Medical pharmacology: Histamine and Anti-histamine Drugs

Medical Pharmacology Chapter 21: Histamine

Table of Contents
Introduction Chemistry/Pharmacokinetics Tissue Distribution Formation Inactivation Storage/Release Immunological Degranulation Release Regulation Response Modulation by Histamine Mechanical/Chemical Pharmacodynamics-Mechanism of Action Receptors Organ Systems Cardiovascular Gastrointestinal Bronchiolar Nerve Endings Secretory Tissue Clinical Pharmacology-Uses Toxicity Histamine Antagonist Introduction Histamine Antagonist Pharmacodynamics H₁Receptor Blockade H₁ Receptor Antagonists General Properties Receptor Types: Sites of Action Non-Histamine Receptor-Mediated Effects Sedation Antiemetic/Antinausea AntiParkinsonism Anticholinergic Anti-α-adrenergic Anti-serotonergic Local Anesthetic	Clinical Uses: H₁ Histamine Receptor Blockers Allergic Reactions H₁ histamine receptor blockers Second-generation H₁ histamine receptor blockers Motion Sickness Nausea and Vomiting (Pregnancy) H₁ Blockers: Toxicity Allergic Rhinitis H₁ Antihistamines - Uses Newer H₁ Antihistamines Topical α-adrenergic Agonists Oral α-adrenergic Agonists Cromolyn sodium Intranasal glucocorticoids Immunotherapy Drug-Drug Interactions: Second-generation H1 blockers H₂ Receptor Antagonists Introduction/Overview Drug Listing Pharmacodynamics Mechanism of Action Effects on organ systems Gastric Acid Secretion and Stomach motility Effects unrelated to H₂ receptor blockade Clinical Uses: H₂ Receptor Antagonists Peptic Ulcer Duodenal Disease Gastric Ulcer Gastroesophageal Reflux Disease Hypersecretory States Toxicity: H₂ Receptor Antagonists Drug-Drug Interactions

Histamine

Autacoids is a general term that refers to a number of compounds such as: histamine, serotonin, endogenous peptides, prostaglandins, and leukotrienes
- The formal definition of autacoids is "self-remedy, referring to the action of local hormones
Chemistry and Pharmacokinetics
- The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid L-histidine
- One of the important issues associated with formation of a biologically active compound is the mechanism that accounts for the compounds inactivation.
  - Histamine is active biologically, but the first step for its inactivation involves the addition of a methyl group (CH₃) followed by a chemical oxidation.
- Most of the time very little histamine is excreted unchanged because of these metabolic steps.
  - One exception would be the case of neoplastic disease (cancer).
  - Sgnificant histamine is excreted unchanged in the presence of these diseases: (a) systemic mastocytosis, (b) gastric carcinoid syndrome or (c) urticaria pigmentosa.
Tissue Distribution:
- The primary site for histamine localization is the mast cell granules (or basophils)
  - Mast cells are important in that they release histamine in response to potential tissue injury
  - Other sites include the central nervous system where histamine may function as a neurotransmitter and the fundus of the stomach (enterochromaffin-like cells) which are major acid secretagogues [They promotes accretion by activation of acid-producing mucosal parietal cells]
Histamine: Storage and Release
- Immunologic Release: The most important mechanism for histamine release is in response to an immunological stimulus.
  - In Mast cells, if sensitized by surface IgE antibodies, degranulate when exposed specific antigen.
    - Degranulation means liberation of the contents of the mast cell granules, including histamine. Degranulation is involved in the immediate (type I) allergic reaction.
      - Release regulation is present in most mast cells.
  - Histamine Modulation is associated with the inflammatory responses. Following local injury, histamine first produces a local vasodilation (reddening of the area) followed by an the release of acute inflammation mediators. Inflammatory cells are involved in this process and include neutrophils, eosinophils, basophils, monocytes & lymphocytes. In
- Mechanical/Chemical Release: A second type of release occurs following chemical or mechanical injury to mast cells. In these injuries caused degranulation as noted above including again histamine release. Common drugs such as morphine or tubocurarine can displace histamine from granule storage sites.

Pharmacodynamics-- Mechanism of Action
- Histamine mediates its effects by interacting with receptors.
- Receptor Types include H_1,H_2,and H₃ types. We will focus our attention on the first two types (H_1,H₂)

Receptor Subtype	Localization	Receptor coupling	Antagonists (partially selective)
H₁	Endothelium, brain, smooth muscle	Receptor activation causes and increased IP₃, DAG (diacylglycerol) production	N/A
H₂	Mast cells, gastric mucosa, cardiac muscle, brain	Receptor activation causes an increase in cAMP production	Ranitidine (Zantac), Cmetidine (Tagamet)
H₃	Presynaptic: brain, mesenteric plexus (other neurons)	G protein coupled	N/A

Receptor subtypes --H₁, H₂, and H₃:
- Intracellular G protein interactions
- H₁:endothelial and smooth muscle cell localization
  - H₁receptor activation causes can increase in phosphoinositol hydrolysis and an increase in intracellular calcium.
- H₂ gastric mucosa, cardiac muscle cells, immune cell localization:
  - H₂receptor activation causes an increase in cyclic AMP.
- H₃: primarily presynaptic
  - Activation causes a decrease in transmitter release (transmitters: histamine, acetylcholine, norepinephrine, serotonin)

Organ System Effects: Histamine

Cardiovascular
- Systolic and diastolic blood pressure
  - Vasodilation of arterioles and precapillary sphincters account for histamine's vasodilating effects.
    - Vasodilation may be due in part to nitric oxide liberation.
- Following from the reduced blood pressure, the heart rate increases by autonomic reflex mechanisms and by direct action.
- Both H₁ and H₂ receptors involved in cardiovascular responses.
- Histamine-associated edema: H₁ receptor effects (postcapillary vessels)
  - Increase in vessel permeability due to separation of endothelial cells, allowing transudation of fluid and molecules as large as small proteins.
    - Responsible for urticaria (hives)
    - Endothelial cell separation: secondary to histamine-induced calcium influx causing intracellular actin/myosin-mediated contraction
- Direct cardiac effects:
  1. Increased contractility (positive inotropism)
  2. Increased pacemaker rate (positive chronotropism)
Gastrointestinal tract:
- Histamine promotes intestinal smooth muscle contraction which is an H₁ receptor mediated effect
Bronchiolar smooth muscle
- Activation by histamine causes bronchoconstriction (H₁ receptor mediated )
- Inhaled histamine is a diagnostic, provocative test for bronchial hyperreactivity (asthma or cystic fibrosis)
Nerve Endings
- Sensory nerve endings are stimulated by histamine, especially those endings which mediate pain and itching.
- These effects are H₁ receptor mediated effect and represent part of the local reaction to insect stings (urticarial responses)
Secretory tissue:
- Histamine cause the stimulation of release by secretory tissues. For example, a significant increase in gastric acid secretion is caused by histamine. Other examples of increased release include gastric pepsin.
- Mechanism of Action: Considering the gastric parietal cells, histamine interacts with H₂ receptors and initiates a second messenger response which proceeds by:
  - (1) Increasing adenylyl cyclase activity which
    - (2) Results in an increase in the second messenger, cyclic AMP which
      - (3) Causes an increase in intracellular calcium levels.
        
        The increase in calcium triggers release.
        
        This releasing characteristic of calcium applies broadly in physiology.
Histamine: Clinical Pharmacology-- Uses
- Pulmonary Function: histamine aerosol may be used to test for bronchial hyperreactivity.
Toxicities include:
- Flushing, hypotension, tachycardia, headache, bronchoconstriction, gastrointestinal disturbances
  - Should not be given to asthmatics (except with extreme caution in pulmonary function testing)
  - Should not be given to patients with active ulcer disease or gastrointestinal hemorrhage.

Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.

Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1597-1616.