Donepezil: an unusual therapy for acute diphenhydramine overdose

Abstract

An elderly man presented with the history of diphenhydramine hydrochloride overdose as a suicidal attempt. At presentation, he was in an acute confusional state with several anticholinergic features and had to be managed in intensive care unit. As an antidote for diphenhydramine hydrochloride, donepezil was used instead of physostigmine due to the unavailability of physostigmine in Bangladesh. The patient improved within the next 24 hours; his level of consciousness improved and the anticholinergic features regressed.

Background

Drug overdose is an important public health problem.¹ Among the prescription drug, diphenhydramine (DPHM) overdose is a frequent one, which commonly manifests as drowsiness and anticholinergic effects.² We report the successful use of donepezil as the antidote of DPHM overdose instead of physostigmine, which has not been reported previously.

Case presentation

An 89-year-old man was brought to the emergency with a history of deliberated self-harm by ingestion of 80 tablets of diphenhydramine hydrochloride (50 mg per tablet) about 6 hours prior to arrival and unconsciousness for the last 3½ hours. On admission, his Glasgow Coma Scale (GCS) was E₁V₂M₃, pulse rate 105 beats/min, respiratory rate 24 breaths/min, blood pressure 140/80 mm Hg, temperature 38.3°C, SpO₂ was 88% in room air and random blood sugar was 5.4 mmol/L. Further physical examination revealed anticholinergic features (ie, dry mouth, absent bowel sound and acute urinary retention). He had medical history of ischaemic heart disease, chronic kidney disease stage-4, type 2 diabetes mellitus, hypertension and hypothyroidism. He was on his routine medications.

Investigations

Investigations were done to exclude other causes of loss of consciousness. Full blood count revealed haemoglobin 173 g/L, white blood cell count 8.17×10⁹/L, platelet count 172×10⁹/L. Biochemistry revealed serum creatinine 3.2 mg/dL, serum urea 94 mg/dL, alanine aminotransferase (SGPT) 125 U/L, serum ammonia <9 μmol/L, serum sodium 134 meq/L, potassium 3.3 meq/L, chloride 96 meq/L, serum bicarbonate level (TCO₂) 25mEq/L and c-reactive protein (CRP) <5 mg/L. CT scan of head was normal for age.

Treatment

The patient was intubated for airway protection and was put on mechanical ventilation. A urinary catheter was inserted to relieve urinary retention. For the management of DPHM overdose associated delirium (DOAD), the drug of choice was injection physostigmine, an acetylcholinesterase inhibitor, which was not available in Bangladesh. Donepezil, also a cholinesterase inhibitor, having similar mechanism of action, was available in Bangladesh. A medical board was set up and patient’s family were informed about the unavailability of physostigmine, the drug of choice, and they were informed about donepezil, the drug that was available, and its similarity of mechanism of action. They were also informed that treating this patient with donepezil was empirical and it lacked scientific evidence, and it had potential side effects. Patient’s family agreed to administer the treatment. Donepezil was given at a dose of 10 mg, enterally, daily for 5 days.

Outcome and follow-up

Within 24 hours of commencement of treatment with donepezil, the patient improved clinically. His GCS rose to E₄V_TM₆ and the anticholinergic features regressed. He was extubated within the next 24 hours and Mini-Mental State Examination (MMSE) was done in which he scored 26. After staying in the intensive care unit (ICU) for 6 days he was shifted to general cabin. Later he died due to acute myocardial infarction, 12 days after his discharge from the ICU.

Discussion

DPHM is a first-generation histamine H₁ receptor antagonist of ethanolamine class and also has anticholinergic properties. Globally, it is commonly used in the treatment of insomnia, colds and allergies, and an easily accessible drug for committing suicide.² In 2003, American Association of Poison Control Center’s Toxic Exposure Surveillance System, USA, reported 28 092 cases of DPHM associated toxicity, of which six patients died from DPHM ingestion only.³ DPHM overdose-associated signs and symptoms appear within a short time due to its rapid absorption and tissue distribution and symptoms include delirium, dryness of mouth, reduced bowl sound, hyperthermia, cardiac arrhythmia, tachycardia and sometimes seizures.^{2 4} Causes of death are mostly seizure and/or cardiac arrhythmia.³ Age is one of the major factors upon which the clinical features depend in DPHM overdose toxicity. In adult patients, seizure is less common and central nervous system (CNS) depression is frequently observed which in turn leads to coma and sometimes, death. A case report showed that their patient took 1.2 g of DPHM and after 3 hours, the patient developed disorientation, loss of memory and confusion. The dose-dependent anticholinergic activity of DPHM enhances its dopaminergic effect and its ability to cross the blood-brain barrier rather easily may cause delirium.²

Delirium may be termed as acute confusional state, acute brain syndrome, acute reversible syndrome, toxic–metabolic encephalopathy, on the basis of its severity and disease orientation. Aetiologically, delirium is a condition which has diverse and multiple clinical factors as its cause and is often associated with critical illness, or appears as complication of a drug or its overdose. Drug induced delirium is frequently observed in elderly patients and among those, anticholinergic overdose-associated delirium is most common, may be as a result of altered kinetics and dynamics of the drugs in aged patients.^{2 5} The patient, reported here, took 4 g of DPHM (80 tablets of 50 mg) orally and symptoms of delirium were observed in the patient after 6 hours. The adverse effect of DPHM is dose-dependent and more than 1 g oral dose can produce symptoms of delirium.²

A selective M1 receptor agonist is an ideal antidote for DOAD. But globally, there is no strongly evidence based, clinically recommended drug therapy for DOAD management. Physostigmine, a prototypical cholinesterase inhibitor, is most commonly used as the antidote in anticholinergic toxicity.⁶ In 1968, physostigmine was first reported in anticholinergic-delirium management and a study showed that it was a safe and efficient drug as an antidote for the management of DPHM overdose-associated complications.^{7 8} However, in our situation, physostigmine was not available in our country at that time for which, we sought for an alternative drug and donepezil was an appropriate substitute with similar mechanism of action. Donepezil hydrochloride was used as a cholinesterase inhibitor for the management. Previous record of using donepezil in DOAD management was searched for but was not found.

Donepezil hydrochloride is a newly developed, piperidine-based cholinesterase inhibitors and a gold standard drug for symptomatic treatment of Alzheimer’s disease used worldwide for many years. It is a special research product which is chemically distinct from ordinary cholinesterase inhibitors. Different studies suggested that donepezil’s specificity to brain tissue and duration of inhibitory action are greater than physostigmine and tacrine. It has a very low affinity for plasma cholinesterases and high affinity for cholinesterase of the CNS and that is why, donepezil is more potent and efficient in the CNS with minimal peripheral activity.⁹ This higher affinity of donepezil to CNS-cholinesterase came to our aid in the management of DOAD, showing improvement in the patient’s conditions in terms of improved GCS and increased cholinergic activities.

A recent cohort study showed that use of donepezil is associated with lower risk of myocardial infarction and mortality, because of its additional vagotonic and anti-inflammatory activities on atherosclerosis.¹⁰ Whereas researcher found that physostigmine used in tricyclic antidepressant overdose management, develops life-threatening bradycardias and asystole.¹¹

Learning points.

• Diphenhydramine (DPHM) overdose is an important and frequent cause of self-harm.

• DPHM overdose produces anticholinergic effects along with drowsiness.

• Donepezil with its selective cholinesterase inhibitory property may be a better option in the management of DPHM overdose associated delirium with desired efficacy and safety profile instead of physostigmine.