Histamine, Type I Hypersensitivity and Anti-histamines

Histamine, Type I Hypersensitivity and Anti-histamines

Instructor: Vanishree Rajagopalan, PhD
Email: vrajagop@touro.edu
Course Code: PRMC 646

Learning Objectives and Study Guide

  • Refer to course materials on Canvas for comprehensive learning objectives and study guide.

Lecture Overview

Topics Covered

  • Histamine

    • Synthesis and degradation

    • Location and physiology

    • Pharmacology: receptors and signaling

    • Pathophysiology in IgE mediated hypersensitivity

  • Antihistamines

    • H1 antagonists

    • H2 antagonists (details next semester)

    • Physiological antagonists

    • Prevention of histamine release

  • Side Effects and Clinical Uses

Histamine: Synthesis and Degradation

Definition

  • Histamine is a biogenic amine and an autacoid.

  • Major mediator of the inflammatory process.

  • Regulates gastric acid secretion.

  • Plays a minor role in neurotransmission.

  • Found in various tissues including:

    • Lungs

    • Vasculature

    • Stomach

    • Central Nervous System (CNS)

    • Peripheral nerves

Synthesis

  • Synthesized in:

    • Mast cells

    • Basophils

    • ECL cells (enterochromaffin-like cells) in gastric mucosa

    • CNS

  • Histamine is stored in granules, with two pools:

    • Slow-turning over pool: Basophils and mast cells (replenished slowly)

    • Rapidly turning over pool: ECL cells and neurons (not stored; synthesized on demand)
      Reference: Golan, Ch. 42

Histamine: Location and Physiology

Location

  • Primarily located in:

    • Mast cells and basophils

    • Lungs, skin, gastrointestinal tract (GIT) - areas where the inside meets the outside

    • Found in venoms and insect stings

Release Mechanism

  • Released following antigen presentation from:

    • Colds

    • Bacterial toxins

    • Bee sting venoms

    • Trauma

    • Allergies

    • Anaphylaxis through IgE sensitization of mast cells (immediate, type 1 allergic reaction)

Physiological Effects

  • Histamine release mediates symptoms of:

    • Allergic rhinitis (hay fever)

    • Acute urticaria (hives)

  • Major mediator of Type I hypersensitivity response, particularly in seasonal allergies.

Flush-Flare-Wheal Reaction

  1. Flush: Dilation of blood vessels results in local redness (erythema).

    • Widespread dilation may decrease vascular resistance, leading to lower blood pressure and shock.

  2. Flare: Stimulation of sensory nerve endings results in itching and pain in the skin.

  3. Wheal: Increased capillary permeability from vascular endothelium contraction results in tissue swelling (edema).

    • Widespread effects can lead to decreased blood volume and shock.

Tissue-Specific Effects

  • Lungs/Bronchi: Bronchoconstriction which may lead to asthma-like symptoms (H1 receptor)

  • Vascular Smooth Muscle: Dilation (Flush) and venoconstriction (H1 receptor)

  • Vascular Endothelium: Contraction leads to edema (Wheal) (H1 receptor)

  • Peripheral Nerves: Sensitization of afferent nerve terminals causing itchiness and pain (H1, H4 receptors)

  • Heart: Minor increase in heart rate and contraction (H2 receptor)

  • Stomach: Increased gastric acid secretion contributing to peptic ulcer disease (PUD) and heartburn (H2 receptor)

  • CNS: Acts as a neurotransmitter affecting circadian rhythms and wakefulness (H3 receptor)

Histamine in IgE-Mediated Hypersensitivity

Role of Histamine

  • Histamine is the major mediator in Type I/IgE-mediated hypersensitivity evidenced by:

    • Primary response: Mast cell degranulation upon initial allergen exposure

    • Secondary response: Effects from basophils and eosinophils

Symptoms Resulting from Histamine Release

  • Flush, flare, and wheal reactions in skin

  • Symptoms include runny nose, itchy eyes, and nasal congestion

  • Anaphylaxis characterized by systemic vasodilation and severe bronchoconstriction

Mast Cell Degranulation

  • Mast cells are located in tissues exposed to the outside environment:

    • Skin, connective tissues, eyes, nasal passages, lungs, digestive system

    • Positioned near small blood vessels and postcapillary venules

Pathophysiology of IgE-Mediated Hypersensitivity

Mechanism

  • Initial exposure to an allergen leads to sensitization of B cells and production of IgE.

  • Subsequent exposure: allergen cross-links IgE antibodies on mast cells, triggering degranulation and releasing histamine, resulting in associated symptoms.

Anaphylaxis Mechanism

  • Induced by systemic mast cell degranulation in individuals previously sensitized to allergens such as:

    • Allergenic food (e.g., nuts)

    • Insect bites

    • Antibiotics (e.g., penicillin)

  • Effects include:

    • Systemic vasodilation

    • Massive hypotension

    • Severe bronchoconstriction

    • Potentially lethal if not treated immediately

Symptomatic Treatment Strategies

  • Epinephrine:

    • Administered for severe systemic anaphylactic reactions

    • Mechanism: Relaxes bronchial smooth muscle, constricts blood vessels, stimulates heart activity

  • Antihistamines:f

    • Block histamine from binding to its receptors on target cells, act as inverse agonists.

  • Steroids:

    • Corticosteroids serve as potent anti-inflammatory agents, applied topically or taken orally.

  • Sodium cromolyn:

    • Prevents mast cell degranulation and subsequent histamine release.

Histamine Receptor Pharmacology

Receptor Subtypes

  • H1:

    • Signaling mechanism: Gq/11 → Increased IP3, DAG, and intracellular Ca2+; activates NF-κB.

    • Tissue distribution: Smooth muscle, vascular endothelium, brain (autoreceptor).

  • H2:

    • Signaling mechanism: Gs → Increased cAMP.

    • Tissue distribution: Gastric parietal cells, cardiac muscle, mast cells, brain.

  • H3:

    • Signaling mechanism: Gi/o → Decreased cAMP.

    • Tissue distribution: CNS and select peripheral nerves.

  • H4:

    • Signaling mechanism: Gi/o → Decreased cAMP, increased intracellular Ca2+.

    • Tissue distribution: Hematopoietic cells, gastric mucosa.

Antihistamines

H1-Antihistamines

Classification

  • First Generation:

    • Chlorpheniramine

    • Diphenhydramine

    • Meclizine

  • Second Generation:

    • Loratadine

    • Cetirizine

    • Fexofenadine

Mechanism of Action

  • Historically referred to as H1 receptor competitive antagonists but more recently shown to be inverse agonists.

CNS Effects

  • First Generation H1-Antihistamines can cross the blood-brain barrier (BBB), leading to central nervous system (CNS) effects.

  • Side effects include sedation due to blockade of both H1 and M receptors.

Second Generation H1-Antihistamines

  • Do not cross BBB, thus have no CNS effects.

Additional Effects

  • Antiemetic (dopaminergic): Doxylamine

  • Anticholinergic: Side effects include urinary retention, dry mouth, constipation, blurred vision

  • Antiadrenergic: Example: Promethazine - causes hypotension.

  • Serotonin blockade: Example: Cyproheptadine.

  • Local Anesthesia: Example: Diphenhydramine can block Na channels in excitable membranes.

Therapeutic Uses

  • Allergic conditions:

    • Used for allergic rhinitis and urticaria.

    • Common medications: chlorpheniramine, meclizine, diphenhydramine (first generations) and fexofenadine, loratadine (second generations).

  • Motion sickness and nausea:

    • Prevents or diminishes nausea primarily through vestibular pathways.

    • Example medications: dimenhydrinate, doxylamine.

  • Somnificants/Sedatives:

    • Due to interaction with other receptors.

    • Example: Diphenhydramine.

Adverse Effects

  • Side effects are related to interactions with other receptors:

    • Antimuscarinic effects: Dry mouth, blurred vision, constipation.

    • Alpha adrenoceptor blocking effects: Orthostatic hypotension.

Review Questions

  1. Histamine H1 receptor blockers are useful in the treatment of which of the following?

    • a. urticaria

    • b. seasonal rhinitis

    • c. asthma

    • d. a and b

  2. Which of the following drugs can reverse one or more smooth muscle effects of large increases in circulating histamine resulting from anaphylaxis in humans?

    • a. chlorpheniramine

    • b. cimetidine

    • c. epinephrine

    • d. sumatriptan

    • e. none of the above

  3. A 22-year-old female student asks for a recommendation for sneezing, watery and itchy eyes, and runny nose. What would be the best recommendation?

    • a. cromolyn sodium

    • b. fexofenadine

    • c. cimetidine

    • d. diphenhydramine

  4. Of the following antihistamines, which one is used for the purpose of sedation?

    • a. loratadine

    • b. cetirizine

    • c. cimetidine

    • d. diphenhydramine