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HISTAMIN&
AUTAKOIDS
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Vascular Changes inInflammation
• Mediators of blood flow and vascularpermeability changes
- vasoactive amines (histamine, serotonin)- vasoactive peptides (bradykinin)- vasoactive lipids (prostaglandins, leukotrienes)
Mediators of leukocyte chemotaxis- leukotriene B4- Eosinophil chemotactic factor of anaphylaxis
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Tissue damage in Inflammation andAutoimmune Disease
• Generation of reactive oxygen species (O2-,H2O2, HOCl) and proteolytic enzymes(collagenases, elastase) by phagocytic cells
• Cytotoxic complement proteins
• Cell- mediated and humeral immune responses
• Release of pro-inflammatory cytokines
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HISTAMIN• Komponen bisa/racun serangga/tumbuhan• Tersimpan di Mast Cell & Basofil
(di lokasi trauma: hidung, mulut, kaki)• Release:
1. Respon ImunImmediate (Type I) Allergic Reaction
Inflamasi akut2. Respon Kimia (gol. Amine: morfin)
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Physiologic effects of histamine
• Smooth Muscle- Vascular- Bronchiolar- Gut
• Cutaneous effects• Secretory Epithelia• GI
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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 diareUterus : aborsiLambung: sekresi HCl
- Pengelolaan:1. Antagonis Fisiologis: epinefrin2. Antagonis Reseptor : CTM, Burimamide anti-H23. Release Inhibitor: Cromolin, Nedocromil
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H1 ANTAGONISGen 1: sedatif, blok reseptor otonomGen 2: <<sedatif ( distribusi di CNS<<)
- p.o. absorbsi cepat (peak 1-2 jam, durasi 4-6 jam)- Metabolisme di hepar- Efek:
- sedasi- anti-nausea/ anti-emetik- anti-Parkinson (Bromokriptin: anti-kolinergik)- anti-kolinergik (Etanolamine, Etilendiamine)- -adrenoceptor blocker: hipotensi postural
(Fenotiazin, Prometazin)- Serotonin blocker (Siproheptadin)- Anestesi lokal (Difenhidramin, Prometazin)
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First vs. Second Generation H1antagonists
• Many first generation H1 antagonists interact withother receptor types
- diphenhydramine – muscarinic receptors- Promethazine – dopamine, muscarinic, 1- Cyproheptadine – serotonergic receptors
Second Generation H1 antagonists are:- highly selective for H1 receptors- do not penetrate the blood-brain barrier; less sedation- Have long half-lives- Are primarily indicated for allergic rhinitis
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Some Uses for H1 antagonists
• Allergic rhinitis – e.g.chlorpheniramine, loratidine• Motion sickness – eg. meclizine, chlorcyclizine• Hypnotic agents – e.g.doxylamaine, 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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Slight sedation; anti-motionsickness activity
–25–50 mgMeclizine (Bonine, etc)
Slight sedation; anti-motionsickness activity
–25–50 mgCyclizine (Marezine)Marked sedationnd15–100 mgHydroxyzine (Atarax, etc)
Piperazine derivativesModerate sedation+25–50 mgTripelennamine (PBZ, etc)
Moderate sedation; componentof OTC "sleep aids"
+25–50 mgPyrilamine (Neo-Antergan)Ethylaminediamines
Marked sedation; now availableonly in OTC "sleep aids"
nd1.25–25 mgDoxylamine
Marked sedation; anti-motionsickness activity
+++25–50 mgDiphenhydramine(Benadryl, etc)
Marked sedation; anti-motionsickness activity
+++50 mgDimenhydrinate (salt ofdiphenhydramine)(Dramamine)
Slight to moderate sedation+++4–8 mgCarbinoxamine (Clistin)EthanolaminesFIRST-GENERATION ANTIHISTAMINES
CommentsAnticholinergicActivity
Usual AdultDose
Drugs
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–5–10 mgCetirizine (Zyrtec)Longer action–10 mgLoratadine (Claritin)
MiscellaneousLower risk of arrhythmia–60 mgFexofenadine (Allegra)
PiperidinesSECOND-GENERATION ANTIHISTAMINES
Moderate sedation; also hasantiserotonin activity
+4 mgCyproheptadine (Periactin,etc)
Miscellaneous
Marked sedation; antiemetic+++10–25 mgPromethazine (Phenergan,etc)
Phenothiazine derivatives
Slight sedation; commoncomponent of OTC "cold"medication
+4–8 mgChlorpheniramine (Chlor-Trimeton, etc)
Slight sedation+4–8 mgBrompheniramine(Dimetane, etc)
Alkylamines
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Penggunaan Klinis- 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 kehamilanpiperasin : teratogenik
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Toksisitasmirip keracunan Atropin
eksitasi, konvulsi, koma- Astemizole, Terfenadine aritmia
pada penderita heparinteraksi dg ketokonazole, makrolidjuice 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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Clinical uses for H2 receptorAntagonists
• Gastric and duodenal ulcers
• Gastroesophageal reflux
• Erosive esophagitis
• Heartburn (available OTC)
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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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Gi ,Gi ,Gi ,Gi ,Gq ,Gq ,Gq ,Gs ,Gs ,
Renzapride5-Hydroxyindalpine
Go; slow EPSPEnteric nervoussystem
5-HT1P
cAMPCortex,hippocampus
5-HT1F
cAMPCortex, putamen5-HT1E
SumatriptancAMPBrain5-HT1Da,b
CP93129cAMPSubstantia nigra,globus pallidus,basal ganglia
5-HT1B
WAY1006358-OH-DPATMultiple, Gicouplingdominates
Raphe nuclei,hippocampus
5-HT1A
PartiallySelectiveAntagonists
PartiallySelectiveAgonists
PostreceptorMechanism
DistributionReceptorSubtype
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Clozapine(5-HT7)
cAMPBrain5-HT6,7
cAMPBrain5-HT5A,B
5-Methoxytryptamine, renzapride,metoclopramide
cAMPCNS and myentericneurons, smoothmuscle
5-HT4
Tropisetron,ondansetron, granisetron
2-Methyl-5-HT,m-chlorophenylbiguanide
Receptor is aNa+-K+ ionchannel
Area postrema,sensory and entericnerves
5-HT3
Mesulergine-Methyl-5-HTIP3Choroid,hippocampus,substantia nigra
5-HT2C
SB204741-Methyl-5-HTIP3Stomach fundus5-HT2B
Ketanserin-Methyl-5-HTIP3Platelets, smoothmuscle, cerebralcortex, skeletalmuscle
5-HT2A
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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
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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
- Dari jamur Claviceps purpurea pada biji-bijianisi: histamin, asetilkolin, tiramin, dsb
- Keracunan (ergotism):demensia, halusinasi, vasospasme/gangrenkontraksi uterus (aborsi), konvulsi
- Absorbsi >> dengan kofein
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+/0– – – (PA)+/0+/0Methysergide
+– –, ++ inCNS
+++0Lysergic aciddiethylamide(LSD)
++++ (PA)0– – (PA)Ergotamine+++– (PA)++Ergonovine0–+++–Bromocriptine
UterineSmoothMuscleStimulation
SerotoninReceptor (5-HT2)
DopamineReceptor
AdrenoceptorErgot Alkaloid
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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:INTRODUCTION
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133 kDa125–135 kDa150–160 kDaApproximatemass
71712Chromosome
YesNoYesCalciumrequirement
ConstitutiveTranscriptionalinduction
ConstitutiveExpression
Endothelial cellsMacrophages,smooth musclecells
Neuronal,epithelial cells
Tissue
eNOS(endothelialNOS)
iNOS (inducibleNOS)
nNOS (neuronalNOS)
Other names
NOS-3NOS-2NOS-1Property
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NONO2Produce NOStable oxidation product of NO
NO3-Nitrate
at acidic pHNO2-Nitrite
Nitrosating agentN2O4Dinitrogen tetraoxide
Nitrosating agentN2O3Dinitrogen trioxide
AnestheticN2ONitrous oxide
Free radical, nitrosating agent,lung irritant
Nitrogen dioxide
Smooth muscle relaxantNO-Nitroxyl anion
Vasodilator, platelet inhibitor,immune regulator,neurotransmitter
Nitric oxide
Known FunctionSymbolName
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Endogenous inhibitorfound in brain
Unknown mechanismProtein inhibitor ofNOS
Nitric oxide scavengerHeme
Partially selective forNOS–1
NOS inhibitionS–Methylthiocitrulline
Markedly selective forNOS–1 in vivo
NOS inhibition7–Nitroindazole
Less selective NOSinhibitor
NOS inhibitionNg–Nitro–L–argininemethyl ester (L–NAME)
May act as substrate insome tissues
NOS inhibitionNg–Monomethyl–L–arginine (L–NMMA)
CommentMechanismInhibitor
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Lipid Autocoids
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THE EICOSANOIDS: PROSTAGLANDINS,THROMBOXANES, LEUKOTRIENES, &RELATED COMPOUNDS:INTRODUCTION
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Thromboxane vs. Prostacyclin
• Thromboxane (platelet) promotes plateletaggregation; prostacyclin (endothelium) inhibitsplatelet aggregation. Question: Why is low-dose aspirinsuch a potent antiplatelet agent?
• Thromboxane is a brochoconstrictor;Prostacyclin is a brochodilator.
• Thromboxane is a vasoconstrictor; Prostacyclinis a vasodilator
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Prostaglandins (PGE2) andInflammatory pain sensitization
• PGE2 has recently been shown to inhibit aglycine receptor (GlyR alpha3) in its actionregulating central inflammatory painsensation.
• GlyR alpha3 is expressed in the superficiallayers of the spinal cord dorsal horn.
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Indications for Prostaglandinanalogues
• 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)
• Irreversibly acetylates cyclooxygenasepermanently disabling the enzyme
• Salicylate moiety competitively inhibitscyclooxygenase
• Aspirin displays dose-dependent kinetics• Signs and symptoms of salicylate toxicity• Dosing of aspirin differs greatly depending on
the indication
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