Diphenhydramine, commonly sold under the brand name Benadryl, is a widely used over-the-counter medication for allergies, insomnia, and motion sickness. Its broad spectrum of effects is due to its interaction with multiple receptor types throughout the body. While it is generally safe at recommended doses, its influence on several key organs explains its side effect profile and potential for serious complications, particularly in cases of overdose or in certain sensitive populations.
Central Nervous System (CNS)
Diphenhydramine's most well-known effect is its impact on the central nervous system, which is a direct result of its ability to cross the blood-brain barrier. In the CNS, it acts as an inverse agonist at the histamine H1 receptors, which blocks the wakefulness-promoting actions of histamine. This causes the sedation, drowsiness, and fatigue commonly experienced by users. The antagonism of H1 receptors also contributes to its antiemetic (anti-nausea) effects, particularly related to motion sickness.
In addition to its antihistaminic action, diphenhydramine is a potent antagonist of muscarinic acetylcholine receptors, contributing significantly to its overall pharmacological profile. This anticholinergic effect can cause a range of symptoms, from mild confusion and impaired coordination to severe delirium and agitation, especially at higher doses. In children, paradoxical CNS stimulation is possible, leading to excitability rather than sedation. Long-term anticholinergic use, particularly in older adults, has been associated with an increased risk of cognitive decline and dementia.
Cardiovascular System
The cardiovascular system is another major organ complex affected by diphenhydramine, particularly at higher or toxic doses. While therapeutic doses typically cause minor changes, severe overdoses can be life-threatening. The medication can cause tachycardia (rapid heart rate) due to its anticholinergic properties, which block parasympathetic nerve signals.
More dangerously, diphenhydramine can block cardiac sodium and potassium channels, which are critical for proper heart rhythm. This blockade can prolong the QTc interval, a measure of ventricular repolarization on an electrocardiogram. A prolonged QTc interval increases the risk of developing life-threatening ventricular arrhythmias, including torsade de pointes. In severe overdose cases, this cardiotoxicity can lead to cardiac arrest.
Hepatic and Renal Systems
Diphenhydramine is primarily metabolized by the liver through the cytochrome P450 enzyme system, notably CYP2D6. The liver converts the active drug into less active metabolites, which are then excreted. While typically safe for the liver at recommended doses, caution is advised for individuals with pre-existing hepatic impairment, as their ability to metabolize the drug may be reduced. Overdose situations or use in sensitive individuals could potentially cause liver stress, especially if combined with other hepatotoxic medications.
The kidneys are responsible for the elimination of diphenhydramine and its metabolites from the body, primarily via urine. However, diphenhydramine's strong anticholinergic properties can affect the genitourinary system by causing urinary retention. This occurs because the medication can cause postrenal obstruction, leading to urine accumulation in the bladder. The increased pressure can then put a strain on the kidneys and potentially cause acute kidney injury, a risk that is higher in older adults. Rhabdomyolysis, or muscle damage, from severe overdoses can also lead to kidney damage.
Gastrointestinal and Ocular Systems
Diphenhydramine's anticholinergic effects extend to the gastrointestinal tract, slowing down peristaltic action and gastric emptying. This can result in common side effects such as:
- Dry mouth
- Constipation
- Epigastric distress or upset stomach
- Nausea or vomiting
In overdose, these effects can become more severe, causing issues like acute megacolon.
The eyes are also impacted by diphenhydramine's anticholinergic actions. These effects can lead to blurred vision due to the paralysis of ciliary muscles and dilated pupils (mydriasis), which can make eyes more sensitive to light. For individuals with narrow-angle glaucoma, this pupil dilation can trigger an acute angle-closure glaucoma attack, which is a medical emergency that can lead to permanent vision loss if untreated. The drug also reduces lacrimal (tear) secretions, leading to a sensation of dry eyes.
Comparison of First-Gen (Diphenhydramine) vs. Second-Gen Antihistamines
Because of its broader impact on multiple organ systems, first-generation antihistamines like diphenhydramine have a higher risk of side effects compared to newer, second-generation antihistamines, which have been engineered to be more selective.
| Feature | First-Generation (Diphenhydramine) | Second-Generation (e.g., Loratadine, Cetirizine) |
|---|---|---|
| Crosses Blood-Brain Barrier | Yes | No (or minimally) |
| Sedation | Pronounced | Non-sedating or minimal |
| Anticholinergic Effects | Strong (e.g., dry mouth, urinary retention) | Minimal or absent |
| Cognitive Impairment | Associated with increased risk, especially in older adults | Lower risk |
| Cardiotoxicity Risk | Higher in overdose (QT prolongation) | Significantly lower |
| Targeted Action | Non-selective, acts on multiple receptors | More selective for H1 receptors |
| Best for | Short-term use, treating allergies, insomnia, motion sickness | Long-term allergy relief with fewer side effects |
Conclusion
While effective for various conditions, diphenhydramine's effects are widespread across the body, impacting several major organ systems. Its ability to cross the blood-brain barrier is responsible for both its sedating effects and potent anticholinergic actions, which contribute to a wide range of side effects. The central nervous system, cardiovascular system, and genitourinary system are all particularly susceptible to its effects, especially at high doses or in sensitive individuals. Given the availability of safer, more selective alternatives for allergy relief, healthcare providers and patients should carefully weigh the risks and benefits associated with its use. Always follow recommended dosages and consult a healthcare provider with any concerns.
Learn more about diphenhydramine's detailed pharmacology from the National Institutes of Health.
