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--- wikitox:2.1.11.4.2_antihistamines [2025/04/13 04:45] – ↷ Links adapted because of a move operation 177.81.79.140
+++ wikitox:2.1.11.4.2_antihistamines [2025/06/03 00:08] (current) – kharris
@@ Line 1: / Line 1: @@
-Link to [[:wikitox:2.1.11.4.2_antihistamines_teaching_resources|2.1.11.4.2 Antihistamines Teaching Resources]]\\
+====== Sedating Antihistamines ======
-Link to [[:wikitox:problems_for_discussion_2_anticholinergics_and_antihistamines|Problems for Discussion]]
 ----
-====== Sedating Antihistamines ======
+===== OVERVIEW =====
-===== DRUGS INCLUDED IN THIS CATEGORY =====
+This monograph discusses the assessment and management of sedating antihistamines. For management of less-sedating antihistamines, see [[:wikitox:non_sedating_antihistamines|Non-Sedating Antihistamines]]
-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
+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.
-===== OVERVIEW =====
+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.
-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.
+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.
-===== KINETICS IN OVERDOSE =====
+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.
-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.
+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.
-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).
+===== RISK ASSESSMENT =====
-===== CLINICAL EFFECTS =====
+With the exception of diphenhydramine, dimenhydrinate and promethazine, the toxic dose of agents is not well defined, except to say that toxicity is dose dependent.
-==== Central nervous system effects ====
+**Diphenhydramine**: Ingestions of >1g are associated with severe effects. Ingestion of <300mg or (<7.5mg/kg in children) are unlikely to have significant effects.
-Sedation or CNS excitation may be seen. Profound coma is uncommon and patients are usually either drowsy or agitated.\\
+**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.
-\\
-**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 [[:concept_serum_alkalinization|partitioning of basic drugs]] between the cell membrane and the Na+ channel binding site and increases Na+ channel blockade.
-==== Gastrointestinal effects ====
+**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).
+===== KINETICS IN OVERDOSE =====
-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.
+==== Absorption ====
-==== Renal effects ====
+Sedating antihistamines are generally well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 to 3 hours after oral administration.
-[[: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.
+==== Distribution ====
-==== Cardiac effects ====
+These drugs are lipophilic and widely distributed throughout the body, readily crossing the blood–brain barrier, which contributes to their central sedative 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.\\
+==== Metabolism ====
-\\
-**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 ====
+Most sedating antihistamines undergo extensive hepatic metabolism, primarily via the cytochrome P450 system, although the specific isoenzymes involved can vary by agent.
-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.\\
+==== Elimination ====
-\\
-**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 =====
+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.
-The following investigations are usually performed:
+===== CLINICAL EFFECTS =====
-  * Electrolytes
+In general, ingestions of all agents in this group lead to dose-dependent 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).
-  * Arterial blood gases (ABGs)
-  * ECG
-==== Biochemistry ====
+  * **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).
+===== INVESTIGATIONS =====
-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.
+  * **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.
+===== TREATMENT =====
-==== Blood gases ====
+==== Supportive ====
-All unconscious patients require arterial blood gas to access adequacy of ventilation and to ensure they are not acidotic.
+**Airway and breathing **
-==== ECG ====
+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.
-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.
+In cases of more significant sedation or seizures, with compromise to airway or breathing, intubate and ventilate.
-==== Blood concentrations ====
+Seizures are a sign of more severe toxicity. They are generally self-terminating and short lived. Treat with benzodiazepines if recurrent or persistent.
-These are unhelpful for management.
+**Circulation**
-===== DIFFERENTIAL DIAGNOSIS =====
+Hypotension can occur and is commonly related to alpha blockade induced vasodilation and responds to IV hydration.
-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).
+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 [[:concept_ecg_changes|ECG in Toxicology]]
-===== DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS =====
+==== Decontamination ====
-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.
+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.
-===== DETERMINATION OF SEVERITY =====
+**Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)  **
-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:
+==== Enhanced Elimination ====
-  * [[:wikitox:3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|cardiac arrest]]
+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.
-  * 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.
+==== Antidote ====
-===== TREATMENT =====
+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].
-==== Supportive ====
+==== Observation and Disposition ====
-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).
+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.
-==== GI decontamination ====
+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.
-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 [[:concept_serum_alkalinization|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.
+  - Buckley NA, Whyte IM, Dawson AH, Cruickshank DA. Pheniramine–a much abused drug. Med J Aust. 1994 Feb 21;160(4):188-92. PMID: 7906008. {{:wikitox:buckley_-_pheniramine_a_much_abused_drug.pdf|PDF}}
+  - Page CB, Duffull SB, Whyte IM, Isbister GK. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM. 2009 Feb;102(2):123-31. doi: 10.1093/qjmed/hcn153. Epub 2008 Nov 28. PMID: 19042969. {{:wikitox:page_-_promethazine_overdose_delirium.pdf|PDF}}
-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
+  - Poluzzi E, Raschi E, Godman B, Koci A, Moretti U, Kalaba M, Wettermark B, Sturkenboom M, De Ponti F. Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe. PLoS One. 2015 Mar 18;10(3):e0119551. doi: 10.1371/journal.pone.0119551. PMID: 25785934; PMCID: PMC4364720. {{:wikitox:pro-arrhythmic_potential_of_or.pdf|PDF}}
+  - Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, Manoguerra AS, Christianson G, Olson KR, Woolf AD, Keyes DC, Booze LL, Troutman WG. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(3):205-23. doi: 10.1080/15563650600585920. PMID: 16749537. {{:wikitox:diphenhydramine_and_dimenhydrinate_poisoning_an_evidence-based_consensus_guideline_for_out-of-hospital_management.pdf|PDF}}
-[[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.
+  - Köppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol. 1987 Sep;6(5):355-9. doi: 10.1177/096032718700600503. PMID: 3679242. {{:wikitox:koppel-et-al-1987-poisoning-with-over-the-counter-doxylamine-preparations-an-evaluation-of-109-cases.pdf|PDF}}
+  - Köppel 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. doi: 10.3109/15563658708992613. PMID: 3586086. {{:wikitox:clinical_symptomatology_of_diphenhydramine_overdose_an_evaluation_of_136_cases_in_1982_to_1985.pdf|PDF}}
-[[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.