ANTIHISTAMINES MODIFIED BY Israa

Histamine Is an endogenous substance synthesized, stored and released in (a) mast cells, which are abundant in the skin, GI, and the respiratory tract, (b) basophils in the blood, and (c) some neurons in the CNS and peripheral NS

Y Y IgE - Antibody Induced Release Non-immune Releasers Inhibitors of (food, penicillin, venoms, etc) ANTIGEN Y IgE Y Non-immune Releasers (opioids, tubocurarine, vancomycin etc) H H Inhibitors of Release (Cromolyn Albuterol) H H H H H ACUTE INFLAMMATORY RESPONSE IMMEDIATE HYPERSENSITIVITY REACTION

Effects of Histamine ↑production of nasal & mucus secretion (H1) Bronchial smooth muscle (H1) → bronchoconstriction. Sensory nerve endings (H1) →cause itching & pain. Stomach (H2) →↑gastric acid secretion. Heart (H1& H2) →↑rate & force of contraction. Arterioles (H1& H2) →vasodilatation. Capillaries (H1)→ vasodilatation &↑ permeability result in redness

The pathological role of histamine Cellular mediator of immediate hypersensitivity reaction and acute inflammatory response Anaphylaxis Seasonal allergies Duodenal ulcers Gastrinoma (Zollinger-Ellison Syndrome) Systemic mastocytosis

Receptors of histamine It acts on specific receptors H1-receptors occurs at postsynaptic sites-Smooth muscle ,Exocrine glands, Brain and Endothelium H2-receptors occurs at postsynaptic sites-Gastric mucosa ,Heart and Mast cells H3-receptors occurs at presynaptic sites-Nerve endings & Brain, inhibit the release of neurotransmitters. H4- Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis.

Classification of antihistamines They are classified into H1-blockers & H2-blockers. No currently available antagonist for H3 or H4 Receptors

H1-blockers They block the histamine action on H1 receptors Best work if given before histamine release(prophylactically ) because they only bind to the free receptors Can be divided in to First Generation: Sedating Second Generation: Non-sedating

First Generation Agents Ethanolamines: DIPHENHYDRAMINE Ethylenediamine: TRIPELENNAMINE Alkylamine: CHLORPHENIRAMINE Phenothiazine: PROMETHAZINE (Phenergan) Piperazines: HYDROXYZINE

First Generation Agents uses In anaphylaxis and other cases where histamine release can occur (epinephrine must also be used) Anti-allergy (allergic rhinitis, allergic dermatoses, contact dermatitis) Sedative/sleep aid To prevent motion sickness Antiemetic: prophylactic for motion sickness Antivertigo Local anesthetic Antitussive

Pharmacokinetics for the first generation Are absorbed from the GIT. Can also be given parenterally & topically. Most of them appear widely distributed throughout the body, but some do not penetrate the BBB, Are most effective when used prophylactically. Most of the them are metabolized extensively in the liver.

additional effects of the first generation Block H1 receptors CNS→ sedation, dizziness & fatigue. Anticholinergic effect → dry mouth, urinary retention, tachycardia α- blocking effect →postural hypotension, reflex tachycardia. Antiserotonin effect → ↑appetite

Adverse Effectsof the first generation Sedation (Paradoxical Excitation in children) Dizziness Fatigue Tachydysrhythmias in overdose - rare Peripheral antimuscarinic effects dry Mouth blurred Vision constipation urinary Retention

Adverse effects observed with first generation antihistamines

The use of first generation H1 antihistamines is contraindicated in treatment of individuals working in jobs where wakefulness is critical

Second generation H1-blockers Examples for this group: loratadine ,fexofinadine, cetirizine, astemazole Are specific for H1 receptors. Do not penetrate the BBB so they show less CNS toxicity.

Pharmacokinetics for the second generation Cetirizine (C), loratadine (L), fexofenadine (F) well absorbed and are excreted mainly unmetabolized form. C and L are primarily excreted in the urine F is primarily excreted in the feces They induce Cyt P450 liver enzymes

Adverse Effects of the second generation in general, these agents have a much lower incidence of adverse effects than the first generation agents. terfenadine and astemizole were removed from the market due to effects on cardiac K+ channels - prolong QT interval (potentially fatal arrhythmia “torsades de pointes”)

H2-blockers These drugs produce their action by blocking histamine H2 receptors→↓ gastric acid secretion. Example: Cimetidine, ranitidine Will be discussed in GIT lectures

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