Article: Diphenhydramine

Diphenhydramine
Systematic (IUPAC) name
2-benzhydryloxy-N,N-dimethyl-ethanamine
Identifiers
CAS number	58-73-1
ATC code	D04AA32 D04AA33, R06AA02
PubChem	3100
DrugBank	APRD00587
Chemical data
Formula	C17H21NO
Mol. weight	255.355 g/mol
Pharmacokinetic data
Bioavailability	86% bound to plasma protein
Protein binding	98 to 99%
Metabolism	Various cytochrome P450 liver enzymes
Half life	Approx. 6-8 hours in adults, 4-6 in children
Excretion	94% through the urine, 6% through feces
Therapeutic considerations
Pregnancy cat.	Class B
Legal status	Over-the-counter, non-regulated
Routes	Oral, parenteral (IM), suppository

Diphenhydramine hydrochloride (trade name Benadryl^®, as produced by Pfizer or Dimedrol outside the US) is an over-the-counter (OTC) antihistamine and sedative. It is also given in conjunction with typical antipsychotics to prevent akathisia. It is a member of the ethanolamine class of antihistaminergic agents.

Diphenhydramine is widely used in nonprescription sleep aids with a 50mg recommended dose 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 never 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 by and large 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, urinary retention, constipation, difficulty concentrating, short-term memory loss, visual disturbances, hallucinations, confusion, erectile dysfunction, and delirium.

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, most notably Tylenol PM. 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 than recommended dose 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. 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, 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 the Warner-Lambert Company, 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.