Spectrum of toxicity due to pheniramine overuse in a COVID-19 patient. How much do we know?

ABSTRACT

Pheniramine maleate is an easily accessible, potent antihistaminic compound used for the treatment of various allergic conditions. It acts on histamine one (H₁) receptors on the central nervous system (CNS) and the peripheral tissues. It is a safe drug in therapeutic doses. However, overdoses as in suicidal cases, can result in serious, life-threatening drug-toxicity. These include atropine-like antimuscarinic effects like dryness of mucosal membranes, blurring of vision, hallucinations, CNS excitation such as irritability, insomnia, and seizures. Rhabdomyolysis can also occur as a result of its direct toxic effect on muscles, resulting in myoglobinuria, renal failure and electrolyte imbalance. Cardiotoxicity though rare, is also reported. We report a case of pheniramine maleate induced ventricular tachycardia, myoglobinuria with acute kidney injury (AKI) in a 20-year-old man who had consumed 50 tablets. He was incidentally also found to have SARS-CoV₂ infection. However, timely intervention and aggressive supportive therapy helped in the recovery of the patient.

Introduction

Pheniramine maleate is a potent antiallergic drug, commonly used for the treatment of rhinitis and allergic conditions. It is an alkylamine derivative with potent histamine one (H₁) receptor antagonist action. Most of the symptoms of drug overdose are due to the antimuscarinic effect on various tissues.[1] Eventually, it can result in deep coma, cardiorespiratory arrest and death within 2 to 18 h in case of fatal drug overdose as in suicidal cases.[2] We report one such case of potentially fatal complication of rhabdomyolysis with acute kidney injury (AKI) and cardiotoxicity in patient who had consumed overdose of pheniramine maleate with suicidal intent. As primary health care professionals play an important role in initial management of the patients, awareness of this possibility would help them in the early recognition of complications and institution of effective treatment resulting in better prognosis, as seen in our case.

Case Report

A 20-year-old man was brought to emergency with alleged history of ingestion of 50 tablets of 25 mg pheniramine maleate (Avil) at 8 am on the day of admission. Patient had several episodes of vomiting with abdominal pain after ingestion. On way to the hospital, he became restless and irritable. There was no history of recent fever, sore throat, or cough. He was taking tablet saridon for 4 years for migraine during severe pain. He did not have any addictions or other co-morbid conditions.

On admission, he was drowsy with Glasgow Coma Scale (GCS) of 11/15. His oral mucosa was dry. There was no icterus, clubbing, lymphadenopathy, cyanosis, and pedal edema. Vital examination revealed pulse rate of more than 150/min, blood pressure of 142/82 mm Hg, normal temperature, tachypnea with respiratory rate of 32/min, and accessories working. Oxygen saturation (SpO2) on ambient air was 68% which increased to 98% with 8 L of oxygen with nonrebreathing face mask (NRBM). Examination of chest revealed bilateral harsh vesicular breath sounds bilaterally. Examination of the cardiovascular and gastrointestinal systems was within normal limits. Neurological evaluation revealed oriented and disoriented person without focal neurological deficits. Pupils were normal size and reacting to light normally. Neck was soft. His electrocardiogram (ECG) showed regular wide complex tachycardia suggestive of ventricular tachycardia (VT) [Figure 1] which was reverted to sinus rhythm [Figure 2] spontaneously while cardioversion was planned. He was given gastric lavage with normal saline and was admitted to critical care unit (CCU). He was started symptomatic treatment with ceftriaxone 1 gm twice daily intravenously (IV), pantoprazole 40 mg IV twice daily, midazolam 2 mg IV as required, Ryle’s tube aspiration and IV fluids up to 2 L per day. Four hours later, his TRUNAT report for SARS-CoV₂ came positive, and he was transferred to COVID critical care ward. His blood investigations obtained 24 h after admission were as shown in the Table 1. His urine routine examination sent on admission was normal.

Figure 1.

ECG showing wide ventricular tachycardia with LBBB* pattern on admission, *LBBB – left bundle branch block pattern

Figure 2.

ECG of the patient in sinus rhythm

Table 1.

Blood investigations on hospital admission

Parameters	On admission	Normal range
Hemoglobin (gm/dL)	14.25	11.5-16.5
TLC (cells per mm3)	20,600	4,000-11,000
Neutrophils (%)	83	60-70
Lymphocytes (%)	14	20-30
Platelet count (cells per mm3)	90,000	150,000-450,000
Serum LDH (U/L)	1533.7	140-280
Total serum protein (gm/dL)	6.7	6.6-8.3
Serum albumin (gm/dL)	3.07	3.5-5.2
Serum globulin (gm/dL)	3.63	2.5-3.5
Serum creatinine (mg/dL)	2.10	0.5-1.5
Total bilirubin (mg/dL)	0.95	0.2-1
Direct bilirubin (mg/dL)	0.7	0.1-0.5
ALT (U/l)	70.3 U/L	5-40
AST (U/l)	344.1 U/L	5-45
ALP (U/l)	67.8 U/L	35-125
PT (seconds)	11.2	11-16
CPK (U/L)	200,600	40-308
Serum Sodium (mmol/L)	142	135-145
Serum Potassium (mmol/L)	5.2	3.5-5

TLC: Total leukocyte count; MCV: Mean corpuscular volume; LDH: Lactate dehydrogenase; ALT: Alanine transaminase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; PT: Prothrombin time, CPK: Creatine phosphokinase

Course in COVID CCU

Subsequently, he developed oliguria with urine output of 100 mL in 24 h for two subsequent days. His creatinine levels showed a rising trend increasing to 6.6 mg/dL on day 4 of admission. His arterial blood gas showed PH of 7.213, bicarbonate (HCO₃) of 12.3 mmol/L, and base excess of − 12.7. His serum potassium increased to 6 mmol/L. On day 4, he passed high colored brownish-red urine [Figure 3]. His serum myoglobin level was more than 3,000 ng/mL (range: 28 –72 ng/mL).

Figure 3.

Tea-colored urine of the patient on fourth day of admission

His CPK level sent on day three was 200, 600 U/L. He was subjected to alkaline diuresis without any benefit. He further developed uremic symptoms like nausea, headache and recurrent vomiting. Blood pressure remained on the higher side. In view of symptoms of uremia, metabolic acidosis and persistent oliguria, he was subjected to hemodialysis. After he turned negative for SARS-CoV₂, he was shifted back to the general ward.

Course in general ward

His oliguric phase lasted for 14 days, during which he underwent hemodialysis thrice a week. He required a total of six settings of hemodialysis. He recovered from oliguria on the15^th day. His urine output gradually increased to 5 L/day with decrease in serum creatinine. His ultrasound abdomen (USG) showed evidence of acute renal parenchymal disease with mild ascites. His hypertension was treated with 25 mg of oral metoprolol twice a day and amlodipine 5 mg twice daily. He was discharged on day twenty-three with advice to follow-up in the out-patient department. His serum creatinine and CPK at discharge were 3.1 mg/dl and 326 U/L, respectively. Psychiatrist’s opinion was taken before discharge. His serial serum creatinine, CPK and urine output were as depicted in the graphs [Figures 4–6] below. A final diagnosis of asymptomatic SARS-CoV₂ infection, suicidal attempt with pheniramine with drug-induced ventricular tachycardia, rhabdomyolysis with acute kidney injury (AKI) was made. His serum creatinine at 4 weeks after discharge was 1.2 mg/dL.

Figure 4.

Urine output during the hospital stay (23 days)

Figure 6.

Serum CPK (U/L) values during the hospital stay (23 days)

Figure 5.

Serum creatinine values during the hospital stay (23 days)

Discussion

Pheniramine maleate is an alkylamine derivative and centrally acting H₁ antagonist. It is a potent antihistaminic and has anticholinergic side effects due to competitive inhibition of muscarinic receptors.[1] The maximum tolerated dose is 3 mg/kg per day and should not be exceeded.[2] Our patient had consumed 1,250 mg of pheniramine. Overdose above the maximum tolerated dose leads to the development of muscarinic features, central nervous system (CNS) stimulation, cardiotoxicity and rhabdomyolysis. Muscarinic features include dryness of the mucous membranes, acute urinary retention, pupillary dilatation, hallucinations, hypertension, and tachycardia.[3] CNS effects include seizures in up-to 30% of cases, tremors, irritability, insomnia, euphoria, vertigo and tinnitus.[4] Cardiotoxicity though rare, can be life-threatening. There are 11 cases of doxylamine associated rhabdomyolysis,[4] three cases of pheniramine,[2,3] and two cases of diphenhydramine,[4,5] induced rhabdomyolysis reported in the literature.

Rhabdomyolysis occurs due to direct muscle trauma (as in burns, electrical shock, crush injury, etc.), muscle overuse (excessive unaccustomed exercise, seizures), re-perfusion injury following ischemia, infections (viral infections, malaria), metabolic disorders (hyponatremia, hypokalemia, hypophosphatemia), inflammatory myopathies, ethanol and drugs (opiates, antihistamines, antibiotics, etc.). Drugs and alcohol constitute about 81% of cases non-traumatic rhabdomyolysis.[6]

Mechanism of rhabdomyolysis includes primary direct toxic effect on the muscle sarcolemma through activation of phospholipase A₂. This leads to leakage of intracellular contents and an increase entry of sodium ions in the cell. High intracellular sodium concentration activates the energy-dependent Na+/K+-ATPase, thus, depleting cellular adenosine triphosphate (ATP). Further, an increase in intracellular sodium leads to an increase in intracellular calcium, enhancing the activity of intracellular proteases.[7] Both these processes cause cellular injury and death. Also, depressing the CNS response, can secondarily lead to prolonged immobilization and pressure-induced muscle necrosis. Further, seizures and hyperthermia caused by antihistamines can also contribute to rhabdomyolysis.[3,7]

The common complication associated with rhabdomyolysis are acute kidney injury (AKI) due to myoglobinuria, electrolyte disturbances and disseminated intravascular coagulation (DIC). Nephrotoxicity is due to oxidative stress resulting from ferrihemate, tubular obstruction due to precipitation of the Tamm–Horsfall protein [THP]–myoglobin complex casts and renal ischemia due to vasoconstriction. AKI develops in about 33% of patients with nontraumatic rhabdomyolysis of which 15% require dialysis.[3]

Elevated levels of creatine phosphokinase (CPK) at least five times the upper limit of normal (ULN) is suggestive of rhabdomyolysis. Patients with CPK levels of more than 40,000 IU/L are at an increased risk of AKI. AKI requiring hemodialysis occurred in only one of 11 patients of doxylamine associated rhabdomyolysis with admission CPK values increasing from 597 to 78,750 IU/L. In a case reported by Paul G et al., patient had maximum CPK level of 14,110 U/L. He developed oliguric renal failure on fourth day onward which persisted for 2 weeks and required hemodialysis.[3] Yet another patient described by Venugopal K et al., had consumed 90 tablets of 50 mg Avil (4,500 mg). He went into status epilepticus, had rhabdomyolysis with AKI, septic shock and died of multi-organ failure. His peak CPK level of 245,650.0 IU/L.[2] Our patient had peak CPK value of 206,000 U/L. There was no history of trauma, seizure, congenital myopathy, recent infection which could have resulted in the muscle injury.

Cardiotoxicity of antihistamines is not mediated through H₁ receptors but by the blockage of cardiac ion currents like potassium and sodium channels. These drugs can cause ventricular tachyarrhythmias like torsades due to delayed cardiac repolarization in genetically susceptible individuals like those having mutations in hERG gene (on chromosome 17) with superadded electrolyte abnormalities and use of drugs that cause prolongation of QT interval.[8] Thus, first generation H1 antihistamines by prolonging the QT interval makes one prone for ventricular arrhythmias as in our case.

He was incidentally found to have asymptomatic SARS-CoV₂ infection. His chest radiograph was normal. Whether COVID 19 could have contributed to his renal dysfunction is not known. AKI is one of the important complications of COVID-19 and is described in 2.9–23% of intensive care unit (ICU) patients. AKI is described in relation to SARS-CoV₂ in those with moderate to severe COVID 19 pneumonia. The cause includes direct viral invasion of tubular epithelial cells (TEC) leading to acute tubular necrosis (ATN), sepsis, renal hypoperfusion due to septic shock, thrombotic complications, cytokine storm and nephrotoxins.[9] As our patient was asymptomatic, it can be presumed that he had mild COVID19 and hence, unlikely to have renal affection.

We did not have patient’s baseline serum creatinine levels prior to pheniramine intake to exclude the possibility of analgesic abuse toxicity. His symptoms started after pheniramine consumption, proving the causal association between the two. Further there was no other potential reason to explain the cause of rhabdomyolysis induced AKI. Treatment includes recognizing the complication associated with antihistamines, aggressive volume replacement, forced alkaline diuresis which increases the solubility of myoglobin-THP complexes,[10] monitoring of electrolytes and renal function and hemodialysis when these conservative measures fail.

Antihistamines are components of readily available sleeping medications. They are often sold over the counter and are one of the commonly abused drugs. Their overdose may lead to rhabdomyolysis with AKI and cardiotoxicity which could be life-threatening. To our knowledge, this is the first case demonstrating antimuscarinic effects, cardiotoxicity and renal complications of pheniramine maleate in the same patient.

Key points

1. Antihistamines are easily available over-the-counter drugs and are used in several allergic conditions.

2. Though they are relatively safe drugs, they may result in rhabdomyolysis when ingested in intentional overdoses.

3. The specific pathophysiology of antihistamine-induced rhabdomyolysis remains unclear.

4. One should be aware of this potential complication and should anticipate AKI in overdose.

5. Treatment is challenging as there is no specific antidote.

6. Early recognition and aggressive treatment may result in good clinical outcome.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.