Diphenhydramine


Article Author:
Vincent Sicari


Article Editor:
Christopher Zabbo


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
4/28/2019 2:37:23 PM

Indications

Diphenhydramine, which is available as an over-the-counter medication, is a first-generation antihistamine that is used in a variety of conditions to treat and prevent dystonias, insomnia, pruritis, urticaria, vertigo, and motion sickness. It also possesses local anesthetic properties for those patients who have allergies to other, more commonly used local anesthetics; however, this is an off-label use of the medication. An additional off-label use is for the treatment of oral mucositis.

Mechanism of Action

Diphenhydramine mainly works through antagonizing the H1 (Histamine 1) receptor, although it has other mechanisms of action as well.[1]

The H1 receptor is located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a wide variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and GIT, and eosinophilic chemotaxis promoting the allergic immune response.

Diphenhydramine acts as an inverse agonist at the H1 receptor, thereby reversing effects of histamine on capillaries, reducing allergic reaction symptoms. 

Given that diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center.[2]

The H1 receptor is similar to muscarinic receptors. Therefore, diphenhydramine also acts as an antimuscarinic; it is a competitive antagonist of muscarinic acetylcholine receptor, resulting in its use as an antiparkinson medication

Lastly, diphenhydramine acts as an intracellular sodium channel blocker, resulting in local anesthetic properties.

The liver metabolizes diphenhydramine via CYP450. It is excreted in the urine, unchanged, and has a half-life of 3.4-9.2h. Its time to peak, serum is 2 hours.

Administration

Diphenhydramine can be given by tablet, capsule, or in solution by mouth; by intramuscular (IM) or intravenous (IV) injection; or topically.

The following are recommended dosages for allergy symptoms:

Mild Symptoms

  • Adult
    • 25 to 50 mg by mouth/IM/IV every 4 to 6 hours as needed
    • Max: 300 mg/day by mouth; 100 mg/dose up to 400 mg/day IM/IV
  • Pediatric
    • 2 to 5 years: 6.25 mg by mouth/IM/IV every 4 to 6 hours as needed; max 37.5 mg/day
    • 6 to 11 years: 12.5-25mg by mouth/IM/IV every 4 to 6 hours as needed; max 150 mg/day
    • 12 years and older: use adult dosing

More Severe Symptoms

  • Adult
    • 25-50 mg by mouth/IM/IV every 2 to 4 hours as needed
    • Max: 300 mg/day by mouth; 100mg/dose up to 400 mg/day IM/IV
  • Pediatric
    • 2 to 11 years: 1-2mg/kg by mouth/IM/IV every 2 to 4 hours as needed; max: 300 mg/day by mouth; 100mg/dose up to 400 mg/day IM/IV
    • 12 yo and older: use adult dosing

Extrapyramidal Symptoms

  • 25 to 50 mg by mouth/IM/IV every 6 to 8 hours as needed
  • Max 300 mg/day by mouth; 100 mg/dose up to 400 mg/day IM/IV
  • Pediatric
    • 2 to 11 years: 1 to 2 mg/kg by mouth/IM/IV every 6 to 6 hours as needed; max: 50 mg/dose up to 300 mg/day IM/IV
    • 12 years and older: use adult dosing

Insomnia (Short Treatment)

  • 25 to 50 mg by mouth at bedtime as needed, start 30min before bedtime
  • Pediatric - 12 yo and older: 25 to 50 mg by mouth at bedtime as needed; start 30min before bedtime

Motion Sickness Prevention

  • 25 to 50 mg by mouth/IM/IV every 4 to 6 hours as needed.
  • Start 30 min before event; max 300 mg/day by mouth; 100 mg/dose up to 400 mg/day IM/IV
  • Pediatric dose:
    • 2 to 5 years: 6.25 mg by mouth/IM/IV every 4 to 6 hours as needed; start 30 min before event; max 37.5 mg/day
    • 6 to 11 years: 12.5-25mg by mouth/IM/IV every 4 to 6 hours as needed; start 30 min before event; max 150 mg/day
    • 12 years and older: use adult dosing

Pruritis/Urticaria

  • 25 to 50 mg by mouth/IM/IV every 4 to 6 hours as needed. Max 300 mg/day by mouth; 100 mg/dose up to 400 mg/day IM/IV
  • Pediatric
    • 2 to 5 years: 6.25 mg by mouth/IM/IV every 4 to 6 hours as needed; max 37.5 mg/day
    • 6 to 11 years: 12.5 to 25 mg by mouth/IM/IV every 4 to 6 hours as needed; max 150 mg/day
    • 12 years and older: use adult dosing

Sedation

  • 25 to 50 mg by mouth/IM/IV every 4 to 6 hours as needed. Max 300 mg/day by mouth; 100 mg/dose up to 400 mg/day IM/IV

Pruritis/Urticaria (Topical Treatment)

  • Apply as needed; max 4 times/day
  • For local anesthesia
    • Prepare a 1% solution of diphenhydramine (10 mg/mL)
    • Draw up entire contents of vial containing 50 mg/mL diphenhydramine into a 10 mL syringe. This should measure at a volume of 1 mL. 
    • Dilute the contents of the syringe with four mL of 0.9% sodium chloride to yield a final volume of 5 mL. This is now Diphenhydramine 1% (10 mg/mL).[3] [4]
    • This use is off-label. 
    • Watch for tissue necrosis

Adverse Effects

Common Adverse Effects

  • Drowsiness
  • Dizziness
  • Impaired coordination
  • Headache
  • Epigastric discomfort
  • Thickened bronchial secretions
  • Dry mucous membranes
  • CNS stimulation, paradoxical
  • Constipation
  • Euphoria
  • Ataxia
  • Dysuria
  • Urinary retention
  • Hypotension
  • Blurred vision
  • Diplopia
  • Palpitations
  • Tachycardia
  • Photosensitivity
  • Diaphoresis
  • Erectile dysfunction
  • Early menses
  • Anorexia

Serious Reactions

  • Anaphylaxis/anaphylactoid reaction
  • QT prolongation
  • Anemia, hemolytic
  • Thrombocytopenia
  • Agranulocytosis
  • Leukopenia
  • Pancytopenia
  • Arrhythmias
  • Seizures
  • Toxic psychosis
  • Labyrinthitis, acute
  • Heat stroke

Cautions

  • May cause postrenal obstruction, which can lead to urinary retention and thus decreased glomerular filtration rate. If acute kidney injury develops, discontinue diphenhydramine and begin supportive care for acute kidney injury if needed.[5]
  • May cause CNS depression, which can impair driving or operating heavy machinery.
  • May potentiate the effects of sedatives, including alcohol.
  • Considered high-risk medication for elderly patients because of increased fall risk from dizziness, sedation, and hypotension.
  • Inhibition of fast sodium channels, and repolarizing potassium channels (Ikr) can prolong the action potential and the QT interval, thereby leading to QTc prolongation.[6][7][8]
  • Use in caution in patients with asthma, hyperthyroidism, cardiovascular disease, hypertension, or increased ocular pressure.

Contraindications

  • Documented hypersensitivity to diphenhydramine
  • Premature infants and neonates
  • Breastfeeding mothers
  • Pregnancy Category B - used only if clearly needed
  • Diphenhydramine has additive effects with alcohol and other CNS depressants (hypnotics, sedative, tranquilizers)
  • Monoamine oxidase A inhibitors prolong and intensify the anticholinergic effects of antihistamines

Monitoring

Obtain baseline creatinine level in pediatric patients.

Monitor all patients for mental alertness and relief of symptoms.

The intravenous infusion rate should be no higher than 25 mg/min.

Store at room temperature of 15 to 30 degrees C, and protect from freezing and light.

Toxicity

Diphenhydramine overdose[9][10] can cause significant toxicity, ranging from agitation to cardiac arrhythmias[11] to rhabdomyolysis and classic anticholinergic toxidrome.[12] Signs and symptoms may include the following:

  • Delirium, agitation, confusion, restlessness, hallucinations, ataxia, tremor, seizure
  • Dry sweat glands and mucous membranes
  • Flushed skin
  • Elevated body temperature
  • Mydriasis and blurry vision
  • Urinary retention
  • Tachycardia
  • Rhabdomyolysis

Treatment involves the following:

  • May attempt activated charcoal if within 1 hour of ingestion
  • Benzodiazepines for agitation and seizures; however, phenobarbital and propofol may be needed (avoid phenytoin/fosphenytoin, as they further block sodium channels)
  • Sodium bicarbonate for widened QRS to overcome sodium channel blockade; 2 mEq/kg, typically 2 to 3 amps of bicarb, then continuous infusion. Mix 3 ampules of sodium bicarbonate in 1L D5W, and run this infusion at 250 mL/hr.
  • Magnesium sulfate should be administered intravenously for prolonged QT interval
  • Vasopressors if hypotension develops
  • May consider physostigmine (acetylcholinesterase inhibitor that binds reversibly to inhibit acetylcholinesterase in the central and peripheral nervous system, which in turn allows acetylcholine to bind to muscarinic receptors to overcome the anticholinergic block.  This should be given in concert with medical toxicologist/poison control.
    • Dose: 0.5 to 2 mg IV over 5 min, onset within 20 min
    • Have atropine at the bedside, and watch for bradycardia
  • Further studies are needed to investigate the potential treatment of diphenhydramine toxicity with the use of sodium bicarbonate and intravenous lipid emulsion therapy.[13]

Enhancing Healthcare Team Outcomes

Diphenhydramine is now available over the counter and it is important for the pharmacist and nurse practitioner to educate the patient on safe use of this agent. While the drug is relatively safe, it should not be combined with alcohol, other sedatives and hypnotics. The user must be taught how to read labels and not take more than the recommended dose. Parents should be educated on the safe storage of this agent to prevent accidental ingestion by children.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Diphenhydramine - Questions

Take a quiz of the questions on this article.

Take Quiz
A skin laceration on the anterior thigh of a patient requires repair. The patient has a history of anaphylaxis to lidocaine and is reluctant to try similar types of local anesthetics. Which of the following can be safely used for local anesthetic in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following drugs has similar side effects as diphenhydramine?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old male brought in by emergency medical services to the emergency department for respiratory distress that developed acutely while at home. His mother reports that 10 minutes before this he was eating a cookie and has a known allergy to peanuts. While in the emergency department he is tachypneic with retractions and stridor, he is afebrile, his blood pressure is 80/52 mmHg, and he is tachycardic, and there is noted to be diffuse urticaria. The patient is given epinephrine immediately as the treatment of choice for anaphylaxis. What additional medication is effective in treating the cutaneous manifestations of anaphylaxis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Diphenhydramine is a sedating antihistamine and has which of the following properties?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Diphenhydramine is a first-generation antihistamine often given for allergic reactions or used as a sleep aid. While available over the counter, it shares a mechanism of action and can cause side effects associated with another well-known antimuscarinic drug. Which of the following would have similar effects?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A female is brought in to the emergency department with a complaint of feeling restless and intermittent head tilting and stiffness. Upon review of the patient's electronic medical record, it is noted that she was seen at the same emergency department earlier the same day for aggressiveness and extreme agitation requiring chemical restraint with medications, and subsequently discharged after psychiatric clearance. She is alert and oriented with no focal neurological deficits, but she is noted to have muscle spasm of the neck and bizarre ocular movements. The medication of choice to treat her symptoms works through which of the following mechanism?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 43-year-old farmer is brought to the emergency department for altered mental status. He was found by neighbors to be confused and wandering outside his home. He has a history of allergic rhinitis, diabetes, depression, and hypertension. His vital signs include a temperature of 102 F, a pulse of 110/min, and blood pressure of 148/82 mmHg. His blood sugar level is 176 mg/dL. On examination, his pupils are 8 mm in size bilaterally, the chest is clear bilaterally, with dry flushed skin and mucous membranes. Bowel sounds are absent. Which of the following is the most likely cause of the patient’s presentation?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Diphenhydramine - References

References

Green SM, What is the role of diphenhydramine in local anesthesia? Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 1996 Mar     [PubMed]
Pavlidakey PG,Brodell EE,Helms SE, Diphenhydramine as an alternative local anesthetic agent. The Journal of clinical and aesthetic dermatology. 2009 Oct     [PubMed]
Church MK,Church DS, Pharmacology of antihistamines. Indian journal of dermatology. 2013 May     [PubMed]
Bolser DC, Older-generation antihistamines and cough due to upper airway cough syndrome (UACS): efficacy and mechanism. Lung. 2008     [PubMed]
Sype JW,Khan IA, Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose. International journal of cardiology. 2005 Mar 18     [PubMed]
Olasińska-Wiśniewska A,Olasiński J,Grajek S, Cardiovascular safety of antihistamines. Postepy dermatologii i alergologii. 2014 Jun     [PubMed]
Husain Z,Hussain K,Nair R,Steinman R, Diphenhydramine induced QT prolongation and torsade de pointes: An uncommon effect of a common drug. Cardiology journal. 2010     [PubMed]
Pham AQ,Scarlino C, Diphenhydramine and acute kidney injury. P     [PubMed]
Radovanovic D,Meier PJ,Guirguis M,Lorent JP,Kupferschmidt H, Dose-dependent toxicity of diphenhydramine overdose. Human     [PubMed]
Krenzelok EP,Anderson GM,Mirick M, Massive diphenhydramine overdose resulting in death. Annals of emergency medicine. 1982 Apr     [PubMed]
Zareba W,Moss AJ,Rosero SZ,Hajj-Ali R,Konecki J,Andrews M, Electrocardiographic findings in patients with diphenhydramine overdose. The American journal of cardiology. 1997 Nov 1     [PubMed]
Köppel C,Ibe K,Tenczer J, Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982 to 1985. Journal of toxicology. Clinical toxicology. 1987     [PubMed]
Abdi A,Rose E,Levine M, Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and i.v. lipid emulsion. The western journal of emergency medicine. 2014 Nov     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Urologic. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Urologic, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Urologic, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Urologic. When it is time for the Surgery-Urologic board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Urologic.