DRUGS USED IN HYPERSENSITIVITY

REACTIONS

Dewi Selvina Rosdiana

Modul infeksi & imunologi, 21-3-20131

Drugs used in Hypersensitivity reactions:- Antihistamine- Adrenaline- Glucocorticoid- Sodium cromoglicate & nedocromil

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Histamine

Histamine biogenic amineImportant mediator in :- Immediate hypersensitivity & allergic responses

- Inflamation- Gastric acid secretion- Modulates neurotransmitter release

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Storage & release of histamin

Storage : (inactive bound form of histamine)Granulle of Mast cell & Basophils Non-mast cell histamine- Brain, as neurotransmitter- Gaster, enterochromaffin-like (ECL) cell

Release :immunological reactionchemical and mechanical

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Pharmacodynamics

Type Location FunctionH1 smooth muscle, Vasodilation,bronchoconstriction

endothelium, CNS smooth muscle activation, vascular permeability,

pain, itching, allergic rhinitis symptoms & motion sickness

H2 gastric parietal cell, Gastric acid secretion cardiac muscle, CNS

H3 CNS:presynaptic, neurotransmitter releasemyenteric plexus

H4 eosinophils, neutrophils, chemotactic effect CD4 T cell (alergic & inflamation responses)

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Histamine effects on :Nervous system - sensory nerve endings pain & itching (H1)- modulates neurotransmitter release (H3)CVS - Vasodilation (H1&H2): BP, flushing, headache

High dose: hypotension shock- Vascular permeability : edema, urticaria (H1)Triple response: red spot, flare, edema

- Heart : contraction , heart rate , automaticity (H2 stimulation & a reflex tachycardia) High dose: arrhythmias 7

Bronchial smooth muscle:H1 : bronchoconstriction, H2 : bronchodilation. Patient with bronchial asthma : bronchoconstrictionGIT smooth muscle:High dose : contraction diarrhea (H1)Other smooth muscle organs :Iris, genitourinary tract: less affectedUterus : no oxitoxic effectExocrine glands :

Gastric acid secretion (H2)

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H1 - Receptor Antagonists

Two types :• First generation / sedating• Second generation / nonsedatingMechanism of action: reversibly compete with

histamine at H1 receptor sitesPharmacokinetic:

Peroral absorption: rapidly absorbedOOA: 15’-30’, Tmax 1-2 hoursDOA: 4-6 hours, 2nd generation : 12-24 hoursMetabolized by CYP3A4Excretion: via urine after 24 hours

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Some H1 antagonist drugs in clinical use:Class Drugs

1st generation AH11. Ethanolamines dimenhydrinate, diphenhydramine,

carbinoxamine2. Ethylaminediamine tripelennamine3. Piperazine derivatives hydroxyzine, cyclizine, meclizine4. Alkylamines brompheniramine, chlorpheniramine5. Phenothiazine deriv. promethazine6. Miscellaneous cyproheptadine2nd generation AH11. Piperidine fexofenadine2. Miscellaneous loratadine, cetirizine, desloratadine,

levocetirizine 10

Indications:

1. Allergic reactionsto prevent or treat the symptoms of allergic reactions- Allergic rhinitis, urticaria- Atopic dermatitis (sedative effect)- Not effective for bronchial asthma

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2. Motion sickness- diphenhydramine, promethazine, cyclizine

meclizine 3. Vestibular disturbances & vertigo:

- dimenhydrinate, meclizine4. Hypnotics : (sedation side effect)

- esp. Etanolamin class : diphenhydramine5. Common cold :

- weak anticholinergic effect of 1st gen H1 antagonist may tend to lessen rhinorrhea.

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Side effects:– drowsiness/sedation (1st generation)– dry mouth– dizziness– nausea, vomiting

• Cetirizine, loratadine, desloratadine, fexofenadine, terfenadine: less likely to cross the blood brain barriere relatively free of drowsiness effect

• Topical antihistamine preparation can be allergenic• Pregnancy:Teratogenic (hydroxyzine, fexofenadine, azelastine)Non teratogenic (chlorpheniramine,diphenhiyramine, cetirizine, loratadine) 13

Side Effects of H1 Antagonist

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Drug interactions:

- Combination with inhibitor CYP3A4 : antifungal (Ketokonazol,itrakonazol) or macrolideantibiotics (erythromycin)

Terfenadine/astemizole blood concentration potentially fatal abnormality in cardiac rhythm

Terfenadine and astemizole have been withdrawnfrom the market

- Alcohol, sedatives, hypnotics and anxiolytic : CNS deppresant effects

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• H2 receptor antagonists reversibly compete with histamine at H2 receptor sites

• Effect: to reduce the secretion of gastric acid • Cimetidine, ranitidine, famotidine

(H2 antagonists were discussed in GIT module)

H2 - Receptor Antagonists

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H3 & H4 Receptor Antagonists

• Still in trials• None has yet been approved for clinical

use.

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Other drugsAdrenalinAnaphylaxis: Medical emergency

– Due to the systemic release of – histamine – other mediators ie.

» 5-hydroxytryptamine (5-HT, serotonine)» Leukotrienes (SRS-A) asthma

– Massive vasodilation shock death.– Bronchoconstriction asphyxia

Management of anaphylaxis:• Adrenaline 0,3-0,5 mg s.c give immediately!!

(Antihistamine alone is not enough)18

Corticosteroids- Hypersensitivity reactions that do not

respond to H1-antagonists- Prednisone, dexametasone, etc

(corticosteroids will be discussed in the next lecture)

Sodium cromoglicate, nedocromil- Prophylaxis for bronchial asthma

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SerotoninSerotonin effects:1. Nervous system

- present in a variety of sites in the brain.- sensory nerve endings : a potent stimulant of

pain & itch- activation of serotonin receptors on vagal nerve endings chemoreceptor reflex bradycardia

& hypotensi- serotonin receptor in GIT & in vomiting center of the medulla vomiting reflex

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2. Respiratory System : -A weak bronchoconstriction effect, hyperventilation

3. CVS: - Vasoconstriction (through 5-HT2 receptors), except

in skeletal muscle and heart (vasodilation)- Triphasic blood pressure response :

1st phase : ↓ HR, CO, BP (caused by chemoreceptor response)

2nd phase : ↑ BP (as a result of vasoconstriction)3rd phase : ↓ BP (vasodilation in vessels supplying

skeletal muscle)- Platelets aggregation (5-HT2)

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4. GIT System :- powerfull stimulant of GIT smooth muscle

tone & peristalsis (5-HT2)- activation 5-HT4 receptors in enteric nervous

system prokinetic effect 5. Skeletal muscle :

- 5-HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood.

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Serotonin agonists :-Buspirone (5-HT1A agonist) : anxiolytic-Tegaserod (5-HT4 agonist): irritable bowel syndrome-Sumatriptan (5-HT1D/1B agonist) : migraine

Serotonin antagonists:- Ondansetron (5-HT3 antagonist) : prevention & treatment of nausea & vomitingassociated with surgery and cancer chemotherapy

- Cyproheptadine (5-HT2 blocker & AH1) : treatment of cold-induced urticaria

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