Diphenhydramine

Diphenhydramine hydrochloride (trade name Benadryl, as produced by Pfizer, or Dimedrol outside the U.S.) is an over-the-counter (OTC) antihistamine and sedative. It may also be used for the treatment of extrapyramidal side effects of typical antipsychotics. It is a member of the ethanolamine class of antihistaminergic agents.

Diphenhydramine is widely used in nonprescription sleep aids with a maximum recommended dose of 50mg (as the hydrochloride salt) being mandated by the FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50 to 100mg recommended dose is permitted. In spite of its use and effectiveness as a sleep-inducing agent, when this drug is sold as an antihistamine, warning of the potential loss of alertness is rarely prominently displayed on packaging.

Diphenhydramine works by blocking the effect of histamine at H1 receptor sites. This results in effects such as the reduction of smooth muscle contraction, making diphenhydramine a popular choice for treatment of the symptoms of allergic rhinitis, hives, motion sickness, and insect bites and stings.

Diphenhydramine is a first generation antihistamine drug. Despite being one of the oldest antihistamines on the market, it is largely the most effective antihistamine available either by prescription or over-the-counter, and has been shown to exceed the effectiveness of even the latest prescription drugs. Consequently, it is frequently used when an allergic reaction requires fast, effective reversal of the often dangerous effects of a massive histamine release. However, it is not always the drug of choice for treating allergies. Like many other first generation antihistamines, is also a potent anticholinergic agent. This leads to profound drowsiness as a very common side-effect, along with the possibilities of motor impairment (ataxia), dry mouth and throat, flushed skin, rapid or irregular heartbeat (tachycardia), blurred vision at nearpoint due to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), pupil dilatation (mydriasis), urinary retention (ischuria), constipation, difficulty concentrating, short-term memory loss, visual disturbances, hallucinations, confusion, erectile dysfunction, and delirium. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine.

It is known that diphenhydramine contains sedative properties. Many new antihistamines have been introduced without the side effect of sedation. The drug is also used as a sleep aid and is an ingredient in many sleep aids, such as Unisom gelcaps, and most notably Tylenol PM where it is combined with Acetaminophen (Paracetamol), and Sominex which has diphenhydramine as its only active ingredient. Several generic and store brands of antihistamines and sleep aids also contain solely diphenhydramine. No physical addictive properties have been noted to this day.

In the 1960s it was found that diphenhydramine inhibits reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). A similar search had previously led to the synthesis of the first SSRI zimelidine from chlorpheniramine, also an antihistamine.

Recreational use
Those who use diphenhydramine recreationally take a higher dose than recommended dose (usually between 100mg and 450mg) for its deliriant effects. The mental effects are described by many as "dreaming while awake" involving visual and auditory hallucinations which, unlike those experienced with most psychedelic drugs, often cannot be readily distinguished from reality. People who consume a high recreational dose can possibly find themself in a hallucination which places them in a familar situation with people and friends and rooms they know, while in reality being in a totally different setting. Many users report a side effect profile consistent with tropane glycoalkaloidal poisoning. This is due to antagonism of muscarinic acetylcholine receptors in both the central and autonomic nervous system, inhibiting various signal transduction pathways. In the CNS, diphenhydramine readily crosses the blood-brain barrier, exerting effects within the visual and auditory cortex, accounting for reported visual and auditory disturbances.

Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia. Toxicology also manifests in the autonomic nervous system, primarily at the neuromuscular junction, resulting in ataxia and extrapyramidal side-effects, and at sympathetic post-ganglionic junctions, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry skin and mucous membranes. Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death. Such a side-effect profile is thought to give ethanolamine-class antihistamines a relatively low abuse liability.

Side effects
It should be noted that taking any medication that depresses the central nervous system is not recommended before driving or operating heavy machinery, due to impaired reaction time.

The most common cardiac dysrhythmias associated with diphenhydramine overdose are sinus bradycardia, elongated S-T segment interval, and premature ventricular contraction.

Diphenhydramine is very similar in its effects to dimenhydrinate (Dramamine®), its 8-chlorotheophyllinate salt, although the latter is approximately 60% the potency in terms of required dosage and is slightly less sedating.

The brand Benadryl is currently trademarked in the United States by Pfizer, but many drug store chains and retail outlets manufacture substantially less expensive generic versions under their own store brands, often sold in boxes that share the size, shape and familiar pink packaging and pill color of the original.