Histamine And Antihistamine Drugs Department of Pharmacology Chalapathi

Histamine And Antihistamine Drugs Department of Pharmacology Chalapathi Institute of Pharmaceutical Sciences Guntur

AUTACOIDS DEFINITION: � “Self-remedy, Referring to the Action of Local Hormones”

What Are Autacoids ? �Histamine �Serotonin �Endogenous Peptides �Prostaglandins �Leukotrienes

HISTAMINE v Histamine ü is A naturally occurring imidazole derivative It is widely distributed in skin, GIT mucosa, lungs, brain, cerebro spinal fluid and bone marrow v It is also a component of some venoms and sting secretions

Synthesis and metabolism of histamine Histidine Histamine N-methyl histamine Imidazole acetic acid Methyl imidazole acetic acid

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 Ig. E 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.

Mechanical /Chemical Release: �A second type of release occurs following chemical or mechanical injury to mast cells. Ø In these injuries caused degranulation Ø drugs like morphine, succinyl choline, d-tubocurarine , hydralazine, dextran, poly vinyl pyridone (PVP) will liberate the histamine

Drugs that inhibit histamine release � β 2 -agonists like adrenaline, ephidrine, isoproterenol � Mast cell membrane stabilisers: disodiumcromoglycate and ketotifen

Receptors & Effects � Two receptors for histamine, H 1 and H 2, mediate most of the well-defined actions; 1. H 1 receptor: important in smooth muscle effects, especially those caused by Ig. E-mediated responses. ① IP 3 and DAG are released. ② Bronchoconstriction and vasodilation. ③ Vasodilation by release of endothelium-derived relaxing factor (EDRF), are typical responses of smooth muscle. ④ Capillary endothelium, in addition to releasing EDRF, also contracts, opening gaps in the permeability barrier and resulting in the formation of local edema.

2. H 2 receptor: activation of adenylyl cyclase → c. AMP↑ ① Mediates gastric acid secretion by parietal cells in the stomach. ② Cardiac stimulant effect. ③ Reduce histamine release from mast cells a negative feedback effect. 3. H 3 receptor: ① involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system. ② In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters.

Tissues and Organ System Effects of Histamine � Exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, and on the secretory cells of the stomach. � Sensitivity to histamine varies greatly among species - Humans, guinea pigs, dogs, and cats are quite sensitive, while mice and rats are much less so.

1. Nervous system: � histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. 2. Cardiovascular system: a. Cardiac effects: increased contractility and increased pacemaker rate. ——mediated chiefly by H 2 -R. But H 1 R mediates the decrease of contractility in human atrial muscle. b. Vascular effects: vasodilator action (H 1 -R, H 2 -R). endothelial cells contraction and increased permeability (H 1 -R). c. Platelet function: aggregation (H 1 -R) anti-aggregation (H 2 -R)

3. 4. Smooth muscle: contraction (H 1 -R) → bronchoconstriction, abort. Histamine - induced contraction of guinea pig ileum is a standard bioassay for this amine. Secretory tissues: stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. (H 2 -R)

Clinical Uses 1. 2. 3. Pulmonary Function Testing: Histamine aerosol is sometimes used as a provocative test of bronchial hyperreactivity. Testing Gastric Acid Secretion: However, pentagastrin is currently used for this purpose, with a much lower incidence of adverse effects. Diagnosis of Pheochromocytoma : Histamine can cause release of catecholamine from adrenal medullary cells. This hazardous provocative test is now obsolete.

Clinical uses, toxicity and contraindications of histamine � Main clinical use of histamine is as a positive control injection for skin allergy testing's ADR’S: � Flushing � Hypotension � Headache � Wheal formation � Bronchoconstriction � Gastric acidity

Other Histamine Agonists � Betahistine : � Impromidine : � α-methylhistamine : H 1 -R agonist H 2 -R agonists H 3 -R agonists Histamine antagonists Receptor antagonists: � Selective types) blockade of histamine receptors (H 1, H 2, H 3

H 1 receptor antagonists First-generation � Highly Sedative: Diphenhydramine, Dimenhydrinate, Promethazine, Hydroxyzine � Moderately Sedative: Pheniramine, Cyproheptadine, Meclizine, Buclizine, Cinnarizine � Mild Sedative: Chlorpheniramine, Dexchlorpheniramine, Dimethindine, Triprolidine, Dimethothiazine, Trimeprazine, Mequitazine, Cyclizine, Mepyramine, Carbinoxamine Second-generation � Fexofenadine, Loratidine, Desloratidine, Cetrizine, Levocetrizine, Azelastine, Mizolastine, Ebastine, Pupatadine, Astemizole

Therapeutic uses 1. Allergic Reactions: �Allergic rhinitis , atopic dermatitis, hay fever, urticaria 2. Motion sickness: �Vestibular disturbances 3. Sedation and hypnotics. : �these agents to be used has sleep-aids, i. e. hypnotics. �The newer H 1 antagonists by contrast, cause minimal or no sedation.

Adverse effects 2 nd generation: Free of CNS effects Ø Dryness of mouth, alteration of bowel movement, urinary hesitancy, blurring of vision (due to anticholinergic effect), Epigastric distress and headache

H 2 receptor antagonists � Cimetidine (Tagamet) � Ranitidine (Zantac) � Famotidine (Pepcid) � Roxatidine � Nizatidine

Clinical uses � Peptic Ulcer and Duodenal Disease � Gastric Ulcer: reduce symptoms promote healing for benign gastric ulcers � Gastroesophageal Reflux Disorder (erosive esophagitis) Hypersecretory Disease: ◦ Zollinger-Ellison syndrome: acid hypersecretion -caused by gastrin-secreting tumor ◦ Systemic mastocytosis and multiple endocrine adenomas: �

Adverse effects Generally well tolerated � Most common adverse effects: headache, dizziness, bowel upset, dry mouth, rashes, � CNS effects: Infrequently Confused state, restlessness, convulsion & coma – in elder with renal impairement especially with large doses infused i. v diarrhea , somnolence , , rash, thrombocytopenia , neutropenia , aplastic anemia) � Bolus i. v inj can release histamine – causes bradycardia, arrhythmias and cardiac arrest � Cimetidine (not other H 2 blockers) – antiandrogenic action – Gyanacomastia, loss of libido, impotence. Temporary decrease in sperm count

Interactions � Cimetidine - inhibits several CYP 450 isoenzymes – inhibits metabolism of theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole, warfarin. Imipramine, lidocaine, nifedipine, quinidine � Antacids reduces absorption of all H 2 blockers