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wikitox:2.1.11.4.2_antihistamines [2018/09/01 09:00] (current)
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 +Link to [[:​wikitox:​2.1.11.4.2_antihistamines_teaching_resources|2.1.11.4.2 Antihistamines Teaching Resources]]\\
 +Link to [[:​wikitox:​problems_for_discussion_2_anticholinergics_and_antihistamines|Problems for Discussion]]
 +
 +----
 +
 +====== 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 [[:​wikitox:​3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|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 [[:​wikitox:​2.1.11.9.2.1_tricyclic_antidepressants|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.\\
 +\\
 +[[:​wikitox:​status_epilepticus_and_treatment_of_seizures|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 [[:​wikitox:​alkalinisation|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 ====
 +
 +[[:​wikitox:​3.4.15_rhabdomyolysis|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 [[:​wikitox:​3.4.8_fluid_resuscitation|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 [[:​wikitox:​3.2.1.3_toxidromes|anticholinergic spectrum]] is generally not life threatening. The [[:​wikitox:​3.2.1.1.5_hallucinations|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 [[:​wikitox:​2.1.11.9.3_antipsychotics|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 [[:​wikitox:​3.4.15_rhabdomyolysis|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:
 +
 +  * [[:​wikitox:​3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|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 [[:​wikitox:​3.4.8_fluid_resuscitation|intravenous fluids]] (normal saline).
 +
 +==== GI decontamination ====
 +
 +If patients are alert and co-operative and present within 2 hours, [[:​wikitox:​3.2.2.2.3_activated_charcoal|charcoal]] may be administered orally without prior [[:​wikitox:​3.2.2.2.2_gastric_lavage|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, [[:​wikitox:​benzodiazepines|diazepam]] 5-20 mg IV followed by [[:​wikitox:​barbiturates|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 [[:​wikitox:​alkalinisation|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 NaHCO<​sub>​3</​sub> ​ to produce a pH of 7.5 to 7.55. Following the rapid correction of pH to 7.5 by IV NaHCO<​sub>​3</​sub>,​ 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<​sup>​+</​sup> ​  ​channel binding site and decrease Na<​sup>​+</​sup> ​  ​channel blockade. \\  \\ **Further drug treatment** \\ All [[:​wikitox:​3.4.3.4_antiarrhythmics|class 1a antiarrhythmic]] drugs are contraindicated and lignocaine and [[:​wikitox:​2.1.11.2.1_phenytoin|phenytoin]] (class 1b drugs) while they may be used they may still exacerbate Na<​sup>​+</​sup> ​  ​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 and noradrenaline) but these should be used cautiously, if at all, in this setting as they may precipitate ventricular tachycardia.
 +
 +==== Elimination enhancement ====
 +
 +[[:​wikitox:​3.2.2.2.3.1_repeated_doses_of_activated_charcoal|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. \\
 + \\
 +[[:​wikitox:​3.2.3.1.2_charcoal_haemoperfusion|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 =====
 +
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=7906008&​dopt=Abstract|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
 +
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=3679242&​dopt=Abstract|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.
 +
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=3586086&​dopt=Abstract|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.
 +
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=&​dopt=Abstract|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.
 +
  
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