1. ANTIHISTAMINES
MODIFIED BY
Israa

2. 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

3. 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

4. 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

5. 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

6. 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.

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

8. 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

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

10. 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

11. 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.

12. 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

14. 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

15. Adverse effects observed with first generation antihistamines

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

17. 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.

18. 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

19. 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”)

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

21. Good luck