Sedating Antihistamines

The sedating antihistamines include brompheniramine, chlorpheniramine, cyproheptadine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, pheniramine and promethazine. In overdose they cause dose-dependent CNS depression, anticholinergic effects and in massive overdose cardiovascular toxicity. These drugs are sometimes abused for their anticholinergic properties.

Toxic Mechanism:

Unlike the non-sedating antihistamines they are more lipophilic and cross the blood-brain-barrier easily. They inhibit the peripheral and central H1 receptors and have a higher affinity for muscarinic, alpha adrenergic and serotingeric (5-HT) receptors. Some lower the seizure threshold – unknown mechanisms and in large overdoses there is sodium and potassium cardiac channel blockade which predisposes to dysrhythmias.

Toxicokinetics: 

• Good oral absorption
• Peak effect 2 -3 hours
• Lipid soluble
• Large volume of distribution >4 L/kg
• Hepatic metabolism and half lives vary between 6 to 18 hours

Resuscitation:

• Rarely required
• Seizures: (Are rare even though all agents lower the seizure threshold)
  • IV benzodiazepines incrementally dosed every 5 minutes to effect.
  • Check the patient is not in a dysrhythmia
  • Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
  • Lorazepam 0.1mg/kg max 4mg
  • Diazepam 0.15mg/kg max 10mg
  • Midazolam 0.2mg/kg max 10mg
• Hypotension: Usually responds to fluid administration, noradrenaline is second line therapy [0.15mg/kg in 50ml D5W at 1-10ml/hr (0.05 – 0.5 mcg/kg/min)].
• In the rare event of QRS prolongation with ventricular dysrhythmia, treat as per sodium channel blockade. Sodium bicarbonate bolus 1-2 mmol/kg at 3 – 5 minute intervals, once haemodynamically stable, intubate and ventilate to a pH of >7.5
• Torsades de pointes:
  • Correct hypoxia, hypokalaemia, hypomagnesaemia and hypocalcaemia
  • If the heart rate is < 100 beats/minute consider isoprenaline infusion IV (1 – 10 microgram/minute or 0.05 – 2 microgram/minute in children) or override pacing to maintain a heart rate of 100 – 120 beats/minute

Risk Assessment

• Dose dependent sedation, anticholinergic effects and orthostatic hypotension.
• Large overdoses predispose to prolongation of the QRS and QT intervals leading to cardiac instability requiring inotropes, sodium bicarbonate, intubation and ventilation and correction of electrolytes.
• Children: Ingestion is associated with drowsiness and anticholinergic features.

Supportive Care

• Agitation: Titrated doses of benzodiazepines are effective e.g. diazepam 2.5 – 5 mg every 5 minutes IV until gentle sedation is achieved.
• Check for urinary retention – benzodiazepines will not fix this.

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
  • If symptomatic patients receive cardiac monitoring for at least 6 hours and a 12 lead ECG every 6 hours until clinical improvement. Once the patient is improving and there is no cardiac abnormality no further ECGs are required.
  • The most common situation would be someone who presents and an ECG is done on presentation and at 6 hours which is normal and the patient is asymptomatic, no further ECGs will be required.
  • The QT should be measured on the QT nomogram (not Bazetts formula in toxicology). Technically the average QT of 6 leads should be plotted on the nomogram but recent evidence would indicate lead V2 is the most accurate if only one lead is to be used.

QT Nomogram

Decontamination:

• Not usually indicated as sedation occurs within a couple of hours post ingestions and good outcomes are achieved with supportive care. Anyone intubated should receive activated charcoal via a nasogastric tube 50g (1g/kg in children – max 50g)

Enhanced Elimination

• Not clinically useful.

Antidote

• Physostigmine if anticholinergic delirium is severe.

Disposition

• If patients are asymptomatic at 6 hours post ingestion with a normal 12 lead ECG are medically cleared. Do not discharge overnight.
• Patients with mild anticholinergic features and a normal ECG can be observed on the ward until symptoms resolve and they can ambulate, pass urine and eat and drink.
• Ongoing cardiac monitoring is required for those patients with cardiac abnormalities on their ECGs until it resolves.
• Patients with significant agitation or cardiac dysrhythmias require admission to HDU or ICU

Additional Resources and References

Additional Resources:

• ECG Library – Drugs causing QT prolongation
• Tox Flashcard – Anticholinergic Toxidrome

Sodium Channel Blockade and the ECG

References:

• Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning.  Annals of Emergency Medicine 2000; 35(4):374-381.
• Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. Annals of Emergency Medicine 1992; 21:318-321.
• Isbister GK. Risk assessment of drug-induced QT prolongation. Australian Prescriber 2015; 38(1):20-24
• Murray L et al. Toxicology Handbook 3rd Edition. Elsevier Australia 2015. ISBN 9780729542241
• Rotella JA, Taylor DM, Wong A, Greene SL. Accuracy of QT interval measurements on electrocardiographs displayed on electronic ‘smart’ devices. Emergency Medicine Australia 2016; 28:187-192