Anticholinergic Toxicity (Anticholinergic Syndrome)

What anticholinergic drugs do

Acetylcholine controls the "rest and digest" functions: it slows the heart, makes saliva, sweat and tears, moves the gut, empties the bladder and narrows the pupils. In the brain it supports memory and attention. Anticholinergic drugs block its muscarinic receptors. In normal doses that is how they dry a runny nose, calm an overactive bladder or help sleep. In excess, they shut these functions down.

Symptoms: the classic toxidrome

Medical students learn a memory aid:

Other signs:

• fast heartbeat (tachycardia), often the earliest sign
• reduced or absent bowel sounds and constipation
• mumbling speech, picking at the air or clothes, and visual hallucinations (often of insects or people)
• muscle twitching, and in severe cases seizures, coma, dangerous heart rhythms, very high body temperature and muscle breakdown

Dry armpits and skin help tell anticholinergic toxicity from stimulant poisoning or serotonin syndrome, in which people sweat heavily.

Causes

Medicines

• Sedating antihistamines: diphenhydramine (in many sleep aids and allergy products), doxylamine, hydroxyzine, chlorpheniramine
• Tricyclic antidepressants: amitriptyline, nortriptyline, imipramine. These also cause dangerous heart rhythm problems and seizures in overdose.
• Antipsychotics: olanzapine, quetiapine, chlorpromazine, clozapine
• Bladder medicines: oxybutynin, tolterodine
• Parkinson's and movement disorder drugs: benztropine, trihexyphenidyl
• Muscle relaxants: cyclobenzaprine
• Antispasmodics and motion sickness drugs: dicyclomine, hyoscyamine, scopolamine patches
• Eye drops such as atropine and cyclopentolate, especially in small children

Plants and other sources

• Jimsonweed (Datura), angel's trumpet and deadly nightshade, sometimes deliberately ingested for hallucinations
• Contaminated herbal products and some illicit drugs

Cumulative anticholinergic burden

Older adults can develop slower-onset toxicity by taking several moderately anticholinergic medicines together. It shows up as confusion, delirium, constipation, urinary retention and falls. The American Geriatrics Society Beers Criteria advise avoiding many strongly anticholinergic drugs in older adults.

Diagnosis

The diagnosis is made clinically from the pattern of signs and a history of exposure. Doctors also:

• check heart rhythm with an ECG, looking for a wide QRS complex that signals tricyclic or diphenhydramine sodium-channel toxicity
• measure blood glucose, electrolytes, kidney function and creatine kinase
• check acetaminophen (paracetamol) and aspirin levels, since many combination products contain them
• use a bladder scan to detect retention
• rule out other causes of delirium and fever, such as infection, heat stroke, alcohol withdrawal, and neuroleptic malignant syndrome

Treatment

Treatment takes place in hospital:

• Supportive care: monitoring of breathing, heart rhythm and temperature, intravenous fluids, and a quiet, low-stimulation environment
• Benzodiazepines for agitation and seizures. Antipsychotics are usually avoided because many are anticholinergic themselves
• Cooling for high temperature
• Urinary catheter for retention
• Activated charcoal in selected patients soon after ingestion, if they can protect their airway
• Sodium bicarbonate for wide QRS complexes or heart rhythm problems from tricyclics or diphenhydramine
• Physostigmine: an antidote that temporarily restores acetylcholine activity. It can rapidly clear delirium in pure anticholinergic poisoning. It is given by experienced clinicians with heart monitoring, and avoided when tricyclic toxicity with ECG changes is suspected

Symptoms usually resolve within 1 to 3 days, though delirium can last longer after large overdoses or long-acting drugs.

Prevention

• check labels: many sleep aids and "PM" pain relievers contain diphenhydramine
• do not combine several antihistamine or sleep products
• store all medicines, including eye drops and patches, out of children's reach
• older adults should have a regular medication review to reduce anticholinergic burden
• be aware that social media "challenges" involving large doses of diphenhydramine have caused deaths in teenagers

Frequently asked questions

What are the symptoms of anticholinergic toxicity?

Typical symptoms are hot, dry, flushed skin, dry mouth, large pupils with blurred vision, a fast heartbeat, fever, urine retention, constipation, and confusion, agitation or hallucinations. Severe cases can cause seizures, dangerous heart rhythms and coma.

What does "mad as a hatter, red as a beet" mean?

It is a memory aid for the anticholinergic toxidrome: hot as a hare (fever), dry as a bone (no sweating), red as a beet (flushed skin), blind as a bat (dilated pupils), mad as a hatter (delirium) and full as a flask (urine retention).

Which common medicines can cause anticholinergic toxicity?

Diphenhydramine and doxylamine in sleep aids and allergy products are the most common. Others include tricyclic antidepressants, some antipsychotics, bladder medicines like oxybutynin, cyclobenzaprine, benztropine, scopolamine patches and atropine eye drops.

How is anticholinergic poisoning treated?

It is treated in hospital with monitoring, fluids, cooling, benzodiazepines for agitation or seizures, and a catheter for urine retention. Sodium bicarbonate treats certain heart rhythm problems. In selected cases, the antidote physostigmine can reverse delirium quickly.

How long does anticholinergic toxicity last?

Most people recover within 24 to 72 hours, depending on the drug, the dose and the person's age. Delirium can last longer, especially with long-acting medicines, large overdoses, or in older adults.