2008 histamin
TRANSCRIPT
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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