Link to 2.1.11.4.2 Antihistamines Teaching Resources
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Sedating Antihistamines


DRUGS INCLUDED IN THIS CATEGORY

  • Azatadine
  • Azelastine
  • Brompheniramine
  • Carbinoxamine
  • Cetirizine
  • Chlorpheniramine
  • Cinnarizine
  • Clemastine
  • Cyclizine
  • Cyproheptadine
  • Dexbrompheniramine
  • Dexchlorpheniramine
  • Dimenhydrinate
  • Dimethindene
  • Diphenhydramine
  • Diphenylpraline
  • Doxylamine
  • Flunarizine
  • Hydroxyzine
  • Loratadine
  • Meclizine
  • Methdilazine
  • Phenindamine
  • Pheniramine
  • Phenyltoloxamine
  • Pyrilamine
  • Trimeprazine
  • Tripelennamine
  • Triprolidine

OVERVIEW


Antihistamine poisoning is a common poisoning. However, there are substantial variations between the antihistamines and their toxicity. The most severe manifestations are seizures and arrhythmias, although for most antihistamines these occur uncommonly. The treatment of minor symptoms, which are mostly due to anticholinergic effects, is best done with sedation and intravenous fluids.

MECHANISM OF TOXIC EFFECTS


Antihistamines as a group block H1 peripheral receptors. In addition, most of the traditional antihistamines have anticholinergic effects (i.e. block muscarinic acetylcholine receptors) and have CNS effects (due to histamine blockade) that result in sedation and are also mildly proconvulsant. The more severe manifestations of antihistamine poisoning are due to cardiac effects which are presumed due to blockade of voltage-gated sodium or potassium channels. Thus, a severe poisoning with these drugs resembles a tricyclic antidepressant overdose. Seizures due to pheniramine probably have some other mechanisms as the high incidence (around 30%) suggests that there is an additional proconvulsant mechanism which is as yet undefined.

KINETICS IN OVERDOSE


Sedating antihistamines are highly lipid soluble drugs that are rapidly absorbed, highly protein bound and have large volumes of distribution. They are generally weak bases and half-lives for these group of drugs are mostly in the order of 4-12 hours. Excretion is predominantly by hepatic elimination.

Non sedating antihistamines are given as prodrugs. These lipid soluble prodrugs are converted in first pass metabolism in the liver to water soluble active metabolites. The water solubility of these drugs limits the distribution of these drugs into the central nervous system and the active metabolites are either renally excreted or further metabolised in the liver. The half-lives of these active metabolites is generally a little bit longer than those of sedating antihistamines (up to 24 hours).

CLINICAL EFFECTS


Central nervous system effects

Sedation or CNS excitation may be seen. Profound coma is uncommon and patients are usually either drowsy or agitated.

Seizures
Seizures have been reported with most of these drugs, however the incidence is low except for pheniramine (incidence of seizures with pheniramine is approximately 30%). Seizures generally occur in association with other CNS signs, particularly delirium. Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity.

Seizures themselves are associated with an increased mortality. The acidosis produced by the seizures causes a subsequent further increase in the free drug concentrations by changing binding to the Na+ channel and plasma proteins. The increased concentrations may then lead to cardiac arrhythmias. In addition, acidosis affects the partitioning of basic drugs between the cell membrane and the Na+ channel binding site and increases Na+ channel blockade.

Gastrointestinal effects

The anticholinergic effects of these drugs lead to nausea, vomiting, delayed gastric emptying and ileus. These effects are not seen significantly with non-sedating antihistamines.

Renal effects

Rhabdomyolysis has been reported in a substantial proportion (about 7%) of doxylamine overdoses and has led to renal failure in some patients. However, the most common effect is of urinary retention due to antimuscarinic effects.

Cardiac effects

Sinus tachycardia is common as are minor degrees of hypo- and hypertension. Hypertension is most likely secondary to agitation and may respond to diazepam.

Hypotension
Hypotension may be due to a number of causes. Theoretically antihistamines could cause direct myocardial depression. However, in practice, the hypotension usually relates to relative volume depletion and vasodilatation resulting from alpha receptor blockade. Thus it usually responds rapidly to intravenous fluids.

The use of inotropes, in particular those with alpha agonist effects, is not advisable. These prolong the effective refractory period (as do neuroleptics) and thus may be proarrhythmic.

ECG abnormalities
QRS and QT prolongation have been reported also however the incidence of these is in the order of a few percent, about a tenth of the incidence in +.

Arrhythmias
Significant arrhythmias have been reported with antihistamine overdose but the incidence is probably very low (<1%). The arrhythmias reported have been similar to those reported for TCA overdose and include ventricular bigeminy, ventricular tachycardia, heart block and torsades de pointes. Patients with QRS and QT prolongation should be monitored until these changes resolve.

Other effects

Patients often have a dry mouth, absence of sweating, flushing, fever and dilated pupils. This anticholinergic spectrum is generally not life threatening. The delirium may necessitate sedation.

Drug induced hyperthermia
Hyperthermia may occur due to impaired sweating (anticholinergic effect), increased production of heat (excessive motor activity, agitation and seizures) and central effects on thermoregulation. A temperature > 39 C degrees is a toxicological emergency and may lead to death if untreated.

INVESTIGATIONS


The following investigations are usually performed
  • Electrolytes
  • Arterial blood gases (ABGs)
  • ECG

Biochemistry

Electrolytes are normally assessed but are rarely of much assistance with the exception of patients who are on other medications that may cause electrolyte abnormalities that increase the risk of arrhythmia.

Blood gases

All unconscious patients require arterial blood gas to access adequacy of ventilation and to ensure they are not acidotic.

ECG

An ECG should be performed on admission and also at 6 hours after the self poisoning. The ECG is probably the most accurate predictor of toxicity for antihistamine poisonings (based on the similarity to TCA poisoning). Patients with abnormal ECGs require further monitoring.

Blood concentrations

These are unhelpful for management.

DIFFERENTIAL DIAGNOSIS


Antihistamines should be considered, along with other drugs with ion-channel blocking effects, in patients with seizures, QRS prolongation and/or ventricular arrhythmias. In contrast to the usual presentation of TCAs, seizures may occur despite a normal ECG. In our centre, a presentation with coma in the presence of anticholinergic signs makes antihistamines the third most likely drug class ingested (after neuroleptics & TCAs).

DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS


There has been little study of the differences within this drug class but they are probably significant. Pheniramine has a much higher incidence of seizures (Buckley et al 1995) and doxylamine causes rhabdomyolysis in about 7% of patients (Koppel et al 1987). The non-sedating antihistamines have a very different toxicological profile and are dealt with separately.

DETERMINATION OF SEVERITY


The majority of complications occur within the first six hours and in patients who are delirious or sedated. An alert patient with a normal ECG six hours after overdose who has had gastrointestinal decontamination is extremely unlikely to develop major complications.

A worse outcome is associated with any of the following
  • cardiac arrest
  • cardiac arrhythmias
  • seizures
  • prolonged QRS (particularly with a slow heart rate)

However the in-hospital mortality is low (<1% in most centres) and therefore patients even from these groups have a reasonable prognosis once they reach hospital.

TREATMENT


Supportive

All patients should have assessment of the adequacy of their airway protection and ventilation. Virtually all comatose patients require management in ICU and will need to be intubated in order to have gastrointestinal decontamination safely.
All patients should have intravenous fluids (normal saline).

GI Decontamination

If patients are alert and co-operative and present within 2 hours, charcoal may be administered orally without prior lavage. In delirious patients, physostigmine (1 to 2 mg IV) may be useful to achieve co-operation with gastrointestinal decontamination.

Treatment of specific complications


Seizures
Initially, diazepam 5-20 mg IV followed by phenobarbitone 15-18 mg/kg IV and elective intubation and ventilation. If neuromuscular blockade is required for management, EEG monitoring is mandatory.

Anticholinergic delirium
Mild delirium can often be managed with reassurance plus or minus benzodiazepines. Severe hallucinations may require treatment with haloperidol. Although physostigmine is effective, the short half-life of this drug and its occasional life threatening adverse effects limit its application to diagnosis in delirium of unknown cause in patients with a normal ECG (and occasionally to facilitate gastrointestinal decontamination). General measures to manage delirium should be followed.

Arrhythmias
It is often very difficult to distinguish whether the patient is having a supraventricular arrhythmia with aberrant conduction or primary ventricular tachycardia. Most arrhythmias, especially if they are associated with low output are treated in a standard cardiac arrest protocol manner. The main difference is the expected benefit from early and large doses of NaHCO3. All other treatments are of questionable efficacy and safety and therefore controversial.

Alkalinisation
Treatment with plasma alkalinisation to a pH of 7.5 using sodium bicarbonate (to alter both pH and sodium) or hyperventilation may be effective for antihistamine induced arrhythmias, extrapolating from TCAs. Initial treatment is normally with sufficient IV NaHCO3 to produce a pH of 7.5 to 7.55. Following the rapid correction of pH to 7.5 by IV NaHCO3, the patient is usually maintained at this pH by mild hyperventilation.

Alkalosis may affect the partitioning of antihistamines between the cell membrane and the Na+ channel binding site and decrease Na+ channel blockade.

Further drug treatment
All class 1a antiarrhythmic drugs are contraindicated and lignocaine and phenytoin (class 1b drugs) while they may be used they may still exacerbate Na+ channel blockade and potentially exacerbate arrhythmias (e.g. convert VT into asystole).

Magnesium is normally the drug of choice for treating torsade de pointes and is used for refractory arrhythmias in other settings. It may aggravate the hypotension and heart block.

Second or third degree heart block should be treated with bicarbonate and isoprenaline followed by a pacemaker.

Hypotension
This usually responds to volume expansion and pH correction.

Refractory hypotension may require drugs with alpha agonist properties (e.g. adrenaline & noradrenaline) but these should be used cautiously, if at all, in this setting as they may precipitate ventricular tachycardia.

Elimination enhancement


Repeated doses of activated charcoal may increase the clearance of these drugs, but it is not clear whether this changes morbidity. If the patient is unconscious & develops increasing abdominal distension with absent bowel sounds, repeated doses of charcoal should be stopped. The excretion of some of these drugs may be increased in an acidic urine. However, acidosis would be expected to worsen the manifestations of toxicity, and acid diuresis is contraindicated.

Haemoperfusion is of no benefit.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


Patients are medically fit for discharge if they have no symptoms or signs of toxicity and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool).

Patients who still have an isolated tachycardia generally would be kept in hospital and observed. As the usual cause is volume depletion, IV fluid to ensure adequate volume replacement should be given.

Patients with a QRS complex of greater than or equal to 100 milliseconds should be monitored until this has returned to normal.

REFERENCES


Buckley NA, Dawson AH, Whyte IM, Cruickshank DA. Pheniramine: A much abused drug. Med J Aust 1994;160(4):188-192.
Donovan JW, Burkhart KK & O'Donnell S: Incidence of electrocardiographic abnormalities and their relationship to seizures in antihistamine overdose (abstract). Vet Hum Toxicol 1992; 34:332.
Koppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987;6(5):355-9.
Koppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol 1987;25(1-2):53-70.
Le Blaye I. Donatini B. Hall M. Krupp P. Acute ketotifen overdosage. A review of present clinical experience. Drug Safety 1992;7(5):387-92.
28/12/99 11:30:47. R


Non-sedating Antihistamines


DRUGS INCLUDED IN THIS CATEGORY


  • Astemizole
  • Cetirizine
  • Loratidine
  • Terfenadine

OVERVIEW


The most severe manifestations of poisoning with non-sedating antihistamines are ECG abnormalities and arrhythmias. The incidence with which these occur is unknown. Minor symptoms, sedation and other central effects are uncommon and can not be used to determine whether patients are at risk of arrhythmias (c.f. sedating antihistamines).

MECHANISM OF TOXIC EFFECTS


Non-sedating antihistamines as a group block H1 peripheral receptors. In contrast to the traditional antihistamines they have little anticholinergic or central effects in therapeutic doses. The severe manifestations of non-sedating antihistamine poisoning are due to cardiac effects which are presumed to be due to blockade of voltage-gated sodium or potassium channels.

KINETICS IN OVERDOSE


Non-sedating antihistamines are given as prodrugs. These lipid soluble prodrugs are converted in first pass metabolism in the liver to water soluble active metabolites. The water solubility of these drugs limits the distribution of these drugs into the central nervous system and the active metabolites are either renally excreted or further metabolised in the liver. The half-lives of these active metabolites is generally a little bit longer than those of sedating antihistamines (up to 24 hours).

CLINICAL EFFECTS


Central nervous system effects


Sedation or CNS excitation are uncommonly seen.

Seizures
Seizures have been reported with a few of these drugs. Seizures would be expected to occur in association with other CNS signs, such as sedation and delirium. Seizures themselves are associated with an increased mortality. The acidosis produced by the seizures may cause a subsequent further small increase in the free drug concentrations by reducing protein binding. The increased concentrations may then lead to cardiac arrhythmias. In addition, and more significantly, acidosis affects the partitioning of basic drugs between the cell membrane and the Na+ channel binding site and increases Na+ channel blockade.

Gastrointestinal effects


The anticholinergic effects are not seen significantly with non-sedating antihistamines.

Cardiac effects


Hypotension
Theoretically non-sedating antihistamines could cause direct myocardial depression. However, in practice, the hypotension usually relates to relative volume depletion and will respond rapidly to intravenous fluids. The use of inotropes, in particular those with alpha agonist effects, is not advisable. These prolong the effective refractory period (as do antihistamines) and thus may be proarrhythmic.

ECG abnormalities
QRS and QT prolongation have been reported. QT prolongation has been reported more frequently than QRS prolongation.

Arrhythmias
Significant arrhythmias have been reported with non-sedating antihistamine overdose and include ventricular bigeminy, ventricular tachycardia, heart block and torsades de pointes. The incidence of these is unknown as no large series of non-sedating antihistamine poisonings has been reported. Case reports of this complication are particularly common for astemizole and terfenadine. Patients with QRS and QT prolongation should be monitored until these changes resolve.

INVESTIGATIONS


The following investigations are usually performed
  • Electrolytes
  • ECG

Biochemistry

Electrolytes are normally assessed but are rarely of much assistance with the exception of patients who are on other medications that may cause electrolyte abnormalities which increase the risk of arrhythmia.

ECG

An ECG should be performed on admission and also at 6 hours after the self poisoning. The ECG is probably the most accurate predictor of toxicity for non-sedating antihistamine poisonings, based on the case reports and the similarity to TCA poisonings. Patients with abnormal ECGs require further monitoring.

Blood concentrations

These are unhelpful for management.

DIFFERENTIAL DIAGNOSIS


The diagnosis of non-sedating antihistamine poisoning is likely in patients with abnormal ECGs (i.e. QT prolongation and torsade de pointes), but who have little preceding impairment of consciousness. Other drugs that often lead to ECG changes without sedation are antiarrhythmic cardiac drugs and antimalarials (chloroquine and quinine like drugs).

DETERMINATION OF SEVERITY


The majority of complications occur within the first six hours. An alert patient with a normal ECG six hours after overdose who has had gastrointestinal decontamination is extremely unlikely to develop major complications.

TREATMENT


GI Decontamination

If patients are alert and co-operative and presents within 1-2 hours, charcoal may be administered orally without prior lavage.

Treatment of specific complications

Arrhythmias
It is often very difficult to distinguish whether the patient is having a supraventricular arrhythmia with aberrant conduction or primary ventricular tachycardia. Most arrhythmias, especially if they are associated with low output are treated in a standard cardiac arrest protocol manner. The main difference is the expected benefit from early and large doses of NaHCO3 and a possible benefit from magnesium. All other treatments are of questionable efficacy and safety and therefore controversial.

Alkalinisation
Treatment with plasma alkalinisation to a pH of 7.5 using sodium bicarbonate (to alter both pH and sodium) or hyperventilation may be effective for non-sedating antihistamine induced arrhythmias, extrapolating from TCAs. Initial treatment is normally with sufficient IV NaHCO3 to produce a pH of 7.5 to 7.55. Following the rapid correction of pH to 7.5 by IV NaHCO3, the patient is usually maintained at this pH by mild hyperventilation. Alkalosis may affects the partitioning of non-sedating antihistamines between the cell membrane and the Na+ channel binding site and decrease Na+ channel blockade.

Further drug treatment of arrhythmias
All class 1A antiarrhythmic drugs are contraindicated and lignocaine and phenytoin (class 1B drugs), while they may be used with caution, they may still exacerbate Na+ channel blockade and potentially exacerbate arrhythmias (e.g. convert VT into asystole). Magnesium is normally the drug of choice for treating torsade de pointes and is used for refractory arrhythmias in other settings. However, as it is a calcium channel blocker, it may cause hypotension and heart block. Second or third degree heart block should be treated with bicarbonate and isoprenaline followed by a pacemaker.

Hypotension
This usually responds to volume expansion and pH correction. Refractory hypotension may require drugs with alpha agonist properties (e.g. adrenaline & noradrenaline) but these should be used cautiously, if at all, in this setting as they may precipitate ventricular tachycardia.

Elimination enhancement


Repeated doses of activated charcoal are unlikely to significantly increase the clearance of these drugs. The excretion of some of these drugs may be increased in an acidic urine. However as acidosis would be expected to increase the cardiac toxicity, acid diuresis is contraindicated. Haemoperfusion is of no benefit.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


Patients are medically fit for discharge if they have no symptoms or signs of toxicity and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool). Patients who still have an isolated tachycardia generally should be kept in hospital and observed. As the usual cause is volume depletion, IV fluid to ensure adequate volume replacement should be given. Patients with a QRS complex of greater than 100 milliseconds or a QT interval greater than 450 milliseconds should be monitored until this has returned to normal.

REFERENCES


Hoppu K. Tikanoja T. Tapanainen P. Remes M. Saarenpaa-Heikkila O. Kouvalainen K. Accidental astemizole overdose in young children. Lancet 1991;338(8766):538-40.
Wiley JF. Gelber ML. Henretig FM. Wiley CC. Sandhu S. Loiselle J. Cardiotoxic effects of astemizole overdose in children. Journal of Pediatrics 1992;120(5):799-802.
Davies AJ, Harindra V, McEwan A, Ghose RR.Cardiotoxic effect with convulsions in terfenadine overdose.BMJ. 1989 Feb 4;298(6669):325.
Simons FE, Kesselman MS, Giddins NG, Pelech AN, Simons KJ.Astemizole-induced torsade de pointes.Lancet. 1988 Sep 10;2(8611):624.

Loebstein R, Lalkin A, Addis A, Costa A, Lalkin I, Bonati M, Koren G.Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.J Allergy Clin Immunol. 1999 Nov;104(5):953-6.