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HISTAMIN

&AUTAKOIDS

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Mediator Perubahan Vaskular pada Inflamasi

Mediator perubahan aliran darah danpermeabilitas vaskuler:

- vasoactive amina (histamin, serotonin)

- vasoactive peptida (bradykinin)- vasoactive lipid (prostaglandin, leukotrien)

Mediator kemotaksis leukosit- leukotrien B4

- Eosinophil chemotactic factor of anaphylaxis

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Penyebab Cedera Jaringan pada

Inflamasi dan Penyakit Autoimmune

Pembentukan reactive oxygenspecies (O2-,

H2O2, HOCl) and enzimeproteolitik

(kolagenase, elastase) oleh sel fagosit

Cytotoxic complement proteins

Respons imun seluler dan humeral

Pelepasan sitokin pro-inflamasi

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HISTAMIN

Komponen bisa/racun serangga/tumbuhan Tersimpan di Mast Cell & Basofil

(di lokasi trauma: hidung, mulut, kaki)

Terlepas pada:

1. Respons Imun

Immediate (Type I) Allergic Reaction

Inflamasi akut

2. Respon Kimia (gol. Amine: morfin)

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EFEK: - Triple Response: merah, edema, nyeri

- Shock anafilaktik

- Rangsang ujung saraf tepi nyeri, gatal H1

- Vasodilatasi + edema jaringan nadi tensi

- Bronkokonstriksi provocatif test

- Kontraksi otot polos: H2

GI : peristalsis diare

Uterus : aborsi

Lambung: sekresi HCl

- Pengelolaan:

1. Antagonis Fisiologis: epinefrin

2. Antagonis Reseptor : CTM, Burimamide anti-H2

3. Release Inhibitor: Cromolin, Nedocromil

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H1 ANTAGONIS

Gen 1: sedatif, blok reseptor otonom

Gen 2:

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H1 Antagonists Generasi I vs. II

Generasi-1 antagonis reseptor H1 tidak spesifik- diphenhydramine muscarinic receptors

- Promethazine dopamine, muscarinic, 1

- Cyproheptadine serotonergic receptors

Generasi-2 antagonis reseptor H1:- Spesifik pada H1 receptors

- Tidak menembus blood-brain barrier sedasi kurang- Half-lives lebih panjang

- Indikasi utama: allergic rhinitis

- Astemizole, Terfenadine aritmia

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Penggunaan H1 antagonists

Allergic rhinitis e.g.chlorpheniramine, loratidine

Motion sickness eg. meclizine, chlorcyclizine

Hypnotic agents e.g.doxylamine, diphenhydramine

Pruritis e.g. hydroxyzine Serum sickness- e.g. promethazine

Anti-emetics- e.g. promethazine

Antitussive

e.g. diphenhydramine Carcinoid tumors (serotonin-mediated)

cyproheptadine

Allergic conjuctivitis e.g. levocobastine

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Drugs Usual Adult

Dose

Anticholin

ergic

Activity

Comments

FIRST-GENERATION ANTIHISTAMINES

Ethanolamines

Carbinoxamine (Clistin) 48 mg +++ Slight to moderate sedation

Dimenhydrinate (salt of

diphenhydramine)

(Dramamine)

50 mg +++ Marked sedation; anti-motion

sickness activity

Diphenhydramine

(Benadryl, etc)

2550 mg +++ Marked sedation; anti-motion

sickness activity

Doxylamine 1.2525 mg nd Marked sedation; now available

only in OTC "sleep aids"

Ethylaminediamines

Pyrilamine (Neo-Antergan) 2550 mg + Moderate sedation; component

of OTC "sleep aids"

Tripelennamine (PBZ, etc) 2550 mg + Moderate sedation

Piperazine derivatives

Hydroxyzine (Atarax, etc) 15100 mg nd Marked sedation

Cyclizine (Marezine) 2550 mg Slight sedation; anti-motion

sickness activity

Meclizine (Bonine, etc) 2550 mg Slight sedation; anti-motionsickness activity

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Alkylamines

Brompheniramine

(Dimetane, etc)

48 mg + Slight sedation

Chlorpheniramine (Chlor-

Trimeton, etc)

48 mg + Slight sedation; common

component of OTC "cold"medication

Phenothiazine derivatives

Promethazine (Phenergan,

etc)

1025 mg +++ Marked sedation; antiemetic

Miscellaneous

Cyproheptadine (Periactin,

etc)

4 mg + Moderate sedation; also has

antiserotonin activity

SECOND-GENERATION ANTIHISTAMINES

Piperidines

Fexofenadine (Allegra) 60 mg Lower risk of arrhythmia

Miscellaneous

Loratadine (Claritin) 10 mg Longer action

Cetirizine (Zyrtec) 510 mg

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Penggunaan Klinis Antihistamin

- Reaksi Alergi: rinitis, urtikaria

asma ? (tidak efektif)

- Motion sickness

- Gen 1: difenhidramin/ dimenhidrinat, prometazin

sikloserin, meclizine: less sedatif- Obat lain : skopolamin

- + efedrin/amfetamin: >>efek

- Nausea/Vomiting pd kehamilan

piperasin : teratogenik

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Toksisitas

mirip keracunan Atropin

eksitasi, konvulsi, koma

- Astemizole, Terfenadine aritmiapada penderita hepar

interaksi dg ketokonazole, makrolid

juice anggur

dilarang di USA

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H2 ANTAGONIS

- Cimetidine

- Ranitidine- Famotidine

- Nizatidine

- Mengurangi sekresi HCl lambung

- Menghambat enzim hepar

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Penggunaan Klinis H2 Antagonists

Ulkus Gastric dan duodenal

Reflux Gastroesofagus

Esofagitis Erosif

Heartburn

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serotonin

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SEROTONIN

- Komponen bisa/racun serangga

- CNS: mood, sleep, appetite, suhu, pain preception

tensi, vomiting, migrain

- Vasokonstriksi + vasodilatasi otot & jantung

trifasik: hipo-hiper-hipo

- GI: release asetilkolin peristalsis

- Otot: malignant hiperthermia (o.k. obat anestesi)

- MAOinhibitor + Serotonis Agonis= serotonin syndrome

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Receptor Distribution Postreceptor Partially Partially

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Gi ,Gi ,Gi ,Gi ,Gq ,Gq ,Gq ,Gs ,Gs ,

Receptor

Subtype

Distribution Postreceptor

Mechanism

Partially

Selective

Agonists

Partially

Selective

Antagonists

5-HT1A Raphe nuclei,

hippocampus

Multiple, Gi

coupling

dominates

8-OH-DPAT WAY100635

5-HT1B Substantia nigra,

globus pallidus,

basal ganglia

cAMP CP93129

5-HT1Da,b Brain cAMP Sumatriptan

5-HT1E Cortex, putamen cAMP

5-HT1F Cortex,

hippocampus

cAMP

5-HT1P Enteric nervous

system

Go; slow EPSP 5-

Hydroxyindalpin

e

Renzapride

5 HT Platelets smooth IP Methyl 5 HT Ketanserin

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5-HT2A Platelets, smooth

muscle, cerebral

cortex, skeletal

muscle

IP3 -Methyl-5-HT Ketanserin

5-HT2B Stomach fundus IP3 -Methyl-5-HT SB204741

5-HT2C Choroid,

hippocampus,

substantia nigra

IP3 -Methyl-5-HT Mesulergine

5-HT3 Area postrema,

sensory and entericnerves

Receptor is a

Na+-K+ ionchannel

2-Methyl-5-HT,

m-chlorophenylbig

uanide

Tropisetron,

ondansetron, granisetron

5-HT4 CNS and myenteric

neurons, smooth

muscle

cAMP 5-

Methoxytryptami

ne, renzapride,metoclopramide

5-HT5A,B Brain cAMP

5-HT6,7 Brain cAMP Clozapine

(5-HT7)

SEROTONIN AGONIS

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SEROTONIN AGONIS

- Buspirone

- Dexfenfluramin: anorexiogenik

ESO: - hipertensi pulmonal

- endokardial hiperplasia

- Sumatriptan: anti-migrain

- Cisapride: perangsang peristalsis

ESO: jantung dilarang di USA

- Fluoksetine: anti-depresi

sering disalahgunakan untuk anorexiogenik

SEROTONIN ANTAGONIS

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SEROTONIN ANTAGONIS

- Reserpin: hambat storage

- Serotonin Reseptor Antagonis

- Phenoksibensamin: long lasting blok

- Alkaloid Ergot: partial agonis

- Siproheptadin (antihistamin)

- Ketanserine: hambat agregasi platelet,

antihipertensi (-blocker)

- Ritanserin: tanpa -blocker

- Ondansentron: anti-nausea/ anti-vomiting

pada pembedahan & kemoterapi kanker

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Alkaloid Ergot

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ALKALOID ERGOT

- Dari jamur Claviceps purpurea pada biji-bijian

isi: histamin, asetilkolin, tiramin, dsb- Keracunan (ergotism):

demensia, halusinasi, vasospasme/gangren

kontraksi uterus (aborsi), konvulsi- Absorbsi >> dengan kofein

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Ergot Alkaloid Adrenoceptor Dopamine

Receptor

Serotonin

Receptor (5-

HT2)

Uterine

Smooth

Muscle

Stimulation

Bromocriptine +++ 0

Ergonovine + + (PA) +++

Ergotamine (PA) 0 + (PA) +++

Lysergic acid

diethylamide

(LSD)

0 +++ , ++ in

CNS

+

Methysergide +/0 +/0 (PA) +/0

Pengg naan Klinik

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Penggunaan Klinik

- anti-migrain: ergotamine

- anti-hiperprolaktinemia (amenore, infertil):

bromokriptin, cabergoline, pergolide

- Perdarahan post partum: ergonovin

- anti-Alzheimer ??

Intoksikasi:

- GI: diare, nausea, muntah

- Prolonged vasospasme.gangren

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NITRIC OXIDE

DONORS & INHIBITORS

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Property NOS-1 NOS-2 NOS-3

Other names nNOS (neuronal

NOS)

iNOS (inducible

NOS)

eNOS

(endothelial

NOS)

Tissue Neuronal,

epithelial cells

Macrophages,

smooth muscle

cells

Endothelial cells

Expression Constitutive Transcriptional

induction

Constitutive

Calcium

requirement

Yes No Yes

Chromosome 12 17 7

Approximate

mass

150160 kDa 125135 kDa 133 kDa

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Name Symbol Known Function

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NONO2Produce NOStable oxidation product of NO

Name Symbol Known Function

Nitric oxide Vasodilator, platelet inhibitor,

immune regulator,

neurotransmitter

Nitroxyl anion NO- Smooth muscle relaxant

Nitrogen dioxide Free radical, nitrosating agent,

lung irritant

Nitrous oxide N2O Anesthetic

Dinitrogen trioxide N2O3 Nitrosating agent

Dinitrogen tetraoxide N2

O4

Nitrosating agent

Nitrite NO2- at acidic pH

Nitrate NO3-

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Lipid Autacoids

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EICOSANOIDS:

PROSTAGLANDINS

THROMBOXANESLEUKOTRIENES

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Prostaglandin analogues

Alprostadil- maintains a patent ductusarteriosus in the fetus; useful in treatingerectile dysfunction

Misoprostil a PGE2 analogue used totreat NSAID-induced gastritis

Carboprost; Dinoprostone

abortafacients, may be used to inducelabor

Lantanoprost used in treatingglaucoma

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Aspirin (Acetyl Salicylic Acid)

Asetilasi COX Irreversibel

hambat enzim permanen

Salicylate

inhibitor kompetitif COX

Dose-dependent

efek tergantung besarnya dosis