Anticholinergic drugs

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". Only cholinergic and anticholinergic agents are mentioned by name in the syllabus pharmacopoeia, as it lists only atropine,  glycopyrrolate, neostigmine and organophosphates as The Drugs You Need To Know for this exam. For this reason, the grey box summary below is mainly focused on the pharmacopoeia items:

  • Anticholinergic agents are those that prevent parasympathetic postganglionic neurotransmission; the term is usually used to refer to antimuscarinic agents
  • The list of drugs with anticholinergic properties is vast and includes:
    • Antiparkinsonian drugs (amantadine and benzatropine)
    • Antipsychotics, tricyclic antidepressants, antihistamines
    • Anticonvulstants (carbamazepine), antiemetics (promethazine)
  • Two classical agents are atropine and glycopyrrolate:
Name Atropine Glycopyrrolate
Class Anticholinergic Anticholinergic
Chemistry Tropane alkaloid Tropane alkaloid
Routes of administration Oral, IV, subcutaneous, inhaled, intraocular, and topical on the mucosa Oral, IV, IM, inhaled
Absorption Well absorbed - 90% bioavailability Poorly absorbed; oral bioavailability is only about 3.3%
Solubility pKa 9.7; the sulfate salt is reasonably water-soluble, 1g in 455ml of water pKa 11.53, good water solubility.
Distribution VOD=1-6L/kg; 50% protein bound VOD = 1.3-1.8 L/kg, 38-44% protein bound
Target receptor Both agents have similar affinities for muscarinic receptors (M1-M5), which are mainly Gq-coupled receptors. Glycopyrrolate does not have a chance to bind the M1 receptors because these are mainly found in the CNS.
Metabolism 50% metabolised, mainly by hepatic enzymatic hydrolysis, into a variety of metabolities, including tropane, tropic acid, and noratropine Minimal hepatic metabolism
Elimination 50% is eliminated unchanged About 85% is excreted unchange din the urine
Time course of action Half life is 2-5 hours, but the duration of tissue-specific efects could be longer, eg. mydriasis could last as long as 96 hours Half-life is 2-4 hours
Mechanism of action By compettively blocking the effets of acetylcholine on Gq-coupled muscrinic receptors, both agents decrease the intracellular concentration of ioniased calcium and cAMP. This results in numerous downstream clinical effects.
Clinical effects

- Decreased airway secretions
- Bronchodilation
- Tachycardia
- Urinary retention
- Decreased gastric acid secretion
- Decreased intestinal motility
- Constipation

CNS effects:

- Delirium, hallucinations
- Mydriasis

- Antiemetic effect

- Decreased airway secretions
- Bronchodilation
- Tachycardia
- Urinary retention
- Decreased gastric acid secretion
- Decreased intestinal motility
- Constipation

- No CNS effects!

Single best reference for further information Shutt, 1979 Chabicovsky et al, 2019

Previous appearances in the exam consisted of:

  • Question 19 from the second paper of 2019 (atropine alone)
  • Question 3 from the first paper of 2011 (atropine vs. glycopyrrolate)

In terms of reading to recommend, for a comprehensive resources there is no possible way to surpass Lounasmaa & Tamminen (1993), which is 113 pages of dense tropane pharmacology, enough to elicit mydriasis and xerostomia in even the most interested reader. 

What is an “anticholinergic” drug?

The neurotransmitter acetylcholine being involved in a whole host of neurotransmitter activities, one might think it should be necessary to define which specific of these activities one is antagonising when one refers to drug activity as "anticholinergic".  For example, neuromuscular junction blockers could be viewed as "anticholinergic" drugs if one considers their mechanism of action. IUPAC, wisely perceiving the need to have control over these possibilities, has defined the term in their Glossary for Chemists of Terms Used in Toxicology (Duffus, 1993) as follows:

  1. adj., Preventing transmission of parasympathetic (acetylcholine releasing) nerve impulses.
  2. n., Substance that prevents transmission of parasympathetic nerve impulses

sn: parasympatholytic; producing effects resembling those caused by interruption of the parasympathetic nerve; also called anticholinergic.

In other words, IUPAC would prefer you to not refer to antinicotinic ganglion blockers and paralysing curare toxins as "anticholinergic" because that would be confusing and bizarre. To focus things even further, in common bedside parlance of toxicology the most common use of the term is in reference to agents which act at the muscarinic acetylcholine receptors, and so when one says "anticholinergic", one usually means "antimuscarinic":

  1. n., Substance inhibiting or preventing the actions of muscarine and muscarine-like agents (e.g., atropine) on the muscarinic acetylcholine receptors.
  2. adj., Inhibiting or preventing the actions of muscarine and muscarine-like agents on the muscarinic acetylcholine receptors.

In short, just like with sympathomimetics and sympatholytics, this description embraces all agents that, once administered, make it look like your parasympathetic nervous system has become deactivated; and just like with those others, this sort of an effect could be exerted at multiple levels. At least theoretically. Consider: you can prevent the parasympathetic impulses from ever being generated in the CNS, or you can interrupt ganglionic neurotransmission, or you can prevent the synthesis or storage of acetylcholine, or you can prevent the release of it from presynaptic vesicles; but there are no agents in regular use that do any of these things. The vast majority (well, let's face it, 100%) of agents that do antimuscarinic-appearing things are generally of the "competitive antagonist" category, i.e.

they displace acetylcholine from its receptor binding sites. The exception is probably hemicholinium, which blocks the reuptake of acetylcholine, and which is the only indirect acetylcholine antagonist; but to say that it is in "routine use" would be silly, as this highly toxic substance is mostly involved in research, and besides that the main effect it has on the test animal is neuromuscular junction blockade, and we already promised IUPAC that we would not be talking about that.

Classification of antcholinergic agents

Broadly speaking, anticholinergic (antimuscarinic) drugs can be divided into two large amorphous piles, that being "agents which are used primarily for their anticholinergic effects" and "agents which happen to have pronounced anticholinergic effects but which are intended for some other use".

The latter group is obviously vast and encompasses entire classes of drugs (eg. all "classical" antipsychotics, all tricyclic antidepressants, most older antihistamines, etc). Lertxundi et al (2013) and Chew et al (2008) estimated there might be about 600 such agents. It would obviously be madness to list them all, but a resource like this should probably offer a selection as some kind of minimum, in case some trainee somewhere is asked to list and categorise them. Here is a representative structure from the Toxicology Handbook (3rd ed):

  • Antiparkinsonian drugs
    • Amantadine
    • Benztropine
  • Antihistamines
    • Brompheniramine
    • Chlorpheniramine
    • Cyproheptadine
    • Dexchlorpheniramine
    • Dimenhydrinate
    • Diphenhydramine
    • Doxylamine
    • Pheniramine
    • Promethazine
    • Trimeprazine
  • Antitussives
    • Dextromethorphan
  • Antidepressants
    • Tricyclic antidepressants
  • Antipsychotic agents (butyrophenones and phenothiazines)
    • Chlorpromazine
    • Droperidol
    • Fluphenazine
    • Haloperidol
    • Thioridazine
    • Trifluoperazine
  • Atypical antipsychotic agents
    • Olanzapine
    • Quetiapine
  • Anticonvulsant agents
    • Carbamazepine
  • Motion sickness agents
    • Hyoscine-scopolamine
    • Meclizine
  • Antimuscarinic agents
    • Atropine
    • Hyoscine
    • Glycopyrrolate
  • Topical ophthalmological agents
    • Cyclopentolate
    • Homatropine
    • Tropicamide
  • Urinary antispasmodic agents
    • Oxybutynin
  • Muscle relaxants
    • Cyclobenzaprine
    • Orphenadrine
  • Plants and herbal remedies
    • Selected mushrooms
    • Datura species
    • Numerous other plant-derived compounds

"Selected mushrooms" might sound dismissively unhelpful but the reader is reminded that the editors of the Handbook were entrusted with some limited page space and were trying to squeeze all of toxicology into a portable paper format, whereas Deranged Physiology has limitless space and could digress extensively on every toxic mushroom species ever identified (and in fact this is not done purely out of respect for the reader's time). A more comprehensive list can be found in this appendix to the study by Carnahan et al (2006), and an even more comprehensive pharmacodynamic reference including receptor selectivity and CNS penetration was compiled in a Herculean effort by Lavrador et al (2023).

These links are left here for the unlikely future possibility that somebody will stumble across this chapter in the search for real depth of knowledge or correctly referenced detail. For the CICM First Part Exam candidate, to know even just the headings in the Toxicology Handbook table would be enough. In any case, the examiners have made it clear that they are mainly interested in drugs which are intentionally antocholinergic, i.e. those which we give specifically to for their antimuscarinic effects. These are easier to list and discuss in the traditional ADME fashion, and this is what follows.

Chemistry of anticholinergic agents

The CICM pharmacopoeia only lists atropine and glycopyrrolate, but the intensivist occasionally has cause to use other agents, and yet other agents are occasionally seen in the wild as toxins. 

  • Atropine
  • Benzatropine
  • Ipratropium
  • Glycopyrrolate
  • Hyoscine hydrobromide (scopolamine)
  • Hyoscine butylbromide (Buscopan)

All of these broadly fall into the category of "tropane alkaloids", except for glycopyrrolate which is a quaternary ammonium compound. "Alkaloid" is a name that gets given to some of these naturally derived substances because many of them have an alkaline pH, an archaic term which was first coined by Meissner in 1819 when he published his attempts to accidentally kill himself by tasting the veratridine he purified from seeds of Schoenocaulon officinale. "The material produced in this way... has a burning taste, and causes a scratchy sensation in the throat", he complained, unaware that his sodium channels were being wedged open. It was not alkaline, but it was alkali-like, and so he called it an alkaloid.  That we now apply this term to some heterocyclic naturally occurring basic nitrogen compounds (but arbitrarily not others) is another case of something being too old to safely change.

At least "tropane" is more chemically sound, referring to an wonky uneven seven-carbon ring structure with a nitrogen in the centre. The chemical structures shown here were shamelessly misappropriated from the excellent paper by Grynkiewicz & Gadzikowska (2008).

Fascinating though the structure and function relationships of these molecules may be, it is an aspect that is unlikely to ever yield any marks in the CICM exam, and therefore will not be emphasised here, except to point out a couple of specific points:

  • Hyosciamine (L-atropine) is unstable and is racemised rapidly under normal storage conditions. The atropine seen on Australian shelves is a 1:1 racemic mixture. Of the two stereoisomers, the levo version is the one that has most of the interesting clinical effects. 
  • Benzatropine is a weird frankenmolecule, combining the tropine portion of the atropine molecule and the benzohydryl portion of diphenhydramine. As the result, it is both an anticholinergic and an antihistamine.

Hyoscine or scopolamine? It seems the names of these chemicals stem from the plant they were derived from. The reader is invited to step carefully around that terrible pun and avail themselves of this ancient page from a 1910 medical dictionary that lists Hyosciamus niger, the henbane plant, as the origin of hyoscine, whereas "scopolamine" came from vaguely decorative Scopolia flowers. Scopolamine was isolated from Scopolia japonica by Schmidt in 1850, and according to Henry in The Plant Alkaloids (1939), Schmidt himself later recognised that it was the same thing as hyoscine, and yet here we are over a hundred years later still baffled by this inconsistent naming strategy. To make matters worse, the butylbromide of hyoscine is sometimes referred to as "butylscopolamine", giving rise to the internationally known brand "Buscopan". For international readers, hyoscine hydrobromide is the preferred name outside of the US. 

Absorption and administration of anticholinergic drugs

Of the anticholinergic agents listed in the selection above, three main groups can be identified. Those agents that have delirium-inducing effects on the CNS are usually lipid soluble, and well absorbed through a variety of routes including oral rectal ocular and cutaneous. The agents with lower lipid solubility (eg. glycopyrrolate) are generally limited to IV use, as they will not absorb well. And lastly there are the agents which have purely regional effects, because their absorption is extremely poor, like ipratropium and tiotropium. Solubility is therefore the most important determinant, and this in turn is dictated by the pKa:

Drug Absorption/bioavailability Solubility  
Atropine Well absorbed - 90% oral bioavailability pKa 9.7; the sulfate salt is reasonably water-soluble, 1g in 455ml of water  
Benzatropine Oral bioavailability is about 29%, mostly because of poor and slow absorption pKa 9.54, highly water-soluble, with excellent penetration of the blood brain barrier  
Ipratropium Less than 1% of the inhaled drug dose is absorbed through the bronchial mucosa; minimal oral bioavailability, but because the majority of the administered dose is swallowed 2% of the systemic levels are due to oral absorption pKa is 15.3; highly alkaline drug. Insoluble in lipids, but highly soluble in water. Does not penetrate the blood-brain barrier, unlike atropine.  
Glycopyrrolate Minimal oral bioavailability, 3.3% pKa 11.53, good water solubility.  
Hyoscine hydrobromide
Good absorption but highly variable oral bioavailability, from 10 to 50% pKa 7.55, highly water-soluble salt, whereas the unionised form of the drug itself is highly lipid soluble  
Hyoscine butylbromide (Buscopan) Minimal oral bioavailability, approximately 1%, mostly because of poor lipid solubility pKa 8.1, highly water-soluble  

Notable take-home points from this table include:

  • Atropine and hyoscine hydrobromide have similar lipid solubility when unionised, and at any given time some of each drug does exist in its lipid-soluble form at physiological pH, but because of its higher pKa, atropine has a lower rate of CNS penetration, whereas hyoscine hydrobromide is close to 50% unionised, and is therefore more available to infiltrate the brain and act as a truth serum. In a study comparing the two agents, Mirakhur (1978) found that measurements of pupillary accommodation and salivary secretions were made impossible by the higher doses of hyoscine (1mg IM) because the subjects became drowsy, delirious and uncooperative. 
  • Benzatropine is the absolute king of blood brain barrier penetration, passing to the CNS effect site as rapidly as cocaine, but its main gimmick is the ability to inhibit dopamine reuptake. It would be otherwise just a longer acting vaguely sedating version of atropine.
  • Glycopyrrolate was designed specifically not to penetrate the CNS (Franko & Lunsford, 1959), mainly by modifying it to make it a quaternary amine. 

In fact a major theme in the structural design of these substances is the addition of something that makes them quaternary amines , rendering them permanently charged and therefore water soluble and incapable of penetrating the blood brain barrier. This largely ameliorates all the embarrassing and exciting CNS consequences of these agents. For example:

  • Ipratropium  is a structural analogue of atropine but is a quaternary ammonia compound, which means it has a permanently charged group, with all the solubility and absorption implications associated therewith. To spell it out: ipratropium cannot penetrate the blood-brain barrier and has difficulty crossing biological membranes, which means it is absorbed rather poorly and can be reliably expected to have a localised, topical effect.
  • Hyoscine butylbromide (Buscopan) is also modified by the addition of  butyl group to make it quaternary, and its absorption from the GI tract is so poor that its bioavailability is estimated as 1%, which means it also has a mostly regional effect in the gastrointestinal tract. 
  • Glycopyrrolate, as above.

Metabolism and elimination of anticholinergic drugs

Of the various interesting properties of these drugs, by far the least spectacular are the patterns of their metabolism:

Drug Metabolism and elimination Half-life  
Atropine 50% metabolised, mainly by hepatic enzymatic hydrolysis, into a variety of metabolities, including tropane, tropic acid, and noratropine     50% is eliminated unchanged    Duration of tissue-specific effects could be longer than the half-life, eg. mydriasis could last as long as 96 hours  2-5 hours  
Benzatropine Undergoes minimal hepatic metabolism. Excreted primarily through the urine and bile unchanged.  7 hrs  
Ipratropium 60% is metabolised in the liver into inactive metabolites, and 40% is excreted unchanged in the urine.     Onset is seen within 3-5 minutes of administration, peak response is seen at about 1.5-2 hours, some effect is still seen up to 6 hours after administration. 1.5-3 hrs  
Glycopyrrolate Minimal hepatic metabolism; about 85% of the dose is eliminated unchanged in the urine 2-4 hrs  
Hyoscine hydrobromide
Extensively metabolised by the liver into inactive metabolites    Clearance is almost completely hepatic; only about 2% is eliminated as unchanged drug through the kidneys, even though it is highly water-soluble      9 hrs  
Hyoscine butylbromide (Buscopan) 50% metabolised by the liver, via hydrolysis of the ester bond, into inactive metabolites    Clearance is 50% renal, as unchanged drug, but of an administered oral dose more than 90% will be eliminated unchanged in the faeces. 1-5 hrs  

In short:

  • Hyoscine hydrobromide is extensively metabolised
  • Atropine, ipratopium and hyoscine butylbromide are about 50% metabolised
  • Glycopyrrolate and benzatropine are eliminated mostly unchanged

This could not possibly be an attractive target for examiners and would likely be a pointless culdesac for a trainee with limited time. By far the most interesting feature of these drugs is their physiological effects and their toxicology.

Pharmacodynamics of anticholinergic agents

Conveniently, all the selected agents act on all of the receptors with similar affinity. Borrowing from the exhaustive effort by Labrador et al (2023), the following table of relative receptor affinities can be constructed for the selection of anticholinergic agents in focus:

Drug M1 M2 M3 M4 M5
Atropine +++ +++ +++ +++ +++
Benzatropine +++ +++ +++ +++ +++
Ipratropium +++ +++ +++ +++ +++
Glycopyrrolate +++ +++ +++ +++ +++
Hyoscine hydrobromide
+++ +++ +++ +++ +++
Hyoscine butylbromide (Buscopan) - +++ +++ - -

That's right, three pluses for everything, whatever that means. Well, to be honest Labrador et al did actually specify exactly what that means: their "+++" characterises the highest range of listed binding affinities for each receptor (pKi > 7; pKd > 7; pIC50 > 7; pA2 > 7). For the reader, this means that the physiological effects of these agents are basically all going to be the same, and the main thing that discriminates between them is whether or not they penetrate the blood-brain barrier.

Clinical effects of anticholinergic agents

Anticholinergic being a surrogate term for antimuscarinic, the following table of muscarinic receptor effects is listed here, to simplify revision, and to help the reader imagine the absence of these effects and functions, so they can themselves reconstruct how an antimuscarinic agent might act:

  • M1- Gq protein coupled – second messenger is IP3
    • Involved in cognitive function, eg. memory
    • Increased seizure activity
  • M2- Gi protein coupled – decreases cAMP
    • Miosis (contraction) of the pupillary sphincter muscle
    • Contraction of the ciliary muscle for far vision
    • Lacrimal gland secretion
    • Significant reduction in heart rate
    • Significant reduction in atrial contractility, and shortened action potential duration
    • Significant reduction in the conduction velocity of the AV node
    • Slight decrease in ventricular contractility
    • Increased motility and tone of the stomach
    • Relaxation of gastric sphincters
    • Stimulation of gastric secretion
    • Contraction of the gallbladder
    • Relaxation of the intestinal sphincters, and increased intestinal motility
  • M3- Gq protein coupled – second messenger is IP3
    • Miosis (contraction) of the pupillary sphincter muscle
    • Contraction of the ciliary muscle for far vision
    • Lacrimal gland secretion
    • Salivation and dilation of the salivary ducts
    • Greatly increased nasal mucus secretion
    • Increased production of nitric oxide synthase by the vascular endothelium
    • Increased motility and tone of the stomach
    • Relaxation of gastric sphincters
    • Stimulation of gastric secretion
    • Contraction of the gallbladder
    • Relaxation of the intestinal sphincters, and increased intestinal motility
    • Bladder detrusor muscle contraction, and relaxation of the trigone sphincter
    • Erection
    • Generalised secretion of the sweat glands (not just sweaty palms, but all over)
    • Increased secretion of the pancreatic juice
  • M4- Gi protein coupled – decrease cAMP
    • Inhibition of neurotransmitter release in the CNS
    • Facilitates dopamine release
  • M5- Gq protein coupled – second messenger is IP3
    • Facilitates dopamine release

From this, it therefore follows that:

  • M1 antagonist effects:
    • Amnesia, sedation and delirium
  • M2 antagonist effects:
    • Mydriasis (dilated pupils)
    • Blurry vision (failure of accommodation)
    • Dry eyes (failure of lacrimation)
    • Tachycardia
    • Increased conduction velocity of the AV node
    • Increased ventricular contractility
    • Decreased motility and tone of the stomach
    • Contraction of gastric sphincters
    • Inhibition of gastric secretion
    • Relaxation of the gallbladder
    • Contraction of the intestinal sphincters, and decreased intestinal motility
  • M3 antagonist effects:
    • Mydriasis (dilated pupils)
    • Blurry vision (failure of accommodation)
    • Dry eyes (failure of lacrimation)
    • Xerostomia, due to failure of salivation 
    • Decreased nasal mucus secretion
    • Decreased motility and tone of the stomach
    • Contraction of gastric sphincters
    • Inhibition of gastric secretion
    • Relaxation of the gallbladder
    • Contraction of the intestinal sphincters, and decreased intestinal motility
    • Bladder detrusor muscle relaxation, and contraction of the trigone sphincter
    • Erectile dysfinction
    • Failure of sweating, and therefore impaired thermoregulation
    • Decreased secretion of the pancreatic juice
  • M4 antagonist effects:
    • Increased neurotransmitter release in the CNS
    • Inhibition of dopamine release
  • M5 antagonist effects:
    • Inhibition of dopamine release

The way to use this for exam revision is obviously not "commit this list to memory", because that would probably be insane. A dirty limerick also does not readily present itself as a mnemonic device. Instead, the candidates are redirected to distressing images and classical fables:

  • Mad as a hatter (delirium)
  • Blind as a bat (accommodation, mydriasis)
  • Hot as hell (unable to sweat for thermoregulation)
  • Red as a beet (flushed skin, also because thermoregulation)
  • Dry as a bone (secretory things are inhibited)

The attentive reader will recognise that the majority of these are M1 and M3 effects, which singles out some specific toxidromes over others. The fable itself is ancient and is seen even in papers from the 1960s (though puzzlingly the authors used "mad as a wet hen", which is a midwerstern US colloquialism describing rage rather than delirium). Variations abound, with authorities such as Borough (2016) adding "tachy as a leisure suit.” The origins of these antimuscarinic similes are rather difficult to trace, and could well be older than the 1960s, but the published literature does not reveal this, as presumably the first emergency physician to coin this turn of phrase would not have been immediately compelled to publish an article about it. 


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