ANTIHISTAMINES

MODIFIED BYIsraa

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, (c) some neurons in the CNS and peripheral NS

H H

H

H

H

H

Y Y Non-immune Releasers(opioids, tubocurarine, vancomycin etc)

IgE

ANTIGENIgE - AntibodyInduced Release(food, penicillin,venoms, etc)

ACUTE INFLAMMATORY RESPONSEIMMEDIATE HYPERSENSITIVITY REACTION

Inhibitors ofRelease (Cromolyn Albuterol)

H

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 1. First Generation: Sedating2. 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

1. dry Mouth2. blurred Vision3. constipation4. 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

Good luck