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 Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs 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 GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease and gastric and duodenal ulcers.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
2. T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells differentiate into Th2, which release interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins.
3. Interleukins stimulate B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics 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 Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and wheal formation
    • Can suppress itching by reducing histamine effects on nerve endings
    • H1 antagonists have anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs 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 Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of representative H1 antagonists
Type Drug Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
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 Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
  • Hepatic metabolism
  • Excretion: urine, feces
2nd generation Cetirizine
  • Oral
  • Rapid absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
  • Half-life: 8 hours
  • Limited hepatic metabolism
  • Excretion: mostly urine
Loratidine
  • Oral
  • Rapid absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
  • Allergic conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis 
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
  • Anaphylaxis (2nd-line treatment)
  • Diphenhydramine: also used to treat drug-induced extrapyramidal symptoms
  • Meclizine: motion sickness, acute vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. 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 Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
      • Tachycardia
      • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics 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 Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of H2 antagonists
Drug Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
Cimetidine
  • Oral
  • Rapidly absorbed
  • Bioavailability: approximately 70%
  • Partial hepatic metabolism
  • Excretion: primarily urine
Famotidine
  • Oral, IV
  • Incomplete absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption (oral)
  • Minimal 1st-pass metabolism
  • Excretion: urine
Nizatidine
  • Oral
  • Bioavailability: approximately 70%
  • Partial hepatic metabolism
  • Excretion: urine

Indications

  • Gastric and duodenal ulcers
  • GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease
  • Heartburn

Adverse effects and contraindications

  • Adverse effects:
    • Headache, dizziness
    • Confusion
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Prolonged use: B12 deficiency
    • Cimetidine: gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. 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 Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
  • Allergic conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
  • Anaphylaxis
  • Others:
    • Drug-induced extrapyramidal symptoms
    • Motion sickness, acute vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
    • Nausea, vomiting
2nd-generation H1 antagonists
H2 antagonists (blockers) Antagonists of H2 receptors located on gastric parietal cells
  • Gastric and duodenal ulcers
  • GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease
  • 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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