Dr. dr. H. Mgs Irsan Saleh, M.Biomed Dept.

of Pharmacology Faculty of Medicine Sriwijaya University

Histamin is a chemical massanger that mediates a wide range of cellular responses, including allergic and inflamatory reactions, gastric acid secretion, and possibly in part of pain. Histamin has no clinical applications Agents that interfere with the action of histamin (antihistamines) have important therapeutic applications

Location: Histamine occurs in practically all tissue High amounts found in lung, skin, GI tract. Histamine is found in high concentration in mast cells and basophils. Histamine also occurs as a component of venome and in insect stings

Synthesis :
Histamine is formed by the carboxylation of the

amino acid histidine. The process is primarily occurred in mast cells, basophils, lungs, skin, GI tract mucosa, where histamin is stored. In mast cell, histamine is stored in granules as an inactive complex composed of histamine and polysulfonated anion. If histamine is not stored, rapidly inactivated by amine oxidase inhibitor.

Release of histamine:
The release of histamine may be the primary

response to some stimuli, but most often histamine is just one of several chemical mediators released.

Stimuli (bacterial toxins, bee-sting venoms, trauma, allergies and anaphylaxis) can trigger release of histamine

Mechanism of action
Histamin effects by binding its receptors (H1, H2, H3

and H4). Some of antihistamines wide range of pharmacologic effect s are mediated by all receptors whereas others are mediated by only one class. H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability H2 receptors mediate gastric acid secretion

The Goodman & Gilman 2008 pages 402

Symptoms associated with allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include histamine, serotonin, leukotrienes and the eosinophil chemotactic factor of anaphylaxis. In some cases, these cause a localized allergic reaction (skin, respiratory tract) or under other condition may cause a full-blown anaphylactic responses. These difference of effects are depended on the site from which mediators are released and their rates of release.

Role of histamine in allergy and anaphylaxis

resulting from IV injection of histamine and those associated with anaphylaxis shock and allergic reactions. These include contraction of smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries and stimulation of sensory nerve endings.

EXOCRINE EXCRETION
Constriction results in intestinal cramps and diarrhea BRONCHIAL SMOOTH MUSCLE Increased production of nasal and bronchial mucus, resulting in respiratoy symptoms INTESTINAL SMOOTH MUSCLE Constriction of bronchioles results in symptoms of asthma, decreased lung capacity SENSORY NERVE ENDING Cause itch and pain

H1-receptors

Otot polos bronkus

GI tract smooth muscles

H1-and H2- receptors

H2-receptors
STOMACH
Stimulation of gastric hydrochloric acid secretion

The term antihistamine refers to the classic H1 receptor blockers. These compounds do not influence the formation or release of histamin, but they competitively block the receptor-mediated response of a target tissue. The H1-receptor blockers can be devided into first, second and third generation drugs

The first generation drugs are still widely used because they are effective and inexpensive. The second generation, because they do not penetrate the blood-brain barrier, show less CNS toxiicity than the older drugs Third-generation H1-antihistamines are the active enantiomer (levocetirizine) or metabolite (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions.

Action:
H1 antihistamines antagonize all actions of histamine

except for those mediated solely by H2-receptors. The action of all of the H1-receptor blockers is qualitatively similar. These blockers have additional effects unrelated to their blocking of H1 receptors. These effects probably reflect binding of the H1 antagonist to cholinergic, adrenergic, or serotonin receptors. Some H1 blockers, such as diphenhydramin have good local anesthetic activity.

Therapeutic uses:
Allergic condition
H1 antihistamines are useful in treating allergies caused by antigens acting on IgE-antibody sensitized mast cell Antihistamines are the drug s of choice in controlling the symptoms of allergic rhinitis and urticaria because histamine is the principal mediator. H1-receptor blockers are ineffective in treating asthma broncial Epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine

Therapeutic use:
Motion sickness and nausea
H1-receptor blockers such as diphenhydramine, dimenhydrinate, cyclizine, meclizine are the most effective agrnts for the prevention of the symptoms of motion sickness. Antihistamines prevent or diminish vomiting and nausea mediated by both chemoreceptor and vestibular pathway.

Somnifacients:
Some antihistamine, such as diphenhydramine, have strong sedative properties and are used in the treatment of insomnia

Pharmacokinetics:
H1-receptor blockers are well absorbed after oral

administration. Maximum serum levels occuring at 1 t0 2 hours Average plasma half life is 4 to 6 hours, except for meclizine has half life 12 to 24 hours. H1-receptor blocker have high bioavailability they are distributed in all tissues including CNS. The major biotransformation is the lever. Minute amounts of unchanged drug and most of metabolites are excreted in the urine

Adverse effects:
H1-receptor blockers have low specifisity. They interact not only histamine receptor, but

also with muscarinic cholinergic receptors, adrenergic receptors, and serotonin receptors. Incidence and severity of adverse reaction varies between individual subject

Particularly diphenhidramine, clemastine,promethazine

Histamine H1-receptor blockers

Particularly promethazine

All H1-anti histamine

Cholinergic (muscarinic) receptor

-adrenergic receptor

Particularly ciproheptadine

Serotonin receptor

Histamin H1 Histamin H2 receptor receptor

Dopamine receptor

Adverse effect:
Sedation Most frequently observed Other central actions include tinnitus, fatigue, dizziness, incoordination, blurred vision, tremors. Sedation is less common with the second generation drugs that do not readily enter the CNS Dry mouth Oral antihistamine also have weak anticholinergic effect, leading not only drying of the nasal passage but also to a tendency to dru the oral cavity

Drug interaction:
Person who takes MAO inhibitors should not take

Overdoses

antihistamin. Erithromycin and clarithromycin interfere the metabolism of terfenadine and astemizol e and may cause serious cardiac arrthmias.
Acute poisoning is relatively common, especially in

young children The most common and dangerous effects of acute poisoning are those on the CNS (hallucinations, excitement , ataxia and convulsion)

The Goodman & Gilman 2008 pages 408-309

The Goodman & Gilmans The Manual of Pharmacological and Therapeutic page 409

Used to treat motion sickness: dimenhydrinate, diphenhydramine, hydroxyzine, meclizine. Potential for producing sedation: triprolidine, dimenhydrinate, diphenhydramine, promethazine, hydroxyzine. May cause increase in appetite and weight gain: cyproheptadine, loratadine. Long duration of action: meclizine, fexofenadine, astemizole.

Concomitant use of macrolide antibodies or imidazole antifungal agents may lead to serious ventricular arrythmias : astemizole. Slow onset of action makes drug unsuitable for treatment 0f acute allergic symptoms : astemizole. Non-sedating : fexofenadine, astemizole, loratadine, cetirizine.
Dept. of Pharmacology Faculty of Medicine Sriwijaya University

The active metabolite of terfenadine, which lacks the cardiac toxicity of terfenadine. Fexofenadine is indicated for the relief of alergic rhinitis symptoms in adults and children 12 yo. Fexofenadine is a selective antagonist of the H1 histamine receptor in the periphery of the body Pharmacokinetics:

Doesnt cross blood-brain barriere Rapidly absorbed following oral administration. Very little of drug is metabolized Excreted primerly in the feces (80%) and urine (11%) Half-life is about 15 hours

In patient 65 years, the peak concentration was twice than of that < 65 yo. Renal impairment increase plasma level Adverse effects are mild and infrequent and include drowsiness, dyspepsia and fatique.