Diphenhydramine

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 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
• 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]