere, nor did the name "prostigmine" completely disappear (being listed as interchangeable with neostigmine as recently as 2002).

Pyridostigmine is at least named clearly from its chemical formula, as it is a pyridine analogue of neostigmine which was first synthesised in 1945 (initially thought to be useless because they severely underdosed their first patients). The main advantage of this agent over neostigmine was the longer duration of action (the side effects, on closer examination, being roughly similar between the two). The development of rivastigmine in the 1980s followed this trend, as the drug is a "pseudoirreversible" inhibitor of acetylcholinesterase with a greatly increased duration of action. Exactly what "riva" means is not clear from any literature (is it the same as the "riva" in "rivaroxaban"?) and the only possible explanation is that it is a derivative. 

Whereas the naming of medicinal anticholinesterases can be traced back to botany, the chemistry and nomenclature of organophosphate and battle-carbamate compounds, in general, seem to be tied to the industry, be it agricultural or the military/industrial complex. The original inventors would have to be Willy Lange and his graduate student Gerda Kruger (1932) because they were the first to note that their ester der monofluorphosphorsäure was hideously toxic:

“the fumes of these compounds have a pleasant, slightly aromatic odor. But a few minutes after inhalation there is a feeling of pressure to the larynx and difficulty in breathing. Then a disturbance of consciousness develops, as well as blurred vision and a painful oversensitivity of the eyes to light. Only after several hours do the problems wear off"

This was dimethyl and diethyl phosphorofluoridate.  Lange was apparently not Aryan enough, and  ended up having his authorization to teach at the University of Berlin withdrawn by the Nazis (this being 1937), but the research was carried on by Gerhard Schrader whose political affiliations were probably more conventional.  His group worked for the I.G. Farbenindustrie (a dye and pesticide cartel) which, like all chemical corporations, readily transformed into a monster under the right conditions and (apart from creating nerve gas) became responsible for such charming activities as using Auschwitz inmates as slave labour for its synthetic oil and rubber industry. Needless to say those members of their board who did not appear immediately useful to the Allies ended up trialled and executed, whereas the others become elected to the supervisory board of Bayer.  

Absorption and administration of cholinergic drugs

Short notes on this would merely consist of the statement that all of these drugs have reasonably good absorption and oral bioavailability, with the exception of "stigmine" drugs, among which only rivastigmine is well absorbed. All of the others are easily able to find their way into the systemic circulation irrespective of how they are presented. Notably, organophosphates can be absorbed in lethal quantities even through the exposed surface of the eyes.

Drug	Routes of administration	Absorption
Nicotine	Oral, IV, IM, inhaled	Well absorbed through mucosal surfaces; oral bioavailability is around 44%. The increase in pH of a solution causes an increase in the concentration of uncharged lipophilic nicotine which can easily traverse membranes.
Pilocarpine	Eyedrops, but also orally	Probably good oral bioavailability, as it undergoes little hepatic metabolism; whereas ocular bioavailability is surprisingly poor for a predominantly ocular agent (1-3%)
Neostigmine	IV or oral	Poor absorption and high firsty pass metabolism; minimal oral bioavailability (less than 5%)
Physostigmine	IV or oral	Poor absorption and high firsty pass metabolism; minimal oral bioavailability (2-3%)
Pyridostigmine	Oral	Poor absorption and high first pass metabolism; minimal oral bioavailability (10%)
Rivastigmine	Oral or transdermal	Completely absorbed, 40% oral bioavailability
Donepezil	Oral	100% oral bioavailability
Chlorpyrifos	Absorbed via contact with anything	100% oral bioavailability, and generally absorbed rapidly via any route, including dermal ocular and inhaled.
Sarin	Absorbed via contact with anything
VX	Absorbed via contact with anything

 Less short notes:

• Nicotine has surprisingly good oral bioavailability, according to studies of radiolabeled oral nicotine capsules by Benowitz et al (1991), who found their 3-6mg doses delivered 1-2mg of nicotine to the systemic circulation (roughly equivalent to one cigarette). This means it would be theoretically possibly to simply eat your cigarettes, and though most people would agree that it is sexier to smoke them, oral toxicity from tobacco is known among children and idiotic adults.
• Pilocarpine should have reasonably good bioavailability, as it has reasonably poor hepatic metabolism. It has been used orally in the treatment of xerostomia with some success, and the investigators reported reasonably high plasma concentrations and substantial systemic effects. 
• Most of the 'stigmines  are minimally bioavailable after oral administration. For example, pyridostigmine is minimally absorbed (bioavailability 10%) and neostigmine is even worse (5%), which means sufferers of myasthenia gravis need to take large amounts to achieve their systemic effects.  According to Aquilonius & Hartvig (1986), this is partly because of poor lipid solubility, which makes these drugs reluctant to absorb across the gut mucosa, as well as due to high first-pass metabolism. The famously CNS-active physostigmine has only 3% oral bioavailability, which means the original Calabar bean brew used for witch trials in east Nigeria was probably incredibly potent. Rivastigmine, in contrast, has comparatively good bioavailability (40%), and is completely absorbed.
• Donepezil has excellent oral bioavailability (most authors confidently report 100%)
• Organophosphates have excellent oral bioavailability, with most commercially available pesticides reported to have 100%, and at least 30% bioavailability.
• Nerve gas agents like sarin and VX are absorbed rapidly no matter what human tissue they are offered, and are sufficiently toxic via skin contact that ungloved rescuers are warned against touching victims who may be eluting clinically significant quantities of the agent off their body surfaces.

Solubility and distribution of cholinergic agents

Drug	pKa and solubility	Volume of distribution and protein binding
Nicotine	Nicotine has two pKa values, the pyrrolidine ring has a pKa of 8.10 and the pyridine ring has a pKa of 3.41. It is lipophilic but water-miscible; about 69% ionized and 31% unionized at physiological pH.	VOD = 2.6 L/kg, less than 5% protein-bound
Pilocarpine	pKa 6.6, good water solubility, poor lipid solubility	VOD = 2.3L/kg, minimally protein-bound
Neostigmine	pKa=12.0; good water solubility, minimal lipid solubility	VOD=0.12 L/kg; 15-25% protein-bound
Physostigmine	pKa= 7.9, good water and lipid solubility, about 75% ionised at physiological pH	VOD = 0.6-0.7L/kg, 29% to 43% protein-bound
Pyridostigmine	pKa=14, highly water-soluble but minimal fat solubility	VOD = 0.53 to 1.76 L/kg, minimally protein-bound
Rivastigmine	pKa = 8.85, good solubility in both water and lipid	VOD = 1.8-2.7 L/kg, minimally protein bound
Donepezil	pKa = 8.9, good solubility in both water and lipid	VOD=12L/kg, 96% protein bound
Chlorpyrifos	pKa = 4.55; poor water solubility (like most organophosphates)	VOD= 9L/kg; highly protein bound (>99%)
Sarin	pKa = 8.89; excellent water and lipid solubility	VOD probably about 1L/kg, probably minimally protein bound
VX	pKa = 7.9; excellent water and lipid solubility	VOD probably about 1L/kg, probably minimally protein bound

Vague generalisations can be made, namely:

• Most of these drugs have good water solubility, and less good fat solubility, with the exception of agents intended for CNS penetration such as physostigmine and donepezil.
• Organophosphates are generally poorly water-soluble, which makes sense because commercially available pesticides should reliably stick to plants and not be washed away with watering. Their high lipophilicity makes them highly protein-bound and gives them a huge volume of distribution, which makes them less susceptible to removal by dialysis.
• In general, the pharmacokinetics of military nerve gas agents are difficult to study because of their tendency to stop circulation, but sublethal doses administered to animals seem to suggest a small volume of distribution. For some reason, Whalley et al. (2007) represented their VOD in grams instead of ml or L, but their guinea pig data seems to suggest a Vss of around 280g in guinea pigs weighing between 248 and 343 g, corresponding to a VOD of around 1L/kg.

Metabolism and elimination of cholinergic agents

Elimination of cholinergic agents is perhaps their least interesting property:

Drug	Metabolism	Elimination	Half life
Nicotine	Extensively metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6)	minimal renal elimination	Half life is ~ 2 hrs
Pilocarpine	Minimal hepatic metabolism; mostly metabolised to pilocarpic acid by serum esterases and acetylcholinesterase in the synaptic cleft	minimal renal elimination	Elimination half-life of approximately 0.76–1.3 h
Neostigmine	Slowly hydrolysed by acetylcholinesterase and also by non-specific plasma esterases	About 70% is eliminated in the urine unchanged	Half-life ~70 minutes, duration of action 20-30 minutes
Physostigmine	Very rapid first pass metabolism; 90% of physostigmine is metabolised by the liver within 2 min of administration	minimal renal elimination	Elimination half-life of 20–30 min
Pyridostigmine	90% metabolised, both by liver enzymes and by plasma esterases	10% is eliminated unchanged in the urine	Half life 1.5-4.5 hrs
Rivastigmine	Rapidly hydrolysed by esterases, with minimal involvement by the liver	minimal renal elimination	Half-life 1.4-1.7 hrs (duration of effect is closer to 10 hours)
Donepezil	Small fraction etabolised in the liver; mostly eliminated unchanged via the urine	50-70% is eliminated renally as unchanged drug	Half-life ~ 80 hours
Chlorpyrifos	Mostly metabolism by CYP 540 enzymes (CYP1A2 and CYP2B6)	minimal renal elimination	Half-life of 27 hours
Sarin	Rapidly and completely metabolised by plasma esterase	minimal renal elimination	Half-life of 3.7 hrs
VX	Rapidly and completely metabolised by plasma esterase	minimal renal elimination	Half-life of several hours

The most important thing to remember here is that the elimination half-lives of many of these agents are totally unrelated to the duration of their effect. This is most relevant to the organophosphate compounds and nerve gas agents which are irreversible inhibitors of acetylcholinesterase. The resulting effects can persist for weeks. A therapeutic example of this is rivastigmine: the drug is "officially" cleared by hepatic and plasma enzymes over the course of an hour, but the pharmacological effect lasts for at least ten hours because in the synapse rivastigmine is hydrolysed to form a carbamoyl derivative which leaves the active site of acetylcholinesterase very slowly.

Pharmacodynamics of cholinergic agents

The broadest shortest explanation of how  these work can be expressed as follows:

• Direct nicotinic agonists (eg. nicotine) act on nicotinic receptors, which are pentameric transmembrane cation channels, and the effect is usually to depolarise the target cell. 
• Direct muscarinic agonists (eg. pilocarpine) act on muscarinic receptors, which are either G_i or G_q protein coupled receptors. The downstream effect is mediated by decreasing cAMP for the former and increasing IP3 for the latter.
• Indirect cholinergic agents increase the concentration of acetycholine in the synapse by inhibiting acetylcholinesterase, which they can do reversibly (eg. the stigmines) or irreversibly (eg. organophosphates and nerve gas agents)

The effects of direct muscarinic agents is obviously going to the effect of activating muscarinic receptors, and it seems pointless to reproduce this list here. In any case, for no real chemical reason true direct cholinergic agents are few, and not used in clinical medicine beyond what is required to manipulate the iris and anterior chamber. It would therefore be more interesting to discuss the action of "ganglionic agonists" such as nicotine, and the effects of acetylcholinesterase inhibitors.

Clinical effects of nicotinic receptor agonists 

Nicotine would have to be the topic of discussion here, there being no other agent even remotely like it in the repertoire of critical care. Of course as soon as you have a receptor there will be pharma companies marketing an agonist to activate it, but nothing is really relevant to the world of ICU here, or even to emergency medicine or anaesthesia, except perhaps where it intersects in a meta sense, where critical care staff try to give up smoking using varenicline. Lobeline, a naturally occurring alkaloid from the Lobelia family of plants, is a non-addicitive nicotinic agonist, was at one stage popular as an "analeptic", an unscientific term used to describe a drug with nonspecific health-restorative properties, listed alongside caffeine (which is genuinely restorative and frankly lifesaving) but also alongside strychnine, atropine, picrotoxin and nikethamide. The purpose of these agents was mostly used to increase the respiratory effort or to improve the level of consciousness of patients who had presented with overdoses of sedatives, and the most vigorous use of these was during the earlier parts of the 20th century, when intubation and mechanical ventilation were not a commonplace response to unconsciousness. These substances, though of low toxicity, have been relegated to the wastebin of history by the advent of well-developed intensive care services; whereas ironically the popularity of the much more toxic nicotine had remained evergreen.

Nicotine acts on a variety of nicotinic receptors scattered throughout the CNS and the autonomic nervous system, and it would probably be pointless to try to tease out each individual receptor effect because there are so many subtypes available. Plus the classify-or-die environment of the CICM exams does call for some kind of a structure. Thus, if one were ever asked to "outline the physiological effects of nicotine", one could do worse than this:

• Postganglionic cholinergic neurons:
  • Nicotine has a parasympathomimetic effect, mediated by downstream muscarinic receptors.
  • This manifests clinically as:
    • Increased gastric acid secretion
    • Bronchoconstriction
    • Intestinal sphincter relaxation
    • Increased bowel motility
• Postganglionic sympathetic neurons:
  • By acting on acetylcholine-gated nicotinic cation channels, nicotine depolarises sympathetic postganglionic fibres, resulting in noradrenaline release. In this fashion, nicotine acts as a sympathomimetic.
  • This effect also mediates systemic adrenaline and noradrenaline release from chromaffin cells of the adrenal medulla
  • The net clinical effects of this are therefore mostly sympathomimetic:
    • Increased blood pressure and heart rate
    • Cutaneous vasoconstriction
    • Increase in plasma free fatty acids
    • Hyperglycemia

Overall, the net effects of ganglionic stimulation by nicotine are sympathomimetic. It is actually remarkably difficult to find the literature that deals with the pharmacology of nicotine directly, or to separate it from the literature concerned with the physiological effects of smoking. The sympathomimetic stuff comes from Haass & Kübler (1997) and the parasympathetic stuff from Comroe (1960).

Clinical effects of acetylcholinesterase inhibitors: the "cholinergic toxidrome"

This is much more relevant to critical care staff, as the effects of acetylcholinesterase inhibitor toxicity are usually serious enough to land the patient in the ICU and make them the subject of everyone's efforts for the entire night shift. "SLUDGEM" or "DUMBBELLS" are the mnemonics used to describe the most clinically obvious muscarinic effects:

• SLUDGEM:
  • Salivation
  • Lacrimation
  • Urination
  • Diarrhoea
  • GI cramping
  • Emesis
  • Miosis
• DUMBBELLS:
  • Diarrhoea
  • Urination (i.e. increased bladder tone, reduced bladder sphincter tone)
  • Miosis
  • Bradycardia
  • Bronchospasm
  • Emesis
  • Lacrimation
  • Lethargy
  • Salivation

But this covers only the muscarinic effects. Acetylcholinesterase is omnipresent and acetylcholine is a neurotransmitter with numerous physiological roles. An excess of acetylcholine also leads to ganglionic stimulation, central nervous system effects, and finally neuromuscular effects:

• Nicotinic ganglionic effects, which mostly manifest as sympathetic:
  • Hypertension
  • Mydriasis
  • Sweating
  • Tachycardia
• CNS effects
  • Agitation or depression
  • Decreased level of consciousness
  • Coma
  • Seizures
• Neuromuscular effects
  • Depolarising blockade; muscle paralysis

The onset of these effects obviously varies depending on the agent, route of administration, and dose. Acetylcholinesterase is everywhere and one might expect that a large dose might be required to antagonise enough of it to produce symptoms, but in fact only 0.22mcg/kg of novichok is required to produce the symptom of death. 

Acetylcholinesterase inhibitor "aging" or "maturation"

Some acetylcholinesterase inhibitors distinguish themselves from the rest by becoming irreversible with time. This means that the inhibition of acetylcholinesterase may be reversible initially, but may become irreversible as the bond between the drug and the enzyme "ages". This phenomenon is due to the dealkylation of the alkoxyl group of the residue bound to the enzyme, and is different for each agent, with some creating such a bond almost immediately (eg. the nerve gas soman,w hcih ages over 5 minutes), and others remaining relatively reversible over hours (eg. VX, which remains susceptible to reversal by pralidoxime for over forty hours).