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==Pharmacological action==
==Pharmacological action==
{{Unreferencedsection|date=December 2007}}
{{Unreferencedsection|date=December 2007}}
Diphenhydramine works by blocking the effect of histamine at [[histamine H1 receptor|H<sub>1</sub>]] [[transmembrane receptor|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 [[Hay fever|allergic rhinitis]], [[hives]], [[motion sickness]], and insect bites and stings.
Diphenhydramine works by blocking the effect of histamine at [[histamine H1 receptor|H<sub>1</sub>]] [[transmembrane receptor|receptor]] sites. This results in effects such as the increase of vascular [[smooth muscle]] contraction, thus reducing the redness, hyperthermia and edema that occurs during an inflammatory reaction. In addition, by blocking the H1 receptor on peripheral nociceptors, diphenhydramine decreases their sensitization and consequently reduces itching that is associated with an allergic reaction. This is why diphenhydramine a popular choice for treatment of the symptoms of [[Hay fever|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 [[antidepressant]]s with similar structures and fewer side effects, culminating in the invention of [[fluoxetine]] (Prozac), a [[selective serotonin reuptake inhibitor]] (SSRI).<ref>Domino, Edward F. [http://www.psychosomaticmedicine.org/cgi/content/full/61/5/591 History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants.] ''Psychosomatic Medicine'' 61:591-598 (1999).</ref><ref>http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002</ref> A similar search had previously led to the synthesis of the first SSRI [[zimelidine]] from [[brompheniramine]], also an antihistamine.
In the 1960s it was found that diphenhydramine inhibits [[reuptake]] of the [[neurotransmitter]] [[serotonin]]. This discovery led to a search for viable [[antidepressant]]s with similar structures and fewer side effects, culminating in the invention of [[fluoxetine]] (Prozac), a [[selective serotonin reuptake inhibitor]] (SSRI).<ref>Domino, Edward F. [http://www.psychosomaticmedicine.org/cgi/content/full/61/5/591 History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants.] ''Psychosomatic Medicine'' 61:591-598 (1999).</ref><ref>http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002</ref> A similar search had previously led to the synthesis of the first SSRI [[zimelidine]] from [[brompheniramine]], also an antihistamine.

Revision as of 05:07, 28 February 2009

Diphenhydramine
Clinical data
Pregnancy
category
  • B
Routes of
administration		Oral, parenteral (IM), topical, suppository
ATC code
Legal status
Legal status
  • Over-the-counter, non-regulated
Pharmacokinetic data
Bioavailability86% bound to plasma protein
Protein binding98 to 99%
MetabolismVarious cytochrome P450 liver enzymes (cyp 2D6 (80%) ,cyp 3A4 (10%)
Elimination half-life2-8 hours
Excretion94% through the urine, 6% through feces
Identifiers
  • [2-(diphenylmethoxy)ethyl]dimethylamine
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.000.360 Edit this at Wikidata
Chemical and physical data
FormulaC17H21NO
Molar mass255.355 g/mol g·mol−1
Indicated for:

Other uses:

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:

Severe:

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

Liver:

  • Hepatotoxicity in extremely large dosages

Musculoskeletal:

  • 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:

Urogenital and reproductive:

  • Urinary retention, sexual dysfunction, vaginal dryness, decreased libido

Miscellaneous:

  • ?

Diphenhydramine hydrochloride Polish pronunciation: [[] Audio file "aɪ" not found, trade name Benadryl as produced by McNeil-PPC a division of Johnson & Johnson, or Dimedrol outside the U.S. & Canada, is a substance found in Nytol and some Unisom products (some other Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCI injectable; mainly used as an 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. Additionally, injectable diphenhydramine can be used for life threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex rather than risking the side effects of epinephrine. It is a member of the ethanolamine class of antihistaminergic agents.

Diphenhydramine is also an anticholinergic and was discovered during the search for synthetic alternatives to scopolamine which would be easier to work with.[citation needed]

Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnati.[1] It became the first FDA-approved prescription antihistamine in 1946.[2]

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 increase of vascular smooth muscle contraction, thus reducing the redness, hyperthermia and edema that occurs during an inflammatory reaction. In addition, by blocking the H1 receptor on peripheral nociceptors, diphenhydramine decreases their sensitization and consequently reduces itching that is associated with an allergic reaction. This is why 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).[3][4] A similar search had previously led to the synthesis of the first SSRI zimelidine from brompheniramine, also an antihistamine.

Common use and dosage

As an antihistamine, recommended doses for adults is 25-50 mg diphenhydramine every 4-6 hours, not to exceed 50-100 mg every 4-6 hours.[5]

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.[6] 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[7]), 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.[citation needed]

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.[citation needed]

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.[8] Severe, prolonged twitching and muscle spasm have also been experienced.[citation needed]

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

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.[9][10]

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.[11][12]

Diphenhydramine has shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a 3rd day of common dosage.[13]

Recreational use

Diphenhydramine is used both clinically and/or recreationally in conjunction with opioids to relieve itching and act as an analgesia potentiator.[14]

It is used recreationally as a deliriant, depressant, in combination with dextromethorphan, or booster for alcohol.[citation needed]

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.[15] Due to its interaction with a broad array of medications, combining diphenhydramine with other medications without medical supervision could have unanticipated and potentially hazardous results.

Many users report a side effect profile consistent with atropine intoxication.[citation needed] 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.[citation needed] Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia.

Toxicology also manifests in the autonomic nervous system, 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.[citation needed]

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.[citation needed]

See also

References

Notes

  1. ^ Hevesi D (2007-09-29). "George Rieveschl, 91, Allergy Reliever, Dies". New York Times. Retrieved 2008-10-14.
  2. ^ Ritchie J (2007-09-24). "UC prof, Benadryl inventor dies". Business Courier of Cincinnati. Retrieved 2008-10-14. {{cite web}}: Cite has empty unknown parameter: |1= (help)
  3. ^ Domino, Edward F. History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants. Psychosomatic Medicine 61:591-598 (1999).
  4. ^ http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002
  5. ^ "Diphenhydramine". Drugs and Human Performance FACT SHEETS. U.S. Department of Transportation. Retrieved 2008-10-14.
  6. ^ Raphael GD, Angello JT, Wu MM, Druce HM (2006). "Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis". Annals of allergy, asthma & immunology. 96 (4): 606–14. PMID 16680933. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ "Drug Facts". Chattem, Inc. Retrieved 2008-10-14.
  8. ^ Smith DW, Peterson MR, DeBerard SC (1999). "Local anesthesia. Topical application, local infiltration, and field block". Postgraduate medicine. 106 (2): 57–60, 64–6. doi:10.3810/pgm.1999.08.650. PMID 10456039. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Heine A (1996). "Diphenhydramine: a forgotten allergen?". Contact dermatitis. 35 (5): 311–2. PMID 9007386. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Coskey RJ (1983). "Contact dermatitis caused by diphenhydramine hydrochloride". Journal of the American Academy of Dermatology. 8 (2): 204–6. PMID 6219138. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ "Labeling of Diphenhydramine-Containing Drug Products for Over-the-Counter Human Use". Federal Register. 67 (235): 72555–9. 2002. Retrieved 2008-10-14.
  12. ^ Pray WS (2007). "Poison Ivy: The Classic Contact Dermatitis". US Pharmacist. 32 (4): 11–5.
  13. ^ Richardson, GS (October 2002). "Tolerance to daytime sedative effects of H1 antihistamines". Journal of Clinical Psychopharmacology. 22 (5). PMID 12352276. Retrieved 2008-12-03. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Carr KD, Hiller JM, Simon EJ (1985). "Diphenhydramine potentiates narcotic but not endogenous opioid analgesia". Neuropeptides. 5 (4–6): 411–4. PMID 2860599. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ "DiphenhydrAMINE: Drug Interactions".

Sources

  • J.A. Lieberman, History of the use of antidepressants in primary care. Primary Care Companion, J. Clinical Psychiatry, 2003; 5 (supplement 7).


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