Antihistamines

Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Additionally, with the ability to block muscarinic receptors, anticholinergic effects are also observed with this class of drugs. The 1st-generation H1 antagonists include chlorpheniramine, diphenhydramine, dimenhydrinate, and meclizine. Second-generation antihistamines generally do not cause drowsiness as these agents do not cross the blood-brain barrier. Examples of 2nd-generation antihistamines include loratadine, desloratadine, and cetirizine. Due to their antihistaminic activity, H1 antagonists are prescribed to treat allergy symptoms. Moreover, 1st-generation antihistamines are also used to treat motion sickness, nausea, and vomiting. H2 antagonists (blockers) target the H2 receptor, reducing gastric acid production and secretion. Thus, the general indications of H2 blockers include treatment of GERD and gastric and duodenal ulcers.

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Overview

Histamine

  • An endogenous substance involved in immediate allergic response and gastric acid regulation
  • Also participates in neurotransmitter modulation
  • Major sites of storage:
    • Mast cells in tissues
    • Basophils in blood
  • Both basophils and mast cells play a major role in type I hypersensitivity reactions.
  • Histamine receptors and distribution:
    • H1: smooth muscles (e.g., intestinal, bronchial), endothelial cells, CNS
    • H2: gastric parietal cells, cardiac muscle, mast cells, CNS
    • H3: CNS
    • H4: cells of hematopoietic origin
Type i anaphylactic hypersensitivity (acute)

Pathophysiology of type 1 hypersensitivity:
1. Antigen-presenting cells (APCs) recognize the allergen and present to naive T cells
2. T cells differentiate into Th2, which release interleukins.
3. Interleukins stimulate B cells to produce IgE.
4. Antigen-specific IgE binds to mast cells and basophils.
5. Subsequent exposure to the same antigen leads to degranulation and release of mediators.

TCR: T cell receptor

Image by Lecturio.

Antihistamines

  • H1 and H2 receptor antagonists (antihistamines) are approved for clinical use.
  • H1 antagonists:
    • Used to manage allergic symptoms
    • 1st-generation drugs cross the blood–brain barrier, thus interacting with the CNS receptors and causing sedation.
    • 2nd-generation drugs do not cross the blood–brain barrier and are considered nonsedating.
  • H2 antagonists:
    • Exert effects on the upper GI tract
    • Prevent histamine-induced acid release

H1 Antagonists

Medications

Table: H1 antagonists
1st generation 2nd generation
  • Carbinoxamine
  • Chlorpheniramine
  • Clemastine
  • Dexchlorpheniramine
  • Dimenhydrinate
  • Diphenhydramine
  • Doxylamine
  • Hydroxyzine
  • Meclizine
  • Promethazine
  • Triprolidine
  • Alcaftadine
  • Azelastine
  • Bepotastine
  • Bilastine
  • Cetirizine
  • Desloratadine
  • Emedastine
  • Epinastine
  • Fexofenadine
  • Ketotifen
  • Levocetirizine
  • Loratadine
  • Olopatadine
  • Rupatadine

Chemistry and pharmacodynamics

  • Many H1 antagonists have a substituted ethylamine moiety.
  • Mechanism of action:
    • Competitive antagonists of H1 receptor
    • Able to block muscarinic receptors (1st generation)
  • Effects:
    • Inhibit constriction of smooth muscles (e.g., respiratory muscles)
    • Inhibit vasodilation (endothelial cells)
    • ↓ Capillary permeability, reducing edema and wheal formation
    • Can suppress itching by reducing histamine effects on nerve endings
    • H1 antagonists have anticholinergic effects due to inhibition of the muscarinic receptors (therapeutically used to treat motion sickness).
Chemical structures of histamine and diphenhydramine

Chemical structures of histamine and diphenhydramine

Image: “Skeletal formula of histamine” by Vaccinationist. License: Public Domain
Image: “Skeletal formula of diphenhydramine” by Fvasconcellos. License: Public Domain

Pharmacokinetics

Table: Pharmacokinetics of representative H1 antagonists
Type Drug Pharmacokinetics
1st generation Chlorpheniramine
  • Oral
  • 33% protein binding
  • Half-life: up to 24 hours
  • Hepatic metabolism (CYP450)
  • Excretion: urine
Diphenhydramine
  • Oral, IM, IV
  • 99% protein binding
  • Half-life: up to 12 hours (adults)
  • Hepatic metabolism (N-demethylation by CYP2D6)
  • Excretion: urine
Meclizine
  • Oral
  • Half-life: approximately 5 hours
  • Hepatic metabolism
  • Excretion: urine and feces
Promethazine
  • Oral, rectal, IV, IM
  • Rapid oral absorption
  • Hepatic metabolism
  • Excretion: urine, feces
2nd generation Cetirizine
  • Oral
  • Rapid absorption
  • Half-life: 8 hours
  • Limited hepatic metabolism
  • Excretion: mostly urine
Loratidine
  • Oral
  • Rapid absorption
  • Half-life: 8 hours
  • Hepatic metabolism
  • Excretion: urine and feces
Olopatadine
  • Nasal, ophthalmic
  • No extensive metabolism
  • Excretion: mostly urine
CYP: cytochrome P450

Indications

  • Allergic rhinitis
  • Allergic conjunctivitis 
  • Urticaria
  • Anaphylaxis (2nd-line treatment)
  • Diphenhydramine: also used to treat drug-induced extrapyramidal symptoms
  • Meclizine: motion sickness, acute vertigo
  • Promethazine: nausea, vomiting (acute)

Adverse effects and contraindications

  • Adverse effects:
    • Sedation (1st generation)
    • Antimuscarinic effects (1st generation):
      • Dryness of mouth and respiratory passages
      • Urinary retention
      • Constipation
      • Tachycardia
      • Skin flushing
    • Loss of appetite, nausea, vomiting
  • Contraindication: hypersensitivity to the drug or its components
  • Avoid the use of sedatives with other medications that cause drowsiness.

H2 Antagonists

Medications

  • Histamine (along with gastrin, acetylcholine) stimulates gastric parietal cells to secrete acid.
  • H2 antagonists (blockers) interfere with pathways of gastric acid production and secretion.
  • Drugs in this class:
    • Cimetidine
    • Famotidine
    • Nizatidine
    • Ranitidine (withdrawn from the market due to presence of a contaminant, N-nitrosodimethylamine (NDMA))

Chemistry and pharmacodynamics

  • Drugs are modified histamine molecules with bulkier side chains.
  • Mechanism of action:
    • Reversible binding to histamine H2 receptors located on gastric parietal cells
    • Highly selective (other histamine receptors generally unaffected)
Chemical structures of histamine and cimetidine

Chemical structures of histamine and cimetidine

Image: “Skeletal formula of histamine” by Vaccinationist. License: Public Domain
Image: “Cimetidine structural formula” by Jü. License: Public Domain

Pharmacokinetics

Table: Pharmacokinetics of H2 antagonists
Drug Pharmacokinetics
Cimetidine
  • Oral
  • Rapidly absorbed
  • Bioavailability: approximately 70%
  • Partial hepatic metabolism
  • Excretion: primarily urine
Famotidine
  • Oral, IV
  • Incomplete absorption (oral)
  • Minimal 1st-pass metabolism
  • Excretion: urine
Nizatidine
  • Oral
  • Bioavailability: approximately 70%
  • Partial hepatic metabolism
  • Excretion: urine

Indications

  • Gastric and duodenal ulcers
  • GERD
  • Heartburn

Adverse effects and contraindications

  • Adverse effects:
    • Headache, dizziness
    • Confusion
    • Diarrhea, abdominal pain
    • Prolonged use: B12 deficiency
    • Cimetidine: gynecomastia (antiandrogen effect)
  • Contraindications: hypersensitivity to the drug or its components

Comparison of Antihistamines

Table: Antihistamines
Medication Mechanism of action Indication
1st-generation H1 antagonists (sedating)
  • Competitive antagonists of H1 receptor
  • 1st generation: able to block muscarinic receptors
  • Allergic rhinitis
  • Allergic conjunctivitis
  • Urticaria
  • Anaphylaxis
  • Others:
    • Drug-induced extrapyramidal symptoms
    • Motion sickness, acute vertigo
    • Nausea, vomiting
2nd-generation H1 antagonists
H2 antagonists (blockers) Antagonists of H2 receptors located on gastric parietal cells
  • Gastric and duodenal ulcers
  • GERD
  • Heartburn

References

  1. McQuaid, K.R. (2021). Drugs used in the treatment of gastrointestinal diseases. In Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250604938
  2. Skidgel, R.A. (2017). Histamine, bradykinin, and their antagonists. In Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172480964
  3. Stringer, J.L. (Ed.) (2017). Histamine and antihistamines. In Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class, 5e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2147&sectionid=161352490
  4. Stringer, J.L. (Ed.) (2017). Drugs that affect the GI tract. In Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class, 5e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2147&sectionid=161352543

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