Diphenhydramine

Sicari V, Zabbo CP.

Continuing Education Activity

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. Additional off-label use is for the treatment of oral mucositis. This activity will highlight
the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of diphenhydramine,
pertinent for members of the interprofessional team in the treatment of patients

Objectives:

Explain the mechanisms of action for diphenhydramine.

Identify the approved and off-label indications for diphenhydramine use.
Review the possible adverse events associated with diphenhydramine.
Review the importance of improving care coordination among interprofessional team members to improve outcomes
for patients where diphenhydramine can play a role in treatment.

Access free multiple choice questions on this topic.

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 patients with allergies to other, more commonly used local anesthetics; however, this is an off-
label use of the medication. 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 the 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 to
9.2hours. The drug's time to peak, serum is 2 hours.

Administration
Diphenhydramine can be given by tablet, capsule, or 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 to 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 the event; max 37.5
 mg/day
6 to 11 years: 12.5 to 25mg by mouth/IM/IV every 4 to 6 hours as needed; start 30 min before the 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 the entire contents of a 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 E!ects
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
Heatstroke

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, leading to QTc prolongation.[6][7][8]
Use 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, sedatives, 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 using sodium
bicarbonate and intravenous lipid emulsion therapy.[13]

Enhancing Healthcare Team Outcomes

Diphenhydramine is now available over the counter, but that does not mean that interprofessional healthcare team members
should not pay close attention to when patients are using it, particularly if they are self-medicating; the clinician (MD, DO,
NP, PA), nurse, and pharmacist needs to educate the patient on the safe use of this agent. While the drug is relatively safe, it
should not be combined with alcohol, other sedatives, and hypnotics. The patient 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. Interprofessional collaboration and information sharing will result in improved patient outcomes and
help to preclude adverse events. [Level 5]

Review Questions
 Access free multiple choice questions on this topic.
Comment on this article.

References
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mechanism. Lung. 2008;186 Suppl 1:S74-7. [PMC free article: PMC3131005] [PubMed: 17909896]
3. Green SM. What is the role of diphenhydramine in local anesthesia? Acad Emerg Med. 1996 Mar;3(3):198-200. [PubMed:
8673772]
4. Pavlidakey PG, Brodell EE, Helms SE. Diphenhydramine as an alternative local anesthetic agent. J Clin Aesthet
Dermatol. 2009 Oct;2(10):37-40. [PMC free article: PMC2923931] [PubMed: 20725573]
5. Pham AQ, Scarlino C. Diphenhydramine and acute kidney injury. P T. 2013 Aug;38(8):453-61. [PMC free article:
PMC3814442] [PubMed: 24222977]
6. Sype JW, Khan IA. Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine
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7. Husain Z, Hussain K, Nair R, Steinman R. Diphenhydramine induced QT prolongation and torsade de pointes: An
uncommon effect of a common drug. Cardiol J. 2010;17(5):509-11. [PubMed: 20865683]
8. Olasińska-Wiśniewska A, Olasiński J, Grajek S. Cardiovascular safety of antihistamines. Postepy Dermatol Alergol. 2014
Jun;31(3):182-6. [PMC free article: PMC4112269] [PubMed: 25097491]
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overdose. Hum Exp Toxicol. 2000 Sep;19(9):489-95. [PubMed: 11204550]
10. Krenzelok EP, Anderson GM, Mirick M. Massive diphenhydramine overdose resulting in death. Ann Emerg Med. 1982
Apr;11(4):212-3. [PubMed: 7073039]
11. Zareba W, Moss AJ, Rosero SZ, Hajj-Ali R, Konecki J, Andrews M. Electrocardiographic findings in patients with
diphenhydramine overdose. Am J Cardiol. 1997 Nov 01;80(9):1168-73. [PubMed: 9359544]
12. Köppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982
to 1985. J Toxicol Clin Toxicol. 1987;25(1-2):53-70. [PubMed: 3586086]
13. Abdi A, Rose E, Levine M. Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic
sodium bicarbonate and i.v. lipid emulsion. West J Emerg Med. 2014 Nov;15(7):855-8. [PMC free article: PMC4251236]
[PubMed: 25493135]

Publication Details

Author Information

Authors

Vincent Sicari1; Christopher P. Zabbo2.

A"liations
1 Kent Hospital

2 Kent Hospital/ UNECOM

Publication History

Last Update: July 15, 2021.

Copyright
Copyright © 2021, StatPearls Publishing LLC.

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Publisher

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NLM Citation

Sicari V, Zabbo CP. Diphenhydramine. [Updated 2021 Jul 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.