Diphenhydramine

Overview
Diphenhydramine hydrochloride (trade name Benadryl, as produced by J&J, or Dimedrol outside the U.S. & Canada. Nytol as a sleeping pill) is an over-the-counter (OTC) antihistamine, sedative and hypnotic. 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 was the first known antihistamine, invented in 1943 by Dr. George Rieveschl.

The brand Benadryl is currently trademarked in the United States by Pfizer, however many drug store chains and retail outlets manufacture less-costly generic versions under their own store brands.

Pharmacological action
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.

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.

Common use and dosage
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.

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 (however, the tablet form of Unisom contains Doxylamine, a different active ingredient ), and most notably Tylenol PM where it is combined with Acetaminophen (Paracetamol), and Nytol and Sominex which have diphenhydramine as the only active ingredient. Several generic and store brands of antihistamines and sleep aids also contain solely diphenhydramine.

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.

There are also topical formulations of diphenhydramine available, including creams, lotions, gels, and sprays. They are used to relieve itching, and have the advantage of causing much less systemic effect (i.e. drowsiness) than oral forms.

Side effects
Like many other first generation antihistamines, diphenhydramine is 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. Some side effects such as twitching may be delayed until the drowsiness begins to cease and the person is in more of an awakening mode. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine. Severe, prolonged twitching and muscle spasm have also been experienced.

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-chlorotheophylline salt, although the latter is approximately 60% the potency in terms of required dosage and is slightly less sedating.

Some patients have an allergic reaction to diphenhydramine in the form of hives.

Recreational use
Those who use diphenhydramine recreationally take a higher dose than recommended (usually between 225mg and 450mg) for its deliriant effects. Diphenhydramine is also a component of the recreational form of heroin known as "cheese" or "chiva". 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. Diphenhydramine generally has a low abuse profile due to the frequently unpleasant nature of the hallucinations. People who consume a high recreational dose can possibly find themselves in a hallucination which places them in a familiar situation with people and friends and rooms they know, while in reality being in a totally different setting. Inexperienced users of hallucinogens are liable to panic. 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 which inhibits various signal transduction pathways. In the CNS, diphenhydramine readily crosses the blood-brain barrier, exerting effects within the visual and auditory cortex.

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. The specific antidote for diphenhydramine poisoning is physostigmine, usually given by IV in hospital.