H1 Receptor Antagonists (Classical Antihistamines)

H₁ Receptor Antagonists (Classical Antihistamines)

■■   Highly sedating—diphenhydramine, dimenhydrinate,doxylamine, embramine, promethazine and hydroxyzine.

■■   Moderately sedating—pheniramine, antazoline, trimepra-zine, meclizine and buclizine.

■■   Mildly sedating—chlorpheniramine, methdilazine,mepyramine, dimethindene, triprolidine, mebhydroline, cyclizine and clemastine.

■■   Non-sedating—terfenadine, astemizole, cetirizine andloratidine.

■■   Anti-vertiginous—cinnarizine.

Two related groups of drugs comprising the following, will also be discussed in this section:

■■   5-Hydroxytryptamine Antagonists— cyproheptadine,*methysergide, pizotifen, ketanserin, and ondansetron.

■■   Decongestants—pseudoephedrine, ephedrine, and phenyl-propanolamine.

Uses

·              Treatment of allergic reactions and allergic disorders.

·              Symptomatic relief of common cold.

·              Treatment of vertigo, travel sickness.

·              Anti-emetic.

·              Sleeping aid.

Adverse Effects (Therapeutic Doses)

■■   Drowsiness, tachycardia, dilated pupils, decreased bowel sounds, and urinary retention are the most common adverse effects following therapeutic administration.

■■   Other adverse effects may include nausea and vomiting, dystonic reactions, and hepatotoxicity.

■■   Pneumonitis, chest tightness, and wheezing have also been reported.

■■   Anticholinergic effects such as mydriasis visual distur-bances, diplopia, nasal dryness and stuffiness, and mouth and throat dryness, can occur with overdose or therapeutic use.

Toxicokinetics

Antihistamines are generally well-absorbed after ingestion. Following oral administration, effects start within 15 to 30 minutes and are fully developed within one hour. Oral bioavail-ability is incomplete, ranging from 25 to 50%. Antihistamines are widely distributed throughout the body including the CNS, and are metabolised in the liver. Unchanged drug and metabo-lites are excreted in the urine.

Clinical (Toxic) Features

·            The toxicity of antihistamines is related to their anticho-linergic (antimuscarinic) activity with the exception of toxic exposure to loratadine, terfenadine, and astemizole. The action of acetylcholine at muscarinic receptors is blocked.

·              Most patients will present with CNS depression and anticholinergic manifestations (except those who have ingested cetirizine, loratidine, terfenadine, or astem-izole). Main symptoms include somnolence, lethargy, mydriasis, blurred vision, convulsions, hallucinations, extra-pyramidal movement disorders and psychosis.

·            Nystagmus and catatonic stupor have been described in relation to diphenhydramine overdose.

·            Other features include sinus tachycardia with hypo- or hypertension, dryness of skin and mucous membranes, cutaneous flushing, anhydrosis, hyperthermia, urinary retention, vomiting and diarrhoea/constipation.

·            Skin is usually flushed, warm and dry after overdose.

·            Hypertension is more commonly reported than hypoten-sion. Tachycardia is also very common.

·            Rhabdomyolysis can occur. Acute renal failure has been reported in patients who developed rhabdomyolysis after overdose.

·            Terfenadine and astemizole are known to cause ventric-ular dysrhythmias and cardiac conduction defects. Several cases of prolonged QTc and QRS intervals and non-specific ST and T-wave changes were reported following antihistamine overdoses.

·            Children are more likely to suffer from CNS stimula-tion, convulsions, and ARDS. Hallucinations, anxiety, restlessness, and agitation have been reported following overdoses of carbinoxamine, cetirizine, dexchlorphenira-mine, diphenhydramine, doxylamine, pheniramine, and tripelennamine.

·            Cetirizine, loratidine, terfenadine, and astemizole cause much less CNS depression and anticholinergic effects.

Treatment

If less than four times the maximum daily dose has been ingested by an asymptomatic patient, he may be observed at home. If symptoms are present (other than mild somnolence), or if greater than four times the maximum daily dose has been ingested, the patient should be referred to a health care facility for evaluation.

·            Monitor vital signs, and watch for development of seizures, hyperthermia, and dysrhythmias.

·            Stomach wash, activated charcoal.

·            Whole bowel irrigation with polyethylene glycol elec-trolyte lavage solution should be considered in patients with extremely large ingestions and those involving sustained release preparations. However, cautious assessment of bowel motility is recommended prior to and during whole bowel irrigation. Antihistamine overdose is frequently complicated by decreased bowel sounds, reduced gastrointestinal motility, or intestinal ileus.

·            Physostigmine for anticholinergic effects.

o     Dose: 2 mg (adults); 0.5 mg (children), by slow IV push. It can be repeated at 5–10 minute intervals if there is no significant improvement.** Reversal within minutes of coma, arrhythmias, hallucina-tions, and other findings can be expected if the diagnosis is correct, and the patient has not suffered anoxia or other insult, or ingested a combination preparation.

o     Note: Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (QRS widening, R wave in aVR). It can precipitate seizures and intractable cardiac arrest.

·              Diazepam IV for agitation/psychosis, or convulsions. If seizures persist or recur administer phenobarbitone. Monitor for respiratory depression, hypotension, arrhyth- mias, and the need for endotracheal intubation.

·              Acute dystonic reactions to antihistamines may be treated with oral or intravenous diazepam.

·              Cooling measures for hyperthermia. Sponge patient with tepid water, and use fans to maximise evaporative heat loss. Avoid phenothiazines.

·              Sinus tachyarrhythmias rarely require treatment. In agitated patients, sedation with benzodiazepines will generally control tachycardia. If severe tachycardia results in haemodynamic compromise or ischaemia, beta blocking agents may be used as a temporising measure. A short- acting cardioselective agent such as esmolol is preferred. Use with caution in patients with asthma or COPD. For mild/moderate asymptomatic hypertension, phar- bing macologic intervention is generally not necessary. Seda- tive agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients especially if a sympathomimetic agent is involved in the poisoning. For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20 to 25% within one hour), nitroprusside is preferred. Nitroglycerine and phentolamine are possible alternatives.

·              Cardiotoxicity necessitates careful cardiac monitoring. Dysrhythmias can be corrected with IV magnesium sulfate (2 to 6 gm in adults ; 25 to 50 mg/kg in children), or lignocaine. Cardioversion can be tried.

Forensic Issues

·              Apart from the fact that these agents are not uncommonly involved in accidental or deliberate overdose, several investigators have evaluated performance while under the influence of therapeutic doses of antihistamines and found that these agents decreased skills. They are therefore not recommended for individuals who drive motor vehicles or operate machinery.

·              Antihistamine (especially cyclizine) abuse has been reported among teenagers in the West. Hallucinations, confusion/ disorientation, tachycardia, and systolic hypertension appeared to be the most commonly occurring effects.