Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

HISTAMINE AND ANTIHISTAMINES

Discovery of Histamine

1910-1911Henry Dale and Patrick

Laidlaw identified and described the properties of histamine (from: histos = tissue, with an amine constituent).

What is histamine ?

Is a physiologically active amine, C5H9N3, found in plant and animal tissue and released from mast cells as part of an allergic reaction in humans. -It stimulates gastric secretion and -causes dilation of capillaries, -constriction of bronchial smooth muscle, and -decreased blood pressure.

Imidazoline ring and amine gp

Synthesis of Histamine :

Formed from the amino acid Histadine in a decarboxylation reaction with the enzyme histadine decarboxylase

Occurs primarily in mast cells and basophils

Histamine

Signal involved in local immune response, also a neurotransmitter

synthesized by the decarboxylation of histidine

Either stored or quickly inactivated by histamine-N-methyltransferase and diamine oxidase

Release of histamine from mast cells is stimulated by IgE antibodies which respond to foreign antigens in the body

Type Location FunctionH1 histamine receptor(H1 &H2- intra dermal injection- can cause tripple reaction)

•Smooth muscle-spasmodic contractions of ileum, uterus, diarrhoea•Exocrine glands-pancreas, salivary, lacrimal• Endothelium• CNS tissue

vasodilationBronchoconstrictionbronchial smooth muscle contraction separation of endothelial cells (responsible for hives), and pain and itching due to insect stings;

the primary receptors involved in allergic rhinitis symptoms and motion sickness;

sleep regulation.

Type Location Function

H2 histamine receptor Located on parietal cells

Primarily stimulate gastric acid secretion

H3 histamine receptor

Found on central nervous system and to a lesser extent peripheral nervous system tissue

Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin

H4 histamine receptor

Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon.

Plays a role in chemotaxis.

Allergic Reaction

Early phase reaction: occurs within minutes of exposure to an allergen and lasts for 30-90 minutes

Late phase reaction: begins 4-8 hours later and can last for several days, often leading to chronic inflammatory disease

Chemicals liberating histamine Morphine, D-tuboocurarine, Trimethophan, Polymyxin-b, Succinyl Choline, Hydralazine, Dextran, Polyvinyl Pyrolidine(pvp), Ditergents, Substance P, Bradykinin, Radiocontrast Media

Drugs inhibiting histamine release

-β-2agonist-Adrenaline, Ephedrine, Isoproterenol Mast cell stabilizers-Disodium Chromoglycate,

Ketotifen Negetive feedback control

Common allergic reactions

Mild/cutaneous

Mild to moderate

Severe/anaphylactic

erythema, urticaria, and/or itching

skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress

severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest

Clinical Symptoms Associated With Histamine Release

Antihistamines

A histamine antagonist (commonly called an antihistamine) is a pharmaceutical drug that

inhibits the action of histamine by either blocking its attachment to histamine receptors, or

inhibiting the enzymatic activity of histidine decarboxylase which catalyzes the transformation of histidine into histamine

Classification

1st Generation: Highly Sedative-dimenhydrinate, Diphenhydramine,

Doxylamine, Hydroxyzine, Promethazine Moderately Sedative-clemastine, Pyrilamine,

Cyproheptadine, Pheniramine, Mild Sedative-chlorpheniramine, Triprolidine,

Cyclizine, Betahistine2nd Generation: Terfenadine, Astemizole, Cetirizine, Loratadine,

Mizolastine, Fexofenadine, Levocetrizine, Ebastine

Histaminics

Receptor type Agonist Antagonist

H1 Histaprodifen , TriprolidineChlorpheniramine

H2 Dimaprit, Amthapine Nizatidine, RanitidineFamotidine

H3 R-α-methyl histamineImetit

IodophenpropitClobenpropitThioperamide

H4 Imetit,Clozapine

Thioperamide

PK, lower drug-drug interactions

Receptor affinity and selectivity, efficacy

Safety, lower cardiotoxicity

Pharmacokinetics General trend: improve tolerability and safety (less

to no sedation; reduce the cholinergic effects)

Targeted Molecules for improvement

Type of Improvement

Loratadine

Hydroxyzine

Terfenadine

Astemizole

ObjectiveClass

Piperidine

Piperazine

Piperidine

Piperidine

Isomer Purification

Levocetirizine

Active metabolite

Desloratadine

Cetirizine

Fexofenadine

No possible improvement

not even designed as an antihistamine; discovered during research of calcium channel-blocking agents

Safety Profiles

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withdrawn from the market due to cardiotoxicity

A SET OF AHS TESTED FOR TOXICITY (INHIBITION OF CELLULAR PROLIFERATION) BY THE MTS ASSAY (SUSSMAN NL ET AL. CELL NOTES, ISSUE 3, 2002: 7-10). ALL DRUGS TESTED IN QUADRUPLICATE AT 80M AND ALL ASSAYS PERFORMED AT 72 HRS.

Still on the market

Clinical uses

• Allergic rhinitis (common cold)• Allergic conjunctivitis (pink eye)• Allergic dermatological conditions• Urticaria (hives)• Angioedema (swelling of the skin)• Pruritis (atopic dermatitis, insect bites)• Anaphylactic reactions (severe allergies)

Adverse Reactions

First Generation Drugs: Anticholinergic CNS interactions Gastrointestinal reactions Common side effects: sedation, dizziness, tinnitus,

blurred vision, euphoria, lack of coordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhea, dry mouth, and dry cough,

thrombocytopenia , neutropenia , aplastic anemia Associated with the first generation H1-

antihistamines and due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression(by crossing BBB)

Adverse Reactions

Second Generation Drugs: Common side effects: drowsiness, fatigue,

headache, nausea and dry mouth Newer second generation H1-antihistamines are

more selective for the peripheral histamine receptors and have far less side effects(doesn’t cross BBB) (drowsiness, fatigue, headache, nausea and dry mouth)

Drug interaction

Ketoconazole , ErythromycinInhibit CYP3A4 microsomal enzymes can lead to

elevated plasma levels of antihistaminesleading to life threatening arrhythmiastorsades-de-pointes

Astemizole and terfenadine –no longer used