Mechanism of Action of Diphenhydramine

Mechanism of Action of Diphenhydramine

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Introduction

Diphenhydramine is a first-generation H₁ antihistamine belonging to the ethanolamine class. It is widely used for the treatment of allergic conditions and is also commonly employed as a sedative, antiemetic, antitussive, and antiparkinsonian adjunct. Because of its strong central anticholinergic and sedative properties, diphenhydramine is a high-yield drug in pharmacology, medicine, nursing, and emergency medicine examinations.

MOA of diphenhydramine
Mechanism of action of diphenhydramine
Diphenhydramine Mechanism of Action Flowchart
Stepwise mechanism of action of diphenhydramine

Mechanism of Action (Step-wise)

Diphenhydramine produces its pharmacological effects primarily through histamine and muscarinic receptor blockade.

Step-wise mechanism:

  1. Histamine Release in Allergic Reactions
    In allergic states, mast cells release histamine, which acts on H₁ receptors to cause vasodilation, increased capillary permeability, itching, and bronchoconstriction.
  2. H₁ Receptor Antagonism
    Diphenhydramine competitively blocks histamine H₁ receptors in peripheral tissues.
  3. Reduction of Allergic Symptoms
    H₁ blockade reduces:
    • Vasodilation
    • Capillary permeability
    • Edema
    • Pruritus
  4. Central Nervous System Penetration
    Due to high lipophilicity, diphenhydramine readily crosses the blood–brain barrier.
  5. Sedative Effect
    Central H₁ receptor blockade in the brain produces sedation and drowsiness.
  6. Anticholinergic (Antimuscarinic) Action
    Diphenhydramine blocks muscarinic receptors, contributing to:
    • Anti–motion sickness effects
    • Antiparkinsonian effects
    • Antiemetic action
  7. Suppression of Vestibular Stimulation
    Combined H₁ and muscarinic blockade suppresses vestibular signaling to the vomiting center.

Pharmacokinetics

  • Absorption: Well absorbed orally
  • Distribution: Widely distributed; crosses blood–brain barrier
  • Metabolism: Hepatic metabolism (CYP450 enzymes)
  • Elimination: Renal excretion of metabolites
  • Half-life: Approximately 4–8 hours
  • Onset of action: 15–60 minutes

Clinical Uses

Diphenhydramine is used in a wide range of allergic and non-allergic conditions:

  • Allergic rhinitis (hay fever)
  • Urticaria and pruritus
  • Motion sickness
  • Vertigo and vestibular disorders
  • Insomnia (short-term)
  • Acute dystonic reactions (drug-induced EPS)
  • Parkinson disease (adjunct)
  • Antitussive in cough syrups

Adverse Effects

Adverse effects are mainly due to CNS penetration and anticholinergic activity:

  • Central nervous system:
    • Sedation
    • Drowsiness
    • Dizziness
    • Confusion (elderly)
  • Anticholinergic effects:
    • Dry mouth
    • Blurred vision
    • Constipation
    • Urinary retention
    • Tachycardia
  • Paradoxical excitation (children, rare)

Diphenhydramine should be used cautiously in elderly patients and those with glaucoma or prostatic hypertrophy.

Comparative Analysis (must include a table + explanation)

Comparison of Antihistamines

FeatureDiphenhydramineLoratadineCetirizine
GenerationFirstSecondSecond
CNS penetrationHighMinimalLow
SedationHighNoneMild
Anticholinergic effectsProminentNoneMinimal
Motion sickness useYesNoNo

Explanation:
Diphenhydramine differs from second-generation antihistamines by its strong central and anticholinergic effects. While this limits its daytime use due to sedation, it provides advantages in motion sickness, acute dystonia, and short-term insomnia.

MCQs (10–15)

  1. Diphenhydramine primarily blocks which receptor?
    a) H₂ receptor
    b) H₁ receptor
    c) Dopamine receptor
    d) Serotonin receptor

Answer: b) H₁ receptor

  1. Diphenhydramine belongs to which generation of antihistamines?
    a) Third
    b) Second
    c) First
    d) Atypical

Answer: c) First

  1. Sedation caused by diphenhydramine is due to:
    a) Dopamine blockade
    b) Peripheral H₁ blockade
    c) Central H₁ blockade
    d) Serotonin inhibition

Answer: c) Central H₁ blockade

  1. Diphenhydramine is useful in motion sickness because of its:
    a) Opioid action
    b) Anticholinergic effect
    c) Dopamine antagonism
    d) GABA agonism

Answer: b) Anticholinergic effect

  1. Which adverse effect is most characteristic of diphenhydramine?
    a) QT prolongation
    b) Sedation
    c) Nephrotoxicity
    d) Hepatotoxicity

Answer: b) Sedation

  1. Diphenhydramine can be used to treat:
    a) Tardive dyskinesia
    b) Acute dystonia
    c) Schizophrenia
    d) Epilepsy

Answer: b) Acute dystonia

  1. Diphenhydramine crosses the blood–brain barrier because it is:
    a) Water soluble
    b) Ionized
    c) Lipophilic
    d) Protein bound

Answer: c) Lipophilic

  1. Diphenhydramine should be avoided in patients with:
    a) Allergic rhinitis
    b) Motion sickness
    c) Glaucoma
    d) Urticaria

Answer: c) Glaucoma

  1. Which property distinguishes diphenhydramine from loratadine?
    a) H₁ blockade
    b) Sedation
    c) Antiallergic effect
    d) Oral absorption

Answer: b) Sedation

  1. Diphenhydramine also acts as a:
    a) Beta blocker
    b) Anticholinergic
    c) Alpha agonist
    d) COX inhibitor

Answer: b) Anticholinergic

FAQs (minimum 5)

  1. What is the primary mechanism of diphenhydramine?
    Competitive antagonism of histamine H₁ receptors.
  2. Why does diphenhydramine cause sedation?
    Due to central H₁ receptor blockade in the brain.
  3. Does diphenhydramine have anticholinergic effects?
    Yes, contributing to its antiemetic and antiparkinsonian actions.
  4. Is diphenhydramine safe in elderly patients?
    Use cautiously due to risk of confusion and urinary retention.
  5. Can diphenhydramine be used for sleep?
    Yes, short-term use due to sedative effects.
  6. Is diphenhydramine useful for asthma?
    No, it does not relieve bronchoconstriction effectively.

References

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