Diphenhydramine

Diphenhydramine
Systematic (IUPAC) name
2-(diphenylmethoxy)-N,N-dimethylethanamine
Identifiers
CAS number 58-73-1
ATC code D04AA32 D04AA33, R06AA02
PubChem CID 3100
IUPHAR ligand 1224
DrugBank APRD00587
ChemSpider 2989
Chemical data
Formula C17H21NO 
Mol. mass 255.355 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 86% bound to plasma protein
Protein binding 98 to 99%
Metabolism Various cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%)[1]
Half-life 2.4-9.3 hrs[2]
Excretion 94% through the urine, 6% through feces [3]
Therapeutic considerations
Pregnancy cat. A(AU) B(US)
Legal status Over-the-counter
Routes Oral, parenteral (IM), parenteral (IV), topical, suppository
 YesY(what is this?)  (verify)
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:
  • 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)

Neurological:

  • restlessness, extrapyramidal side effects, restless-leg syndrome, confusion, clouded thinking, drowsiness, hallucinations, delirium, dysphoria, 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 (pronounced /ˌdaɪfɛnˈhaɪdrəmiːn/, abbreviated DPH or DHM) is a first generation antihistamine mainly used to treat allergies. Like most other first generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason is often used as a non-prescription sleep aid and a mild anxiolytic. The drug also acts as an antiemetic. It is produced and marketed under the trade name Benadryl by McNeil-PPC (a division of Johnson & Johnson) in the U.S. and Canada, and Dimedrol in other countries. It is also found in the name-brand products Nytol, Unisom, Tylenol PM, Midol PM and Advil PM though some Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCl injectable. It may also be used for the treatment of extrapyramidal side effects of many 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. An alternative IUPAC name is [2-(diphenylmethoxy)ethyl]dimethylamine.

Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnati.[4] In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA).[5]

The brand name Benadryl is trademarked in the United States by Johnson & Johnson. Many drug store chains and retail outlets sell less-costly generic versions.

Contents

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 is 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).[6][7] A similar search had previously led to the synthesis of the first SSRI zimelidine from brompheniramine, also an antihistamine.

Diphenhydramine also acts as a sodium channel blocker, which is responsible for its actions as a local anesthetic.[8]

Common use and dosage

As an antihistamine, the recommended dose for adults is 25–50 mg diphenhydramine every 4–6 hours.

Diphenhydramine is a first-generation antihistamine drug. Despite being one of the oldest antihistamines on the market it is more effective than even some of the latest prescription drugs.[9] 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 and is widely used in nonprescription sleep aids with a maximum recommended dose of 50 mg (as the hydrochloride salt) being mandated by the U.S. FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50–100 mg recommended dose is permitted.

The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol). An example of the latter is Tylenol PM. Examples of products having diphenhydramine as the only active ingredient include Unisom gelcaps (the tablet form contains doxylamine, a different active ingredient), Tylenol Simply Sleep, Nytol, and Sominex (the version sold in the US; that sold in the UK uses promethazine). Both types are also sold as generic or store brands.

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 has strong sedation, and is a potent anticholinergic agent. This leads to profound drowsiness as a very common side effect. Diphenhydramine has also been used as an anxiolytic because of these sedating side effects. Side effects include motor impairment (ataxia), dry mouth and throat, flushed skin, increased heart rate (tachycardia), blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), pupil dilation (mydriasis), urinary retention, constipation, difficulty concentrating, short-term memory loss, visual disturbances, hallucinations, irregular breathing, dizziness, irritability, itchy skin, confusion, decreased body temperature (generally in the hands and/or feet), erectile dysfunction, excitability, and delirium.[10] 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.[11]

Diphenhydramine is similar in its effects to dimenhydrinate, 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.[12][13]

Since 2002, the US FDA requires special labeling warning against using multiple products that contain diphenhydramine.[14] Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage.[15]

Paradoxical reactions to diphenhydramine are documented, particularly amongst children, and it may cause excitation instead of sedation.[16][17]

Because of potential for more severe side effects, diphenhydramine is on the "Beers list" to avoid in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf).

Benadryl Itch Stopping Gel contains additional ingredients including camphor. It is dangerous when swallowed.[18]

Recreational use

Diphenhydramine is used both clinically and/or recreationally in conjunction with opioids to relieve itching and act as an analgesia potentiator.[19] It is used recreationally as a deliriant, depressant, or as a potentiator of alcohol, DXM and some opiates.

The anticholinergic action of diphenhydramine can produce a characteristic euphoria similar to that seen with orphenadrine, a very close chemical relative, as well as dicylomine (dicycloverine), trihexyphenidyl, scopolamine &c.

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, 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.

Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambia.[20] Travelers are advised not to bring this drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine.[21]

It is also strictly prescription-only in most of the former Soviet Union. While most prescription medications are regularly dispensed without prescriptions, diphenhydramine is firmly associated with intravenous opiate use, will not be sold, and possession may cause complications with law enforcement.

Measurement in body fluids

Diphenhydramine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or assist in a medicolegal death investigation. Blood or plasma diphenhydramine concentrations are usually in a range of 10-150 μg/L in persons taking the drug orally for its antiemetic, antihistaminic or sedative effects, 0.7-2.7 mg/L (700-2700 μg/L) in those arrested for impaired driving, 1–5 mg/L in survivors of acute overdosage and 5–30 mg/L in victims of fatal overdosage. In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.[22][23]

See also

References

Notes

  1. ↑ "Showing Diphenhydramine (DB01075)". DrugBank. http://www.drugbank.ca/drugs/DB01075. Retrieved 5 September 2009. 
  2. ↑ "Drug information of Benadryl syr from Johnson & Johnson". MIMS Malaysia. http://www.mims.com/Page.aspx?menuid=mng&name=Benadryl+syr&brief=false&CTRY=MY. Retrieved 5 September 2009. 
  3. ↑ Garnett, WR (1986). "Diphenhydramine". Am Pharm (NS26(2)): 35–40. 
  4. ↑ Hevesi D (2007-09-29). "George Rieveschl, 91, Allergy Reliever, Dies". The New York Times. http://www.nytimes.com/2007/09/29/business/29rieveschl.html?ref=health. Retrieved 2008-10-14. 
  5. ↑ Ritchie J (2007-09-24). "UC prof, Benadryl inventor dies". Business Courier of Cincinnati. http://www.bizjournals.com/cincinnati/stories/2007/09/24/daily52.html. Retrieved 2008-10-14. 
  6. ↑ Domino, Edward F. History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants. Psychosomatic Medicine 61:591-598 (1999).
  7. ↑ http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002
  8. ↑ Kim YS, Shin YK, Lee C, Song J (October 2000). "Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine". Brain Research 881 (2): 190–8. doi:10.1016/S0006-8993(00)02860-2. PMID 11036158. http://linkinghub.elsevier.com/retrieve/pii/S0006899300028602. 
  9. ↑ Raphael GD, Angello JT, Wu MM, Druce HM (April 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. doi:10.1016/S1081-1206(10)63557-0. PMID 16680933. 
  10. ↑ "Diphenhydramine Side Effects". Drugs.com. http://www.drugs.com/sfx/diphenhydramine-side-effects.html. Retrieved 2009-04-06. 
  11. ↑ Smith DW, Peterson MR, DeBerard SC (August 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. 
  12. ↑ Heine A (November 1996). "Diphenhydramine: a forgotten allergen?". Contact dermatitis 35 (5): 311–2. doi:10.1111/j.1600-0536.1996.tb02402.x. PMID 9007386. 
  13. ↑ Coskey RJ (February 1983). "Contact dermatitis caused by diphenhydramine hydrochloride". Journal of the American Academy of Dermatology 8 (2): 204–6. doi:10.1016/S0190-9622(83)70024-1. PMID 6219138. 
  14. ↑ Food and Drug Administration, HHS (2002). "Labeling of Diphenhydramine-Containing Drug Products for Over-the-Counter Human Use". Federal Register 67 (235): 72555–9. PMID 12474879. http://www.fda.gov/OHRMS/DOCKETS/98fr/120602a.htm. Retrieved 2008-10-14. 
  15. ↑ Richardson, GS; Roehrs TA; Rosenthal L; Koshorek G; Roth T. (October 2002). "Tolerance to daytime sedative effects of H1 antihistamines.". Journal of Clinical Psychopharmacology 22 (5): 511–5. doi:10.1097/00004714-200210000-00012. PMID 12352276. 
  16. ↑ [1]
  17. ↑ de Leon J, Nikoloff DM (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports". CNS Spectr 13 (2): 133–5. PMID 18227744. 
  18. ↑ "Warning. Do NOT swallow Benadryl Itch Stopping Gel!"]. ConsumerMedSafety. Institute for Safe Medication Practices (ISMP). December 26, 2008. http://www.consumermedsafety.org/alerts.asp?p=2008_12_AL32. 
  19. ↑ Carr KD, Hiller JM, Simon EJ (February 1985). "Diphenhydramine potentiates narcotic but not endogenous opioid analgesia". Neuropeptides 5 (4-6): 411–4. doi:10.1016/0143-4179(85)90041-1. PMID 2860599. http://linkinghub.elsevier.com/retrieve/pii/0143-4179(85)90041-1. 
  20. ↑ "The Drug Enforcement Commission ZAMBIA: LIST OF PROHIBITED AND CONTROLLED DRUGS ACCORDING TO CHAPTER 96 OF THE LAWS OF ZAMBIA". http://www.deczambia.gov.zm/listofdrugs.html. 
  21. ↑ "travel.state.gov: Zambia". http://travel.state.gov/travel/cis_pa_tw/cis/cis_1062.html. 
  22. ↑ Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J. Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death. J. Anal. Toxicol. 29: 738-743, 2005.
  23. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 489-492.

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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