Diphenhydramine, commonly known by the brand name Benadryl, is a widely accessible over-the-counter medication used primarily to treat allergy symptoms and as a sleep aid. As a first-generation antihistamine, it is a fixture in many household medicine cabinets, leading many to regard it as harmless. However, a serious concern exists regarding its potential to cause seizures, particularly when taken in doses exceeding the therapeutic range. This article examines the pharmacological basis for this risk and provides clear guidance on safe usage and emergency response.
Diphenhydramine’s Interaction With the Central Nervous System
Diphenhydramine exerts its primary effects by acting as an inverse agonist at the histamine-1 (\(\text{H}_1\)) receptor, which is responsible for blocking the effects of histamine that cause allergy symptoms and promoting sedation. As a first-generation antihistamine, it easily crosses the blood-brain barrier, allowing it to affect the central nervous system (CNS) directly. This action on the \(\text{H}_1\) receptors in the brain is why the drug commonly causes drowsiness.
The drug also acts as a potent antimuscarinic, meaning it blocks acetylcholine receptors in the brain and body. While therapeutic doses cause CNS depression, leading to sleepiness, higher or toxic doses can paradoxically cause CNS excitation. This shift from sedation to excitation ultimately lowers the brain’s seizure threshold, making it more susceptible to abnormal electrical activity.
The mechanism behind the increased seizure risk is linked to the drug’s effects on neurotransmitter activity, specifically the blockade of acetylcholine and histamine receptors, which disrupts normal brain electrical function. Diphenhydramine also blocks intracellular sodium channels, an action typically associated with cardiotoxicity, which further contributes to its overall toxicity profile. The accumulation of these effects can trigger generalized seizures.
Situations That Significantly Increase Seizure Risk
The risk of seizures is highly dose-dependent and primarily associated with acute toxicity or overdose. Ingestions greater than one gram of diphenhydramine can result in severe symptoms like delirium, psychosis, and seizures, with the risk increasing when the dose exceeds 1.5 grams. For children, the risk is higher; ingestions as low as 100 to 150 mg in a toddler have been reported to cause severe toxicity, including seizures.
Combining diphenhydramine with other medications can also increase the seizure risk, even at lower doses. The drug has additive effects with substances that also depress the CNS, such as alcohol, opioids, and benzodiazepines, which can intensify side effects. Other medications with strong anticholinergic properties, including certain antipsychotics or tricyclic antidepressants, should not be combined with diphenhydramine due to the heightened risk of additive toxicity.
Certain groups are significantly more susceptible to the neurological effects of diphenhydramine:
- Individuals with a pre-existing seizure disorder, such as epilepsy, should use the drug with caution, as it can lower the seizure threshold.
- Young children are at a particular risk for accidental overdose because they are more sensitive to the effects of antihistamines.
- The elderly are more prone to adverse effects due to changes in metabolism and increased fall risk.
- Patients with liver or kidney impairment may also be at higher risk, as their bodies may clear the drug less efficiently, leading to toxic concentrations.
Recognizing Signs of Severe Toxicity and Seizure Activity
Before a seizure occurs, a person experiencing severe diphenhydramine toxicity will often exhibit signs of anticholinergic syndrome. These symptoms include flushed, dry skin, an abnormally fast heart rate (tachycardia), and dilated pupils. The person may also have difficulty urinating, experience dry mouth, and have a fever.
Neurological signs of toxicity include extreme confusion, agitation, and disorientation. Hallucinations, where the person sees or hears things that are not present, are a common manifestation of severe overdose. In some cases, the initial presentation may be somnolence, which can then rapidly progress to delirium, psychosis, and agitation.
A seizure resulting from diphenhydramine toxicity is often a generalized tonic-clonic seizure, which involves a loss of consciousness and full-body convulsions. However, in the context of overdose, seizures are typically an indication of a severe, life-threatening emergency. Other severe complications that may accompany a seizure include dangerously irregular heart rhythms and wide-complex tachycardia.
Immediate Response and Safe Usage Guidelines
If a person has taken too much diphenhydramine and is experiencing severe symptoms, such as hallucinations, an inability to be awakened, or a seizure, immediate medical attention is required. Call 911 or contact the US National Poison Control Center at 1-800-222-1222. If a seizure is actively occurring, the goal is to protect the person from injury, which involves gently guiding them to the floor and placing something soft under their head.
Avoid restraining the person or putting anything into their mouth while they are seizing. Time the seizure duration, as this information will be crucial for emergency medical personnel. While waiting for help, do not attempt to give the person anything to eat or drink.
Prevention of toxicity begins with adherence to the drug’s label instructions, ensuring the recommended dose is never exceeded. For adults, the maximum dose is 50 to 100 mg for a single dose, not to exceed 300 mg in a 24-hour period. Children under six years old should avoid this medication, and parents should consult a pediatrician before administering it. Always check combination cold and flu products to ensure they do not already contain diphenhydramine, which could lead to accidental overdose. Individuals with a history of seizures or cardiac issues should consult with a healthcare provider before using the drug.