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Toxidromes


Essentials

Anticholinergic (anti-muscarinic) toxic syndrome

Anticholinergic toxic syndrome (ACTS) occurs as a result of the blockade of post-synaptic muscarinic receptors and/or a reduction or inhibition of cholinergic transmission at muscarinic receptor sites by drugs.

Serotonin toxicity

Clonus (spontaneous, inducible and ocular) can be diagnostic of serotonin toxicity (ST) once a serotonergic agent ingestion/toxicity has been identified.

  • 1

    The interaction of selective serotonin reuptake inhibitors (SSRIs) with monoamine oxidase inhibitors can be lethal and may require aggressive treatment.

  • 2

    Dopamine agonists (e.g. bromocriptine, used to treat neuroleptic malignant syndrome [NMS]) can have dual receptor action (5-HT and dopamine agonist) and can worsen ST.

  • 3

    In combination with other serotonergic drugs, fluoxetine can cause ST up to 5 weeks after its cessation.

  • 4

    Patients should be monitored for ST, which is based on clinical findings of particular clonus and hyperreflexia

Sympathomimetic toxicity

  • 1

    The salient features of a sympathomimetic toxidrome include agitation, repetitive movements, delirium, pressured speech, hypertension, tachycardia and hyperthermia. Complications can result in end-organ toxicity in almost all organ system in the body.

  • 2

    Tachycardia accompanied by diaphoresis or increased bowel sounds points to adrenergic toxicity, whereas tachycardia accompanied by decreased sweating, absent bowel sounds and urinary retention is likely to be a sign of anticholinergic toxicity.

  • 3

    Patients on monoamine oxidase inhibitors (MAOIs) or bupropion are at greater risk of adrenergic toxicity with lower doses of stimulants.

  • 4

    Management is based on supportive care, benzodiazepines, and the exclusion of end-organ injury. Hyperthermia must be identified and managed.

Cholinergic toxicity

  • 1

    Cholinergic toxicity can result from overstimulation of the acetylcholine (ACh) receptors nicotinic and muscarinic receptors or from a total increase in cholinergic transmission.

  • 2

    Clinical manifestations of nicotine toxicity are those of nicotinic cholinergic excess, most commonly including vomiting and agitation. Severe poisoning may cause seizures, cardiac arrhythmias, hypotension, neuromuscular over-excitation and subsequent neurotransmitter depletion, with muscular paralysis leading to respiratory failure.

  • 3

    Muscarinic agonists produce bradycardia, miosis, salivation, lacrimation, vomiting, diarrhoea, bronchospasm, bronchorrhea and micturition. However, central muscarinic agonists produce sedation, extrapyramidal dystonias, rigidity, coma and convulsions.

  • 4

    Management is mainly supportive, including advanced life support. Atropine, fluids and acetylcholinesterase (AChE) reactivator may be used for significant organophosphate toxicity.

Anticholinergic (anti-muscarinic) toxic syndrome

General notes

Anticholinergic toxic syndrome (ACTS) occurs owing to the blockade of post-synaptic muscarinic receptors and/or the reduction or inhibition of cholinergic transmission at muscarinic receptor sites by drugs. ACTS can occur as a part of alkaloid-containing plant ingestion or associated with multiple classes of medication in both acute overdose or chronic ingestion in special populations. The result is central and peripheral clinical effects that are a consequence of relative cholinergic deficiency at the muscarinic receptors.

Mechanism and associated clinical signs

Symptoms of ACTS have classically been described as ‘mad as a hatter, blind as a bat, red as a beet, hot as a hare, dry as a bone’. The most commonly observed peripheral effects in clinical practice include dry mucous membranes, tachycardia, urinary retention, blurred vision, reduced gastrointestinal (GI) motility (ileus) and fever. However great pharmacodynamic variation can be observed among the peripheral signs. Mechanisms for fever include decreased heat loss (due to absent sweating), increased heat production (due to agitation and activity) and central nervous system (CNS) dopamine mediated temperature dysregulation.

Central symptoms are predominantly agitation, confusion and hallucinations.

High-risk populations

  • Those with co-ingestion of other agents or agents with multiple receptor actions (e.g. antipsychotics, antihistamines)

  • Geriatric populations, due to altered kinetics, but also due to decreased central cholinergic capacity

  • Infants and children with trisomy 21,who have an increased sensitivity to anticholinergic drugs

  • Individuals with any organic CNS disease (e.g. Parkinson disease, dementia, psychiatric illnesses)

Compounds

Over 600 compounds, most of which are medications, have anticholinergic properties. See Box 25.21.1 .

Box 25.21.1
List of agents with anticholinergic properties (not comprehensive)

Antipsychotics

  • Olanzapine

  • Acepromazine

  • Aceprometazine

  • Fluphenazine

  • Levomepromazine

  • Periciazine

  • Thioproperazine

  • Thioridazine

  • Clozapine

  • Chlorpromazine

  • Quetiapine

Gastrointestinal/urinary antispasmodics

  • Aconite

  • Belladonna alkaloids

  • Buzepide metiodide

  • Solifenacin

  • Clidinium bromide

  • Homatropine methylbromide

  • Hyoscyamine

  • Isopropamide iodide

  • Oxybutynin

  • Prozapine

  • Tiemonium

H1-antihistamines

  • Chlorpheniramine

  • Clocinizine

  • Cyproheptadine

  • Dexchlorpheniramine

  • Diphenhydramine

  • Doxylamine

  • Hydroxyzine

  • Meclozine

  • Mequitazine

  • Oxomemazine

  • Phenyltoloxamine

  • Promethazine

  • Dimenhydrinate

  • Pizotifene

Bronchodilators

  • Ipratropium bromide

  • Oxitropium bromide

  • Antiemetics

  • Metopimazine

Tricyclic antidepressants

  • Amitriptyline—single and combination products

  • Amoxapine

  • Clomipramine

  • Desipramine

  • Dosulepin

  • Imipramine

  • Maprotiline

  • Nortriptyline

  • Opipramol

  • Trimipramine

  • Doxepin

  • Nortriptyline

Antiparkinsonian anticholinergics

  • Orphenadrine

  • Trihexyphenidyl

  • Benztropine

Plants

  • Angel trumpet (Brugmansia)

Dose relationship

There is a dose/response relationship between toxicity and the severity of symptoms at presentation. Patients may present to medical attention without peripheral symptoms (these having resolved early after ingestion) and have predominant persistent central symptoms such as delirium or agitation.

Prognostic indicators

Outcomes associated with pure ACTS are favourable, with mortality being extremely unusual. However, this toxidrome is seldom seen in isolation. Complications may be observed as a result of the associated cardiac or central nervous system ion channel effects, or the presence of co-ingestants. For example in tricyclic antidepressant toxicity mortality is as a result of cardiovascular toxicity rather than anticholingeric effects.

The presence of fever, which correlates with larger ingestions, has been shown to be a poor prognostic indicator.

The CNS symptoms and delirium associated with anticholinergic drugs have been graded based on a severity score ( Table 25.21.1 ).

Table 25.21.1
Scale for grading the severity of central nervous system stimulation
(From Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med . 2000;35(4): 374–381, with permission.)
Severity score Clinical findings
0 Relaxed, cooperative
1 Anxious, irritable, tremulous
2 Intermittently or mildly disoriented, confused, and hallucinating; moderate agitation and motor hyperactivity
3 Incomprehensible speech, marked agitation and motor hyperactivity (requiring restraints)
4 Seizures, deep coma (unresponsive to voice or pain)
CNS , Central nervous system

Management

In the case of large-dose toxic ingestions where there is a high probability of delirium developing (e.g. with sedating antihistamines), early administration of charcoal (within 2 hours) has been shown to reduce the risk of secondary delirium.

CNS symptoms of agitation and delirium often require pharmacological intervention. AchE inhibitors increase acetylcholine (ACh) concentrations at both muscarinic and nicotinic receptors, leading to the reversal of muscarinic blockade. In ACTS, AchE inhibitors are used to reverse agitation and delirium with the benefit of restoring GI motility. The risk of seizures with AChE administration is less than 1%. Despite the large clinical variation in the use and dosing of AchE inhibitors in anticholinergic delirium, there is now well-documented evidence for their role in moderate to severe ACTS delirium. Although most studies describe the use of physostigmine, there have also been case reports of other AChEs (such as donepezil and galantamine) demonstrating efficacy in the management of delirium.

Mild (severity score 0–1)

  • Benzodiazepines: limited use for agitation only

    • Monitoring required for respiratory depression/worsening of delirium

Moderate to severe (severity score 2–4)

  • Droperidol

    • 10 to 20 mg for severe agitated delirium

  • Reversal of toxicity is achieved by increasing ACh levels with

    • Physostigmine

      • Dose: 0.5 to 1 mg IV titrated to response (i.e. observe for reversal of delirium every 15 minutes). The most effective approach is to start with low doses and increase incrementally to response (slowly). Higher doses will start to cause nicotinic stimulation and lead to unwanted effects.

      • The best response (83% to 100%) is seen with drugs that have pure anticholinergic action.

      • Half-life of duration of response is 100 minutes.

      • Potential complications include pro-convulsant effects (seizures ∼1%), cholinergic toxicity due to excessive treatment and cardiotoxicity (brady/tachycardia).

      • Contraindications : (relative) asthma, cardiotoxicity (wide QRS complex or bradycardia on electrocardiogram [ECG], asthma and pulmonary disease) underlying seizure disorder (if uncontrolled) (absolute): none

    • Rivastigmine oral

      • Dose: 2 to 4 mg orally titrated to effect when prolonged delirium is expected. The onset of effect is slower for both oral dosing and transdermal patches than for intravenous agents. Other AChE agents include donepezil and galantamine.

Peripheral symptoms are managed expectantly depending on the severity of symptoms. In cases where ileus develops, peripheral cholinesterase inhibitors such as neostigmine are effective in reversing colonic pseudo -obstructions. Neostigmine can induce both smooth muscle contraction and propulsion.

  • Neostigmine intravenous

    • Dose: 2.5 mg over 10 to 20 minutes

    • Side effects: salivation, nausea, vomiting, abdominal pain, bradycardia, hypotension and bronchospasm

Monitoring

Cardiac monitoring is required (both for toxidrome and with AChE administration).

Visual and/or auditory hallucinations are hard to identify.

  • Patients may have visual perceptual abnormalities and be seen to be picking at objects on their bed sheets. This may be precipitated by asking the patient to pick up small pieces of white tissue. They will either be unable to distinguish the tissue or continue to pick at non-existent tissue.

    • The presence of peripheral signs can help to diagnose a central cause of delirium when organic causes have been ruled out and ACTS is suspected.

    • Cholinergic symptoms such as salivation, diaphoresis, bradycardia, lacrimation, urination, or defecation are signs of too much AChE inhibition.

    • Sinus tachycardia and delirium can persist for days.

    • Antipsychotics with anticholinergic activity (e.g. olanzapine and quetiapine) should be avoided in the treatment of ACTS delirium as they exacerbate the delirium.

    • Treatment may be difficult in a profoundly delirious patient. Benzodiazepines and an AChE agent, such as physostigmine, can be used.

Serotonin toxicity

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