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Diphenhydramine

[dahy-fen-hahy-druh-meen]

Indicated for:

Other uses:

Halting allergic reactions, controlling extrapyramidal side-effects induced by antipsychotics

Contraindications:

Use in neonates and premature infants
Use in nursing mothers
Use as a local anesthetic
Use in people with hypersensitivity to diphenhydramine hydrochloride and other antihistamines of similar chemical structure

Non-medical use/abuse:

Used as a deliriant/hallucinogen

Side effects:

Myocardial infarction (Heart Attack), serious ventricular dysrhythmias, coma and death

Atypical sensations:

Feelings of heaviness, hearing disturbance

Cardiovascular:

Hypertension in sensitive individuals

Ear, nose, and throat:

Dryness of the nose and throat, heartburn

Endocrinal:

Increased or decreased appetite

Eye:

Dryness of the eyes, redness of the eyes, yellowing of the eyes

Gastrointestinal:

Constipation, nausea

Hematological:

Hepatotoxicity in extremely large dosages

Musculo skeletal:

Incoordination, slow muscle response, fasciculations (twitching), restlessness, extrapyramidal side-effects, restless-leg syndrome

Neurological:

Confusion, clouded thinking, drowsiness, hallucinations, delirium, euphoria, short-term memory loss

Psychological:

Agitation, anxiety, emotional lability, depression, excitability (especially in children), paranoia

Respiratory:

Decreased respiration

Skin:

Photosensitivity, flushing

Urogenital and reproductive:

Urinary retention, sexual dysfunction, vaginal dryness, decreased libido

Miscellaneous:

Diphenhydramine hydrochloride (trade name Benadryl as produced by McNeil-PPC a division of Johnson & Johnson, or Dimedrol outside the U.S. & Canada. Unisom and Nytol as sleeping pills) is an over-the-counter (OTC) antihistamine, antiemetic, sedative, and hypnotic. It may also be used for the treatment of extrapyramidal side effects of typical antipsychotics, such as the tremors that haloperidol can cause. It is a member of the ethanolamine class of antihistaminergic agents.

Diphenhydramine is also an anticholinergic, possessing 58 per cent of the anti-muscarinic power of atropine and was discovered during the search for synthetic alternatives to scopolamine which would be easier to work with.

Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl. It became the first FDA-approved prescription antihistamine in 1946.

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 (dye fen hye' dra meen) 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

As an antihistamine, recommended doses for adults is 25-50 mg diphenhydramine every 6-8 hours, not to exceed 50-100 mg every 4-6 hours.

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.

Diphenhydramine has sedative properties. 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), Nytol and the US version of Sominex -not to be confused with the UK version which uses Promethazine- which have Diphenhydramine as the only active ingredient. Several generic and store brands of antihistamines and sleep aids also contain solely diphenhydramine, such as Tylenol Simply Sleep.

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, though in the case of New Zealand the purchaser is required to provide the pharmacist with their name, address and other personal identification to be later logged in a national police data base following any purchase of over the counter medications containing diphenhydramine such as Unisom.

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 owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), pupil dilation (mydriasis), urinary retention (ischuria), constipation, difficulty concentrating, short-term memory loss, visual disturbances, hallucinations, irritability, itchy skin, 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 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.

Since 2002 the US FDA requires special labeling: avoid using multiple products including Diphenhydramine, or using topical forms to treat poison ivy Urushiol-induced contact dermatitis.

Recreational use

Diphenhydramine is used both clinically and recreationally in conjunction with opioids to relieve itching and act as an analgesia potentiator in a dose of 100-800 mg depending on body size and length of diphenhydramine use. It is used recreationally as a deliriant, depressant,in combination with dextromethorphan, or booster for alcohol. Diphenhydramine is a moderate CYP2D6 inhibitor, and as a result can cause increases in blood levels of drugs that are CYP2D6 substrates. Diphenhydramine can also have an additive effect with other CNS depressants. Due to its interaction with a broad array of medications, combining diphenhyrdamine with other medications without medical supervision could have unanticipated and potentially hazardous results.

Those who use diphenhydramine recreationally take a higher dose than recommended. In smaller recreational doses (100-250mg) the side effects are mild and are mainly limited to sleepiness and labored breath. The mental effects of higher doses (250+mg) are described by many as "dreaming while awake involving visual and auditory hallucinations that, unlike those experienced with most psychedelic drugs, often cannot be readily distinguished from reality. 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.

Many users report a side effect profile consistent with atropine intoxication. 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.