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wikitox:2.1.11.4.2_antihistamines [2025/06/02 21:59] – kharriswikitox:2.1.11.4.2_antihistamines [2025/06/03 00:08] (current) – kharris
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-===== OVERVIEW =====+====== Sedating Antihistamines ======
  
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-This monograph discusses the assessment and management of sedating antihistamines. For management of less-sedating antihistamines, see **Link** =+===== OVERVIEW ===== 
 + 
 +This monograph discusses the assessment and management of sedating antihistamines. For management of less-sedating antihistamines, see [[:wikitox:non_sedating_antihistamines|Non-Sedating Antihistamines]]
  
 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. 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.
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 ===== MECHANISM OF TOXIC EFFECTS ===== ===== MECHANISM OF TOXIC EFFECTS =====
- 
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 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. 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.
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 ===== RISK ASSESSMENT ===== ===== RISK ASSESSMENT =====
  
----- +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.
- +
-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. **Diphenhydramine**: Ingestions of >1g are associated with severe effects. Ingestion of <300mg or (<7.5mg/kg in children) are unlikely to have significant effects.
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 **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). **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 ===== ===== KINETICS IN OVERDOSE =====
- 
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 ==== Absorption ==== ==== Absorption ====
- 
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 Sedating antihistamines are generally well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 to 3 hours after oral administration. Sedating antihistamines are generally well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 to 3 hours after oral administration.
  
-==== Distrubution  ==== +==== Distribution ====
- +
-----+
  
 These drugs are lipophilic and widely distributed throughout the body, readily crossing the blood–brain barrier, which contributes to their central sedative effects. These drugs are lipophilic and widely distributed throughout the body, readily crossing the blood–brain barrier, which contributes to their central sedative effects.
  
-==== Metabolism  ==== +==== Metabolism ====
- +
-----+
  
 Most sedating antihistamines undergo extensive hepatic metabolism, primarily via the cytochrome P450 system, although the specific isoenzymes involved can vary by agent. Most sedating antihistamines undergo extensive hepatic metabolism, primarily via the cytochrome P450 system, although the specific isoenzymes involved can vary by agent.
  
 ==== Elimination ==== ==== Elimination ====
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 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. 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.
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 ===== CLINICAL EFFECTS ===== ===== CLINICAL EFFECTS =====
  
----- +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).
- +
-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).   * **CNS**: sedation (dose-dependent), anticholinergic toxicity, seizures (most commonly seen with pheniramine).
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   * **Other effects:**  rhabdomyolysis (doxylamine and diphenhydramine).   * **Other effects:**  rhabdomyolysis (doxylamine and diphenhydramine).
 ===== INVESTIGATIONS ===== ===== INVESTIGATIONS =====
- 
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   * **ECG**: looking for QT prolongation and/or QRS widening   * **ECG**: looking for QT prolongation and/or QRS widening
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   * **Creatine kinase**: Detect rhabdomyolysis in cases of doxylamine or diphenhydramine toxicity.   * **Creatine kinase**: Detect rhabdomyolysis in cases of doxylamine or diphenhydramine toxicity.
 ===== TREATMENT ===== ===== TREATMENT =====
- 
----- 
  
 ==== Supportive ==== ==== 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).+**Airway and breathing **
  
-==== GI decontamination ====+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.
  
-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.+In cases of more significant sedation or seizures, with compromise to airway or breathing, intubate and ventilate.
  
-==== Treatment of specific complications ====+Seizures are a sign of more severe toxicity. They are generally self-terminating and short lived. Treat with benzodiazepines if recurrent or persistent.
  
-**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. \\ +**Circulation**
- \\ +
-**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 ====+Hypotension can occur and is commonly related to alpha blockade induced vasodilation and responds to IV hydration.
  
-[[: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. \\ +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]]
- \\ +
-[[:wikitox:3.2.3.1.2_charcoal_haemoperfusion|Haemoperfusion]] is of no benefit.+
  
-===== LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP =====+==== Decontamination ====
  
- \\ 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.+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.
  
-===== REFERENCES =====+**Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)  **
  
-[[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.+==== Enhanced Elimination ====
  
-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+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.
  
-[[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.+==== Antidote ====
  
-[[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.+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]. 
 + 
 +==== Observation and Disposition ==== 
 + 
 +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. 
 + 
 +===== REFERENCES =====
  
-[[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.+  - 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}} 
 +  - 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}} 
 +  - 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}}