This monograph discusses the assessment and management of sedating antihistamines. For management of less-sedating antihistamines, see Non-Sedating Anithistamines

There are many agents in this class including brompheniramine, chlorphenamine, cyclizine, cyproheptadine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, pheniramine and promethazine. Many are available as individual agents, but several can also be found in co-formulation with other medications such as ibuprofen and paracetamol in cold and flu medicines or motion sickness remedies.

Ingestion of these agents is common, due to their easy availability. Most ingestions result in sedation and anticholinergic effects which can be managed with supportive care, however in rare cases seizures and arrhythmias may occur.

Antihistamines as a group block H1 peripheral receptors. In addition, most of the traditional antihistamines have anticholinergic effects (blocking muscarinic receptors) and have CNS effects (sedation and mild proconvulsant effects) due to central histamine receptor blockade.

The more severe manifestations of antihistamine poisoning are related to cardiac effects which are presumed to be due to blockade of voltage-gated sodium or potassium channels.

Seizures following pheniramine overdose, probably have other mechanisms as the high incidence (around 30%) suggests that there is an additional proconvulsant mechanism which is as yet undefined.

With the exception of diphenhydramine, dimenhydrinate and promethazine, the toxic dose of agents is not well defined, except to say that toxicity is dose dependant.

Diphenhydramine: Ingestions of >1g are associated with severe effects. Ingestion of <300mg or (<7.5mg/kg in children) are unlikely to have significant effects.

Dimenhydrinate: Ingestions <300mg (<7.5mg/kg in children) are unlikely to cause significant effects. Dimenhydrinate dissociates into diphenhydramine to produce its effects and therefore effects are more delayed than those seen when taking diphenhydramine.

Promethazine: Ingestion of promethazine commonly leads to anticholinergic delirium, the incidence of which is dose-dependent (31% probability following 250mg, 42% probability following 500mg, 55% probability following 1g).

Sedating antihistamines are generally well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 to 3 hours after oral administration.

These drugs are lipophilic and widely distributed throughout the body, readily crossing the blood–brain barrier, which contributes to their central sedative effects.

Most sedating antihistamines undergo extensive hepatic metabolism, primarily via the cytochrome P450 system, although the specific isoenzymes involved can vary by agent.

Elimination occurs predominantly via renal excretion of metabolites, with half-lives ranging from 4 to over 24 hours depending on the specific drug, age, and hepatic/renal function.

In general ingestions of all agents in this group lead to dose-dependant sedation and anticholinergic toxicity. The initial sedation often masks an underlying anticholinergic delirium which then becomes more troublesome as the sedation lifts (typically after 6-18hrs).

• CNS: sedation (dose-dependent), anticholinergic toxicity, seizures (most commonly seen with pheniramine).
• CVS: Tachycardia, postural hypotension, QRS widening and QT prolongation (both rare).
• Other effects: rhabdomyolysis (doxylamine and diphenhydramine).

• ECG: looking for QT prolongation and/or QRS widening
• Bladder scan: detect urinary retention in anticholinergic toxicity which can be a strong driver of agitation.
• Creatine kinase: Detect rhabdomyolysis in cases of doxylamine or diphenhydramine toxicity.

Airway and breathing

Most ingestions will result in a period of sedation which may or may not be accompanied by anticholinergic toxicity. The majority of cases can be managed well with supportive care alone.

In cases of more significant sedation or seizures, with compromise to airway or breathing, intubate and ventilate.

Seizures are a sign of more severe toxicity. They are generally self-terminating and short lived. Treat with benzodiazepines if recurrent or persistent.

Circulation

Hypotension can occur and is commonly related to alpha blockade induced vasodilation and responds to IV hydration.

If there is evidence of QRS widening or QT-interval prolongation on ECG, then the patient should remain on continuous cardiac monitoring. Manage urgently according to advice on ECG in toxicology ECG [WikiTox]

Most ingestions should be managed well with supportive care alone. However, if a patient presents within 2 hours following a large overdose, then offer single dose activated charcoal. In the case of promethazine this has been shown to reduce the risk of developing an anticholinergic delirium.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g) 

Repeated dose activated charcoal may increase the clearance of this class of agents, but it is not clear that this has any clinical impact, and its use is not suggested.

Physostigmine can be used to manage anticholinergic delirium, accompanying sedation may also be needed to ensure safe management whilst the patient is delirious. Dosing and treatment advice can be found here: Anticholinergic Toxidrome [WikiTox].

Patients can be discharged at 6 hours post ingestion if they are asymptomatic with a normal ECG and have been able to pass urine. Patients who have been treated with cholinesterase inhibitors require a period of observation after the last dose to ensure there is not recurrent delirium once the effects abate: physostigmine – 6 hours. Rivastigmine- 12 hours.

Patients with signs of toxicity or abnormal ECG should be admitted until these signs have resolved and the patient has returned to their baseline status.

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