Anticholinergic toxicity, to varying degrees, is seen relatively frequently in toxicology patients. The main clinical challenge is the safe management of the delirium which occurs due to central anticholinergic effects.

The mainstay of treatment is supportive care, whilst time is allowed for the toxicity to resolve; however, patients frequently require sedation and antidotal therapy with physostigmine/rivastigmine for both their own and staff safety.

There are many drugs and natural substances that have anticholinergic effects.

Pure anticholinergic agents include:

• Atropine
• Benzatropine
• Hyoscine

Drugs with anticholinergic effects include:

• Antihistamines
• Tri-cyclic antidepressants
• Antipsychotics e.g. quetiapine, olanzapine

Plants with anticholinergic effects include:

• Brugmansia species
• Atropa belladonnna
• Datura stamonium

Angel's Trumpet (Brugmansia), Belladonna, Datura

Agents causing antichoinergic toxicity, do so by blocking the muscarinic acetylcholine receptors in the autonomic and central nervous system. This is a competative blockade, which becomes important when understanding the role of acetylcholinesterase inhibitors in its treatment.

It is the blockade at the central muscarinic-1 (M1) receptors that is most important in driving the delirium.

Synape showing role of acetylcholine, the acetylcholine receptor and acetylcholinesterase

The anticholinergic toxidrome consists of both central and peripheral effects. It is common for the peripheral effects to abate before the central effects, meaning that later in the course of the toxidrome, patients may present with delirium as the main or sole effect.

Most anticholinergic toxicity seen in clinical practive, results from ingestion of agents with multiple receptor effects (as apposed to pure anticholinergics) this may also lead to clouding of the classic toxidrome - a common example being miosis in a patient suffering from an anticholinergice delirium secondary to olanzapine or quetipaine, due to their alpha blocking effects.

• Peripheral effects include - dry skin/mouth, mydriasis, tachycardia, urinary retention, ileus, raised temperature (more connomly seen in children).
• Central effects include - confusion, picking movements, agitation, aggression, delirium, sedation, hallucination (mainly visual), seizure (less frequently)

Image depicting the classical anticholinergic effects

The amin management challenge is the control of the delirium which is often accompanied by agiation and aggression. Agents that cause anticholinergic delirium often also cause sedation and the delirium may only become apparent once the sedation begins to resolve - in ICU this is a common resason for delayed extbation in this patient group.

Supportive care

• Manage patients in a low stimulus environment, with appropriate nursing support
• Urinary retention can be a potent drive of agitation, so seek and relieve by placement of a urinary catheter
• Ensure adequate hydration is maintained

Antidotal theralpy: Anticholinesterase inhibitors

Anticholinesterase inhibitors slow the breakdown of acetylcholine in the synaptic cleft, The resultant increase in synaptic acetylcholine levels can outcompete the competitive bloackade of the anticholinergic agent and restore cholinergic tone.

Physostigmine is a parenteral agent that was used frequently in the past with reported high efficacy at controlling anticholinergic delirium. Its use fell out of favour following reports of deterioration and mortality following its use in serveral tri-cyclic antidepressant overdoses.

On more recent review of these cases, it is evident that these patients were suffering with severe sodium channel blockage and required treatment of this, with alkalinisation and intubation, and it was the lack of providing this that led to their deterioration, rather than the provision of physostigmine.

Treatment of achicholinergic delirium with anticholinesterase inhibitors has been shown to both reverse the delirium and control agitation, far better then sedation alone. Their use should be avoided in patients with bronchospasm or bradycardia. Use:

• Physostigmine 0.5mg (Child: 0.01mg/kg up to 0.5mg) intravenously by slow push. Repeat every 15mins if there is no or patial response. Maximum 2mg (Child: 1mg) within any 60min period.

The effects often dissipate before the drug toxicity and repeat doses may be needed every 1-2 hours, alternatively, if the patient is able to tolerate orally (after intial response to physostigmine), rivastigmine tablets can be used, which have a longer duration of action. Use:

• Rivastigmine: 6-9mg orally, every 6 hours.

Rivastigmine is also available as a transdermal patch, which can be used in those that are not able to take the oral preparation, however its effects are less reliable with a slow onset of action and prolonged offset due to a depot effect in the skin.

These agents are not always easily available, in particular physostigmine is only available via Special Access Scheme (SAS) in Australia.

Note: Neostigmine and pyridostigmine (which are readily available) do not cross the blood-brain barrier and are of no use in treating anticholinergic delirium.

Sedation

Sedation may be required as a sole treatment (if physostimine is not available) or as an adjunct to anticholinesterase therapy - particularly in mixed ingestions or ingestion of agents with multiple receptor effects.

In those with mild symptoms, oral sedation may be adequate to contol behaviour. Use:

• Diazepam 5-20mg (Child: 0.2mg/kg up to 10mg). Repeat after 20min if required.

In those with severe symptoms, particularly when physostigmine is not available, parenteral sedation is often required. Options include:

• Droperidol 10mg (Child 0.2mg/kg max 10mg) intravenousely or intramuscularly, repeat at 10mins if requried. Max 20mg for a single even, 30mg in 24hours.
• Midazolam 2.5-5mg intravenously (child: 0.05-0.1mg/kg up to 5mg), repeat every 3-5 mins until sedated but rousable.

Note: Guidelines often advise to avoid droperidol due to its percieved anticholinergic effects worsening the delirium. Droperidol has minimal effects at the central M-1 receptor so this is not a concern. Olanzapine, another drug commonly used in agitated patients, however does have effects at this receptor and should be avoided.

1. Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000;35(4):374-381. doi:10.1016/S0196-0644(00)70057-6. PDF
2. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - theory, evidence and practice. Br J Clin Pharmacol 2016;81(3):516–24. PDF
3. Chiew AL, Holford AG, Chan BSH, Isoardi KZ. Rivastigmine for the management of anticholinergic delirium. Clin Toxicol (Phila). 2024 Feb;62(2):82-87. doi: 10.1080/15563650.2024.2319854. Epub 2024 Mar 11. PMID: 38465631. PDF