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Khoerul Anwar,S.F.,M.Sc.,Apt.
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1
HISTAMIN
SEROTONIN
PROSTAGLANDIN
Definisi Autakoid
substansi (kimia) selain transmitor
yang secara normal ada di dalam
tubuh.
Memiliki fungsi fisiologik penting baik
dalam keadaan normal (sehat)
maupun patologik (sakit)
Disebut juga sebagai hormon lokal
(autopharmacological agents)
Cont.
Memiliki aktivitas secara biologik
Berasal dari bahasa Yunani:
autos(self) = sendiri
akos(medicinal agent or remedy) =
menyembuhkan
KLASIFIKASI AUTAKOID
Biologically active amines:
histamine serotonin
Lipid derived autacoids (Eicosanoids)
prostaglandins leukotrienesthromboxanes
Vasoactive polypeptides e.g.
kinins Angiotensin EndothelinNatriuretic peptide- Vasopressin
substance P
Endothelium derived autacoids
Nitric oxide
Histamin
Histamin : persenyawaan amin endogen
(- aminoethylimidazole)
Merupakan molekul hidrofilik yang terdiri dari cincin
imidazol dan group amino yg dihubungkan oleh 2 group
methylene.
CH2CH2NH2
struktur :
HN
NH2
5
1
H
4
N
2
Histamine
Sumber Histamin
Endogen : hampir semua sel jaringan mamalia
yg mengandung histamin dpt membentuk
histamin dari histidin.
depot utama pd mast cell dan basofil dlm
darah.
kadar histamin plg tinggi di kulit (sel
epidermis), mukosa usus dan paru-paru.
Eksogen : bersumber dari daging dan bakteri
dlm lumen usus/kolon yg membentuk histamin
dari histidin
Cont
Tersebar di alam, terdapat di ergot dan
tanaman lain, serta disemua organ dan
jaringan tubuh manusia.
Histamin bersifat basa, gugus amino rantai
samping memp. pKa = 9,70 dan gugus
imidazol amin memp.pKa = 5,90.
Pada pH tubuh senyawa ini berada sebagai
kation bervalensi tunggal
SINTESIS
Histidine
dekarboksilase
Histamin
N-methylhistamine
Monoamine
oxidase
Diamine oxidase
Imidazoleacetic acid
Ribose
Sifat Histamin
- merangsang sekresi asam lambung,
- menaikkan laju jantung
- menghambat kontraksi uterus tikus
- stimulasi sel parietal pada perut, sehingga
sekresi HCl meningkat
- pengerutan otot polos saluran cerna yang
menyebabkan sakit epigastrik, mual
muntah dan diare.
- dilatasi arteriol pra dan pasca kapiler
sehingga terjadi peningkatan permeabilitas
PELEPASAN HISTAMIN
Pelepasan histamin dari sel mast
dilakukan melalui 2 mekanisme:
Pelepasan imunologi:
Jika IgE berikatan dg sel mast muncul
antigen merangsang degranulasi sel mast
histamin release.
MEKANISME AKSI
Aksi histamin muncul melalui ikatan
dengan reseptor spesifik pada berbagai
jaringan target
Terdapat 4 tipe reseptor dari histamin,
yaitu reseptor H1, H2, H3 dan H4.
Reseptor H1 : sel otot polos, endotel dan
otak (pascasinaptik)
Reseptor H2 : mukosa lambung (sel
parietal), otot jantung, sel mast dan otak
(pasca sinaptik)
Reseptor H3 : presinaptik (otak, pleksus
mienterikus & saraf lainnya
Fungsi Histamin
Fungsi fisiologis sbg mediator yg tersimpan dlm
mast cell dan dilepaskan karena adanya interaksi
antara antigen dan IgE di permukaan mast cell
(respon immediate hypersensitivity dan allergy)
Aksi histamin pd otot polos bronkial dan pembuluh
darah merupakan bagian dr simtom allergi.
Berperan penting dlm regulasi sekresi asam
lambung dan merupakan modulator pelepasan
neurotransmitter.
Histamin dpt dilepaskan karena obat, protein, dan
senyawa lain. Dpt menyebabkan reaksi
anaphylactoid, red man syndrom dan hipotensi.
Histamin dpt jg dilepaskan krn faktor2 lain spt
dingin, kolinergik, sinar matahari ataupun
kerusakan sel yg tdk spesifik.
Sistem saraf
Sistem kardiovaskular
Vasodilatasi pembuluh darah H1 reseptor
Takikardia, Peningkatan kontraktilitas jantung dan
meningkatkan denyut jantung H2 reseptor
CONT
Berperan dalam kontraksi otot polos
bronkus (bronkokontriksi), konstriksi otot
polos mata dan saluran kemih dan organ
genital
Menstimulasi sekresi asam lambung
aktivasi reseptor H2 pada sel parietal
lambung dan berhubungan dg peningkatan
aktivitas adenil siklase, konsentrasi cAMP
dan konsentrasi Ca intraselular.
Actions of histamine
21
FARMAKOLOGI KLINIS
HISTAMIN
Penggunaan Klinis
Toksisitas dan KI
Adverse effects of histamine release, are dose-related:
Flushing, hypotension, tachycardia, headache, wheals,
bronchoconstriction, and gastrointestinal upset are noted
HISTAMIN
ANTAGONIS/ANTIHISTAMIN
Menghambat aksi histamin pada reseptor histamin
Efek histamin endogen dapat dihambat melalui :
1. Penghambatan secara fisiologis, ex : adrenalin
2. Penghambatan pelepaan/degranulasi histamin yg
timbul, ex :pemberian kromolin & stimulan
adrenoseptor 2
H1 RESEPTOR ANTAGONIST
Mekanisme aksi :
- Menghambat reseptor histamin H1 secara
kompetitif, tetapi tdk memblok pelepasan
histamin
Pada inflamasi, obat ini menghambat
pembengkakan yg diakibatkan histamin &
menghambat vasodilatasi
Efek samping utamanya adalah sedasi
Antagonis Reseptor H1
Bersifat reversibel, merupakan
competitive inhibitor interaksi histamin
dg reseptor H1.
Kemiripan strukturnya dg histamin :
mempunyai ethylenamine. Perbedaan:
pd histamin : amino primer dan cincin
aromatil tunggal, pd antagonis : amino
tersier terhubung dg 2 substituen
aromatik oleh 2 atau 3 rantai atom
membentuk formula ttt.
Allergic rhinitis
urticaria
Pharmacokinetics
Well absorbed orally
Short duration 3-6 hour, cetirizine & terfenadin (12-24
hour), astemizol (24 hour)
Widely distributed (SSP & urine in metabolit)
Penetrate BBB cause sedation
Metabolized in the liver.
Side effects
Klasifikasi
1. Ethanolamine:
Diphenhydramine- Doxylamine (sedativeantiemetic)
2. Piperazine:
Meclizine cyclizine (antiemetic)
3. Phenothiazine:
promethazine (sedative - antiemetic)
4. Alkylamine: chlorpheniramine
(cold/allergy, OTC)
5. Miscellaneous: Cyproheptadine
H2 RESEPTOR ANTAGONIST
Bekerja dgn cara menghambat interaksi histamin
dgn reseptor H2 secara kompetitif & selektif shg
tdk memberikan efek pada reseptor H1
Berperan utama dalam sel parietal mukosa
lambung
Menurunkan sekresi asam lambung
Digunakan dlm terapi tukak peptik, refluks
gastrointestinal
Ex :
Cimetidine
Ranitidine
Famotidine
Farmakokinetika
Diabsorpsi cepat & baik pd pemberian
oral
Konsentrasi puncak plasma : 1-2 jam
T1/2 eliminasi ranitidin, simetidin &
famotidin kurang lebih 2-3 jam
Mengalami metabolisme hepatik
Diekskresikan dlm jumlah besar di urine
dlm bentuk utuh shg perlu penyesuaian
dosis pada pasien ginjal
Toxicity:
Well tolerated and side effects reported in
only 1-2% of px. Most common,
headache, nausea, vomiting, dirhhoea,
rash and constipation.
Interactions:
- Cimetidine reduce liver blood flow and
inhibits oxidative metabolism of other
drugs like propranolol, warfarin,
phenytoin, diazepam or theophylline.
5-Hydroxytryptamine (5-HT,
Serotonin)
Cont
Serotonin is an amine synthesized from Ltryptophan by an hydroxylase enzyme
MAO & aldehyde de-hydrogenase degrade 5HT into 5-hydroxyindoleacetic acid (5-HIAA)
Storage:
90% is present in enterochromaffin cells of the
GIT
Other in platelets & CNS
Distribution
Postulated Roles
5-HT1
5-HT2
5-HT3
Nausea, anxiety
5-HT4
Neuronal excitation, GI
5-HT5,
6, 7
Brain
Not known
Serotonin Pharmacological
Actions
CNS: 5-HT plays a role in regulation of mood, food
intake & sleep (5-HT1A-D)
5-HT3 receptors in the gastrointestinal tract and in the
vomiting center of the medulla participate in the
vomiting reflex
Blood vessels:
- Vasodilation (5-HT1A-D) in skeletal muscles &
coronaries & cerebral constriction
- Vasoconstriction receptor 5-HT2 in splanchnic,
renal, pulmonary vasculature
Cont
Heart: increased heart rate & contractility
(5-HT1)
Reflex cardiac slowing & hypotension via
5-HT3 receptor stimulation in coronaries &
baroceptors
Stimulation of platelet aggregation
activating 5-HT2 receptor
GIT 5-HT2 powerful stimulant of
gastrointestinal smooth muscle,
increasing tone and facilitating peristalsis
over serotonin cause diarrhea
5-HT Antagonists
Phenoxybenzamine has a long-lasting blocking action at
5-HT2 receptors.
Cyproheptadine resembles the phenothiazine antihistaminic
agents in chemical structure and has potent H1-receptorblocking as well as 5-HT2-blocking actions. It prevents the
smooth muscle effects of both amines but has no effect on the
gastric secretion stimulated by histamine. It also has
significant antimuscarinic effects and causes sedation. In
children, it may cause weight gain & increased growth rate
Ketanserin blocks 5-HT2 receptors on smooth muscle and
other tissues and has little or no reported antagonist activity at
other 5-HT or H1 receptors. It causes vasodilation lowering
blood pressure, and considered for hypertension treatment. It
has - & H1- receptor blocking activity
CON,T
Ritanserin, another 5-HT2 antagonist, to
alter bleeding time and to reduce
thromboxane formation, presumably by
altering platelet function.
Ondansetron is the prototypical 5-HT3
antagonist. This drug and its analogs are very
important in the prevention of nausea and
vomiting associated with surgery and cancer
chemotherapy.
Side effects: headache, cardiac rhythm changes,
PROSTAGLANDIN
PGS are endogenously generated
substances biosynthesized by most human
organs
Thromboxanes lipids synthesized by the
body from same precursor as PGS
leukotrienes also lipids from same
precursor
PGS
Thromboxanes
eicosanoids
Leukotreins
Sintesis prostaglandins:
Prekusor utama Arachidonic acid, a 20-carbon
fatty acid component of the phospholipids of
cell membranes, primarily phosphatidylinositol
and other complex lipids
2 jalur utama sintesis eikasonoid dari as.
Arakidonat:
Jalur siklooksigenase
Jalur lipooksigenase
Inhibitors of synthesis
1.corticosteroids inhibit phospholipases and
therefore prevent arachidonic acid release
from cell membrane. Therefore block
eicosanoids synthesis.
2.Nsaids e.g. (aspirin) and indomethacin
block PGS and thromboxanes synthesis by
inhibiting cyclo-oxygenases
Therapeutic uses of
prostaglandins
1. Abortion: Several of the prostaglandins
find use as abortifacients (agents
causing abortions). The overall casefatality rate for abortion is less than one
death per 100,000 procedures.
Infection, hemorrhage, and retained
tissue are among the more common
complications.
2. Peptic ulcers: Misoprostol is sometimes
used to inhibit the secretion of gastric
acid and to enhance mucosal
resistance to injury in patients with
gastric ulcer who are chronically taking
nonsteroidal anti-inflammatory agents.
TERIMA KASIH
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