HISTAMINE & ANTIHISTAMINICS

Dr.Vijay bhushanam

HISTAMINE (Introduction)

• First Autacoid to be discovered. (Greek: autos=self; akos=cure)

• Synthesized in 1907• Isolated and demonstrated to be a natural

constituent of mammalian tissues (1927); hence the name Histos=Tissue

• H1 was discovered in1966

• H2 in1972

• H3 in1987

• H4 in 2001

HISTAMINE (Introduction)

• Sinus problems, hay fever, bronchial asthma, hives, eczema, contact dermatitis, food allergies and reactions to drugs are all allergic reactions associated with the release of histamine and other autocoids, such as serotonin, leukotrienes, and prostaglandins.

• Histamine is involved in inflammatory and anaphylactic reactions.

• Histamine also acts as a neurotransmitter in the central nervous system (CNS).

HISTAMINE (Chemistry)

• Histamine is a hydrophilic molecule consisting of• An imidazole ring and • An amino group connected by two methylene groups.

HISTAMINE (Distribution)

• Almost all mammalian tissues contain histamine.• Widely distributed in skin, GIT mucosa, lungs, brain, CSF

and bone marrow. • It is also a component of some venoms, sting secretion,

bacteria and plants.• The mast cell is the predominant storage site for histamine

in most tissues• The concentration of histamine is particularly high in

tissues that contain large numbers of mast cells, such as skin, bronchial tree mucosa, and intestinal mucosa.

HISTAMINE (Synthesis, Storage, and Metabolism)

• Formed by the decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase

• The chief site of histamine storage in most tissues is the mast cell; in the blood, it is the basophil.

• Metabolised to N-methylhistamine by histamine-N-methyltransferase and Imidazoleacetic acid by the nonspecific enzyme diamine oxidase (DAO)

• These metabolites have little or no activity and are excreted in the urine.

HISTAMINE (Release and functions)

• It is released from storage granules as a result of the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface,

• Histamine plays a central role in immediate hypersensitivity and allergic responses.

• The actions of histamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the allergic response.

• In addition, certain clinically useful drugs can act directly on mast cells to release histamine, thereby explaining some of their untoward effects.

• Histamine has a major role in the regulation of gastric acid secretion and also modulates neurotransmitter release

HISTAMINE (Pharmacological Effects)

• Histamine receptors are GPCRs

• H1 receptors: mediate effects on smooth muscle leading to vasodilatation, increased vascular permeability, and contraction of nonvascular smooth muscle.

• H2 receptors: mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation.

• H3 receptors: feedback inhibitors in CNS, gastrointestinal tract, lung, heart.

HISTAMINE (Receptors)

HISTAMINE (Pharmacological Effects)

1. Cardiovascular system.

a. Triple effect on terminal vasculature (itching & pain):– reddening at injection site due to vasodilation– wheal or disk of edema within 1 to 2 min– a large, bright crimson flare or halo surrounding the wheal

b. IV Histamine: fall in blood pressure, cutaneous flushing, over the face and upper trunk, rise in skin temperature, intense headache.

2. Smooth muscle of bronchioles; contraction of nonvascular smooth muscle.

3. Exocrine glands: potent stimulation of gastric secretion (HCl & pepsin), salivary and lacrimal gland secretion, catecholamines secretion.

4. Peripheral Nervous system: itching and pain

HISTAMINE (Pharmacological Effects)

• Exocrine Glands• Gastric glands• Salivary glands• Sweat glands Secretion• Pancreas• Bronchial glands• Lacrimal glands

HISTAMINE (Pharmacological Effects)

• Arterioles,

• Capillaries• Venules

• Vasodilation• Increased permeability(edema)• Systemic

hypotension

HISTAMINE (Pharmacological Effects)

• Vascular Smooth Muscles• Bronchial tree• GIT• Uterus

• Contraction

HISTAMINE (Clinical Uses)

• Practical applications of histamine are limited to uses as a diagnostic agent.

• Histamine (histamine phosphate) is used to assess nonspecific bronchial hyperreactivity in asthmatics and as a positive control injection during allergy skin testing.

H1-RECEPTOR ANTAGONISTS(Conventional Antihistaminics)

1. First generation Antihistaminics

Highly sedative: Diphenhydramine, Dimenhydrinate, Promethazine, Hydroxyzine

Moderately sedative: Pheniramine,Cyproheptadine, Meclizine, Buclizine, Cinnarazine

Mild sedative: Chlorpheniramine, Dexchlorpheniramine, Dimethindene, Triprolidine, Mebhydroline, Cyclizine, Clemastine

2. Second generation Antihistaminics: Fexofenadine, Loratadine, Desloratadine, Cetrizine, Levocetrizine, Azelastine, Mizolastine, Ebastine, Rupatadine

Antihistaminics(Pharmacokinetics)

• Absorption: Antihistaminics (H1 receptor antagonists) are well absorbed from oral and parenteral routes

• Distribution: widely in the body and enter brain. Newer compounds penetrate the brain poorly.

• Metabolism: In liver

• Excretion: In urine

Antihistaminics(Pharmacological actions)

• Smooth Muscle: Inhibit most of the effects of histamine on smooth muscles, especially the constriction of respiratory smooth muscle

• Capillary Permeability. H1 antagonists strongly block the increased capillary permeability and formation of oedema and wheal brought about by histamine.

• Flare and Itch. The flare component of the triple response and the itching caused by intradermal injection of histamine are two different manifestations of the action of histamine on nerve endings. H1 antagonists suppress both.

Antihistaminics (Pharmacological actions)• Immediate Hypersensitivity Reactions (Anaphylaxis

and Allergy): Oedema formation and itch are effectively suppressed. Other effects, such as hypotension, are less well antagonized. Bronchoconstriction is reduced little, if at all.

• Central Nervous System: • The first-generation H1 antagonists can both stimulate

and depress the CNS. – Stimulation Restless, nervous, sleeplessness & convulsions– Central depression Diminished alertness, slowed reaction

times, and somnolence are common manifestations.

• The second-generation ("nonsedating") H1 antagonists do not cross the blood-brain barrier appreciably.

Antihistaminics (Pharmacological actions)

• Anticholinergic action: Many H1 blockers in addition antagonize muscarinic actions of Ach.

1. High Anticholinergic action: Promethazine, Diphenhydramine, Dimenhydrinate, Pheniramine, Cyproheptadine

2. Low Anticholinergic action: Chlorpheniramine, Hydroxyzine, Triprolidine, Cyclizine

3. Minimal/No Anticholinergic action:Fexofenadine, Astemizole, Loratadine, Cetrizine, Mizolastine

• Local anesthetics: some drugs like Pheniramine have strong membrane stabilizing property. But not used clinically.

• BP: Most antihistaminics cause a fall in BP on IV injection.

Antihistaminics(Side effects and toxicity)

• Side effects are frequent but mild.• Sedation, diminished alertness and concentration, light

headedness, motor incordination, fatigue and tendency o fall asleep.

• Second generation antihistaminics are largely free of CNS effects.

• Anticholinergic propertiesDryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision

• Epigastric distress and headache.

• Acute overdose causes excitation, tremors, hallucinations, muscular incordination, convulsions, flushing, hypotension,death.

AntihistaminicsComparison between 1st generation and 2nd generation

• 2nd generation antihistaminics have

• Higher H1 selectivity; hence no anticholinergic side effects

• Absence of CNS depressant property; Less/No sedation

• Additional anti-allergic properties apart from histamine blockade; some inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor.

Antihistaminics(Uses)

• Allergic disorders,• Other conditions involving histamine: Insect bite, Ivy

poisoning etc.• Pruritides • Common cold• Motion sickness• Vertigo• Pre anesthetic medication• Cough• Parkinsonism• Acute muscle dystonias• As sedative, hypnotic, anxiolytic

H2 and H3Receptor Antagonists

• H2 antihistaminics: Cimetidine, Ranitidine, Famotidine, Roxatidine

• Primarily used in peptic ulcer and other gastric hypersecretory states

• H3 antihistaminics: Thioperamide

• No clinical utility.

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