HOW ANTI-HISTAMINES RELAX ALLERGIC SYMPTOMS

Histamine Synthesis, Storage, Release, Actions, and Clinical Manifestations of Histamine Shock

Histamine Synthesis

Histamine is a bioactive amine synthesized from the amino acid histidine. This process involves a single enzymatic step catalyzed by the enzyme L-histidine decarboxylase (HDC). During this reaction, histidine undergoes decarboxylation to form histamine. The enzyme HDC requires pyridoxal phosphate (a derivative of vitamin B6) as a cofactor for its activity.

Histamine synthesis occurs in various cells and tissues, including:

Mast cells: Found in connective tissues throughout the body.
Basophils: A type of white blood cell circulating in the bloodstream.
Gastric enterochromaffin-like cells: Located in the stomach lining and involved in gastric acid secretion.
Neurons: Particularly in the posterior hypothalamus, where histamine functions as a neurotransmitter.

Histamine Storage

Once synthesized, histamine is stored in intracellular granules within mast cells and basophils. These granules are specialized vesicles that protect histamine from premature degradation. In addition to mast cells and basophils, histamine can also be stored in other cell types such as enterochromaffin-like cells in the stomach and certain neurons.

The storage mechanism ensures that histamine remains inactive until it is needed for physiological or pathological processes. The granules contain heparin or chondroitin sulfate proteoglycans that bind to histamine and stabilize it.

Histamine Release

Histamine release occurs when specific stimuli trigger degranulation of mast cells or basophils. Common triggers include:

Allergic reactions: In response to allergens, immunoglobulin E (IgE) binds to receptors on mast cells or basophils, leading to degranulation.
Tissue injury or inflammation: Physical damage or inflammatory mediators like cytokines can stimulate histamine release.
Certain drugs or toxins: Opioids, radiocontrast agents, and venoms may induce non-IgE-mediated degranulation.

Upon activation, these cells release preformed histamine into surrounding tissues or the bloodstream.

Actions of Histamine

The effects of histamine depend on which receptor subtype it binds to. There are four known histamine receptors (H1–H4), each with distinct locations and functions:

H1 Receptors

Found in smooth muscle cells (airways and blood vessels), endothelial cells, and neurons.
Activation causes:
- Vasodilation via nitric oxide release from endothelial cells.
- Increased vascular permeability leading to edema.
- Contraction of bronchial smooth muscles causing bronchoconstriction.
- Stimulation of sensory nerves resulting in itching or pain.

H2 Receptors

Primarily located on gastric parietal cells but also found on heart muscle cells and immune system components.
Activation leads to:
- Increased gastric acid secretion by parietal cells.
- Positive chronotropic (heart rate) and inotropic (contractility) effects on cardiac tissue.

H3 Receptors

Predominantly expressed in the central nervous system (CNS).
Regulate neurotransmitter release (e.g., dopamine, norepinephrine).
Play roles in sleep-wake cycles and cognitive function.

H4 Receptors

Found mainly on hematopoietic stem cells and immune system components like eosinophils.
Involved in chemotaxis during inflammatory responses.

Clinical Manifestations of Histamine Shock

Histamine shock refers to a severe systemic reaction caused by excessive release of histamine into circulation. This condition often results from anaphylaxis—a life-threatening allergic reaction—or massive tissue injury.

Pathophysiology

In cases of anaphylaxis or other triggers:

Massive amounts of histamine are released into systemic circulation.
Widespread activation of H1 receptors causes profound vasodilation and increased vascular permeability:
- Leads to hypotension due to reduced systemic vascular resistance.
- Causes fluid leakage from capillaries into tissues resulting in edema.
Bronchoconstriction mediated by H1 receptor activation contributes to respiratory distress.

Symptoms

Key clinical manifestations include:

Cardiovascular symptoms:
- Severe hypotension progressing to circulatory shock if untreated.
- Tachycardia as a compensatory response initially; bradycardia may occur later due to cardiovascular collapse.
Respiratory symptoms:
- Bronchospasm causing wheezing or difficulty breathing.
- Laryngeal edema leading to airway obstruction.

Cutaneous symptoms:
- Urticaria (hives), flushing, pruritus (itching).

Gastrointestinal symptoms:
- Nausea, vomiting, abdominal cramps due to smooth muscle contraction.

Management

Treatment focuses on reversing the effects of excessive histamine release:

Epinephrine injection: First-line treatment for anaphylaxis; counteracts vasodilation and bronchoconstriction by stimulating alpha and beta adrenergic receptors.
Antihistamines: Block H1/H2 receptors; used adjunctively for symptom relief but not sufficient alone for severe cases.
Corticosteroids: Reduce inflammation; useful for preventing late-phase allergic responses.

Mechanisms of Action of Antihistamines

Antihistamines are drugs that counteract the effects of histamine, a chemical involved in allergic reactions, inflammation, and gastric acid secretion. Histamine exerts its effects by binding to specific histamine receptors located throughout the body. Antihistamines work by targeting these receptors and either blocking their activation or reversing their activity.

Types of Histamine Receptors

Histamine acts on four types of receptors:

H1 Receptors: Found in smooth muscle, endothelium, and the central nervous system (CNS). Activation leads to allergic symptoms such as itching, swelling, and vasodilation.
H2 Receptors: Located primarily in the stomach lining; activation stimulates gastric acid secretion.
H3 Receptors: Found in the CNS and peripheral nervous system; regulate neurotransmitter release.
H4 Receptors: Present on immune cells like mast cells and eosinophils; involved in immune responses.

Most antihistamines target either H1 or H2 receptors:

H1-antihistamines block H1 receptors to alleviate symptoms of allergies (e.g., itching, sneezing).
H2-antihistamines block H2 receptors to reduce gastric acid production.

Inverse Agonism

Contrary to earlier beliefs that antihistamines were simple receptor antagonists, most modern antihistamines are classified as inverse agonists. They bind to histamine receptors and stabilize them in an inactive state, reducing both constitutive activity (baseline receptor activity) and histamine-induced activation.

Classification of Antihistamines

1. H1-Antihistamines

These are primarily used for treating allergies such as hay fever, urticaria (hives), and atopic dermatitis.

First-generation H1-antihistamines:
- Cross the blood-brain barrier easily.
- Cause sedation due to CNS effects.
- Examples: Diphenhydramine, Chlorpheniramine, Hydroxyzine.
Second-generation H1-antihistamines:
- Do not readily cross the blood-brain barrier.
- Non-sedating or minimally sedating.
- Examples: Loratadine, Cetirizine, Fexofenadine.

2. H2-Antihistamines

Used for conditions involving excessive stomach acid production such as peptic ulcers and gastroesophageal reflux disease (GERD). Examples include Ranitidine (withdrawn in many countries), Famotidine, and Cimetidine.

Pharmacokinetics

Absorption

Most antihistamines are well absorbed after oral administration. Peak plasma concentrations are typically reached within 1–3 hours for both first- and second-generation drugs.

Distribution

First-generation H1-antihistamines distribute widely throughout the body due to their lipophilicity and can cross the blood-brain barrier.
Second-generation H1-antihistamines have limited CNS penetration because they are substrates for P-glycoprotein efflux pumps at the blood-brain barrier.

Metabolism

Many first-generation antihistamines undergo hepatic metabolism via cytochrome P450 enzymes.
Second-generation drugs like Cetirizine are minimally metabolized and excreted largely unchanged.

Elimination

Elimination half-lives vary widely:

First-generation drugs often have shorter half-lives (~4–6 hours).
Second-generation drugs generally have longer half-lives (~12–24 hours), allowing once-daily dosing

Uses

H1-Antihistamines