The role of histamine in pharmacology Dr.

Nelson Brown
Textbook: Basic & Clinical Pharmacology Katzung, Masters and Trevor, 11th or 12th edition

Histamine

Biologically active amine (autacoid, like serotonin) found in plant and animal tissues; active component of some venoms and stinging secretions Nervous tissues Also found in non-neural tissues (mast cells, basophils) Released locally

Histamine
Multiple receptors in multiple tissues

Complex physiologic / pathologic effects: - Mediator of immediate allergic reactions (urticaria, allergies) and inflammatory reactions - Neurotransmitter or neuromudulator - Gastric acid secretion

Basic pharmacology of histamine

Formed by de-carboxylation of L-Histidine

Stored in intracellular granules; upon release, histamine is metabolically inactivated (methylation, oxidation) In tissues granules in mast cells and basophils

Mast cell

Basic pharmacology of histamine

Enterochromaffin-like (ECL) cells of the stomach (fundus): activate the acid-producing parietal cells of the gastric mucosa

Some tumors (gastric carcinoid, systemic mastocytosis) are

associated with increased number of mast cells or basophils secretion of histamine or histamine metabolites Brain (neurotransmitter) Neuro-endocrine control Cardio-vascular regulation Thermal / body weight

regulation

Storage and release of histamine

Immunologic release: Part of type I hypersensitivity (immediate) response (urticarial, allergic reactions)

Chemical and mechanical release: Displacement secondary to other amines (morphine), chemical mast cell injury

Pharmacodynamics
Four different cell surface receptors (H1-H4)
Belong to the 7-transmembrane spanning G protein coupled receptors

Variable post-receptor mechanisms (depending on type of G protein) H1: smooth muscle, endothelium, brain, nerves (IP3, DAG, Ca++) H2: gastric mucosa, cardiac muscle, mast cells, brain (cAMP production) H3: pre-synaptic, brain, myenteric plexus H4: eosinophils, neutrophils, lymphocytes

Tissue / organ effects

Cardiovascular system: decreases systolic / diastolic pressure and increases heart rate (H1, H2) Flushing, headache

1. Direct vasodilator action (arterioles and pre-capillary sphincters)

2. Separation of endothelial cells

Edema (transudation of fluids and proteins)

3. Direct cardiac effects

Increased contractility and heart rate

Tissue / organ effects

Bronchiolar smooth muscle:

Bronchoconstriction (H1-mediated)

Patients with asthma (or cystic fibrosis) are very sensitive to histamine

Tissue / organ effects

Gastrointestinal tract smooth muscle:

Contraction of intestines (H1-mediated)

* Large doses of histamine may cause diarrhea

Tissue / organ effects Secretory tissues:

- Powerful stimulant of gastric acid secretion - Activation of H2 receptors on gastric parietal cells (increased cAMP, increased Calcium)

* Stimulates secretion in the small and large intestine

Tissue / organ effects Nervous system

- Stimulates sensory nerve endings (pain, itching) during urticarial response and reactions to insect stings (H1-mediated)

- Control of the appetite (H1, H3) - Sleep (central effect) Metabolic effects: H3 receptor knockout mice > food intake < energy expenditure obesity insulin resistance

Histamine antagonists

1. Physiologic antagonists:
Epinephrine: smooth muscle actions opposite to histamine; Injection of epinephrine can save your life in systemic anaphylaxis!

2. Release inhibitors:
Reduce degranulation of mast cells (cromolyn, nedocromil). Mechanism of action unclear

3. Histamine receptor antagonists:

The most commonly used are H1 and H2 antagonists (antihistamines)

H1 receptor antagonists 1. Pharmacokinetics

Stable amines Rapid absorption after oral administration Metabolized in microsomal system (liver) Effective duration of action of 4-6 hours Used to treat allergic conditions

- First generation H1 antagonists: enter the CNS, sedating, block autonomic receptors (Diphenhydramine, Chlorpheniramine) - Second generation H1 antagonists: less complete distribution into the CNS, less sedating (Cetirizine, Loratidine, Desloratidine). Some are metabolized by a P450 type that is inhibited by drugs such as the antifungal ketoconazole.

H1 receptor antagonists 1. Pharmacodynamics

Reversible competitive binding to H1 receptors Many inverse agonists Low potency at the H2 receptor First generation H1 antagonists have many actions in addition to blocking the actions of histamine (cross reactivity with muscarinic cholinoceptors, alpha-adrenoceptors, serotonin and local anesthetic receptors): - Sedation (variable between drugs and patients) - Anti-nausea, anti-emetic (prevent motion sickness) - Anti-parkinsonism effects - Atropine-like effects (anti-cholinoceptor) - Adrenoceptor-blocking actions (promethazine) - Serotonin-blocking actions (cyproheptadine) - Local anesthesia (block Na channels similar to procaine or lidocaine)

Clinical use of H1 receptor antagonists

1. Allergic reactions: - First choice to treat symptoms of allergic reactions and urticaria - Not effective in asthma - In atopic dermatitis, used mainly as sedative - Second generation: allergic rhinitis, chronic urticaria 2. Motion sickness and vestibular disturbances: - First generation (prevention): diphenhydramine, promethazine (sedating) cyclizine, meclizine (less sedating) 3. Nausea and vomiting of pregnancy (morning sickness): - Possible teratogenic effects

Adverse effects
1. First generation H1 antihistamines: Sedation Visual disturbance Urinary retention Arrhytmias

2. Second generation H1 antihistamines: - Important drug-drug interactions: Macrolides (erythromicin, clarithromicin), ketoconazol.

H2 receptor antagonists
Inhibit histamine-induced acid secretion

H2 receptor antagonists
1. Selective competitive antagonism at H2 receptors: Cimetidine Ranitidine Famotidine

2. Effects: Reduction of acid gastric secretion Other (non-related to H2 blocking): inhibition of P450 system

(cimetidine), anti-androgen effects (binding to androgen

receptors, cimetidine)

Clinical uses of H2 receptor antagonists

Peptic ulcer disease

Gastric ulcer Gastro-esophageal reflux disorder

Hypersecretory disease:
Zollinger-Ellison syndrome (acid hypersecretion associated with gastrin-secreting tumor)

Systemic mastocytosis and multiple endocrine adenomas

H2 receptor antagonists
Adverse effects: These agents are generally well tolerated Diarrhea, dizziness, somnolence, headache, rash Confusion, delirium (the elderly) Gynecomastia (men) and galactorrhea (women), anti-

androgenic effect (cimetidine)