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FARMAKOLOGI AUTAKOID DAN

ANTAGONISNYA
NOOR CAHAYA,S.Si.,M.Sc.,Apt.

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Pokok Bahasan
1

DEFINISI & KLASIFIKASI AUTAKOID

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

Ada 3 macam reseptor histamin : Reseptor H1, H2 dan


H3 (baru ditemukan dan belum diyakini mempunyai
fungsi klinis)

NH2
5

4
3

1
H

N
2

Histamine

Sir Henry Dale,


Penemu histamin
Dari Dr.Jhon Buynak, dalam medicinal chemistry

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

Dalam tubuh histamin berasal dari hasil


dekarboksilasi histidin dari alam.
Reaksinya dikatalisir oleh histidin
dekarboksilase

SINTESIS

Asam amino L-histidine

Histidine
dekarboksilase

Histamin

Distribusi dan Biosintesis Histamin


Tdpt pd hewan, tanaman maupun bakteri.
Hampir semua jaringan mamalia mengandung
histamin, paling banyak tdpt pd mast cell.
Jaringan yg banyak mengandung mast cell spt
kulit, mukosa pd cab bronkia/paru, dan mukosa
usus mengandung banyak histamin.
Setiap mamalia yg mengandung histamin
mampu mensintesisnya dari histidine oleh Lhistidine decarboxylase.
Ada 2 macam jalur metabolisme histamin dlm
tubuh manusia.

Jalur metabolisme histamin pd manusia


Histamine
N-methyltransferase

N-methylhistamine
Monoamine
oxidase

N-methylimidazole acetic acid

Diamine oxidase

Imidazoleacetic acid
Ribose

Imidazole acetic acid


riboside

Jalur metabolisme histamin


Jalur yang kiri adlh lebih banyak terjadi, yaitu metilasi
cincin membentuk N-methylhistamine. Kmdn diubah
mjd N-methylimidazolacetic acid yg dikatalisa oleh
enzim MAO. Proses ini dihambat oleh MAO inhibitor.
Untuk jalur kanan, tdk terlalu penting karena
metabolitnya nantinya akan dikeluarkan beserta urin.
Terdaptnya N-methylhistamine di dlm urin menunjukkan
kemungkinan terjadinya infeksi pd saluran genitourinary
oleh bakteri yg dpt mendekarboxilasi histidine. Jadi
bukan karena adanya histamine
Pd pasien dgn mastocytosis tjd kelainan metabolisme
histamine, shg pada urine jg dijumpai adanya metabolit
histamin

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.

Pelepasan kimia dan mekanik


Curare morphine - apomorphine
Chemical and physical injury of mast cells

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.

Efek histamin terhadap sistem


organ dan jaringan
Sistem saraf
Menstimulasi sistem saraf sensorik memediasi
gatal dan nyeri.
H1: respon urtikaria dan gigitan serangga,
memodulasi ekspirasi dan inspirasi paru.
H3: memodulasi pelepasan beberapa transmiter di
sistem saraf H3 agonis menurunkan pelepasan
asetilkolin, amina, dan peptida transmiter di otak dan
sistem saraf tepi.

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
In pulmonary function laboratories, histamine aerosol
as a provocative test of bronchial hyperreactivity.
Histamine has no other current clinical applications

Toksisitas dan KI
Adverse effects of histamine release, are dose-related:
Flushing, hypotension, tachycardia, headache, wheals,
bronchoconstriction, and gastrointestinal upset are noted

KI: Histamine should not be given to patients with


asthma (except as part of a carefully monitored test of
pulmonary function) or to patients with active ulcer
disease or gastrointestinal bleeding.

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

3. Histamine receptor antagonists


H1- receptor blockers (antihistaminics-allergy)
H2- receptor blockers (peptic ulcer).

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
Dibagi menjadi (didasarkan persenyawaan
kimia):
Generasi pertama
Generasi kedua

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.

Antagonis H1 reseptor generasi pertama


Bersifat lipofilik shg dapat menembus barier darah otak
Therapeutic use:
1. For allergic reactions such as:
a.
b.

Allergic rhinitis
urticaria

2. Motion sickness, nausea and vomiting


3. For sedation: some H1 antagonists (e.g. promethazine,
diphenhydramine) are strong sedatives & may be used for this
action.
Additional effect:
1. CNS sedation, dizziness & fatigue.
2. Anticholinergic effect dry mouth, urinary retention, tachycardia
3. - blocking effect postural hypotension, reflex tachycardia.
4. Antiserotonin effect appetite

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

Sedation and drowsiness


Antimuscarinic effects
Alpha blocking adverse effects
Excitation in high doses in children

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

Antagonis H1 reseptor generasi kedua


Ex: Fexofenadine- Cetirizine, Loratidine
Advantages of second generation
Can not cross BBB
No sedation
Longer duration of action
BUT More expensive

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

Cytochrome p450 inhibitor (only cimetidine).

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)
Serotonin merupakan neurotransmiter
penting:
Hormon lokal di saluran cerna
Komponen pada proses pembentukan
clot platelet
Berperan pada sakit kepala migraine

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

Serotonin Receptors & Functions


Seven receptors, 5-HT1- 5-HT7 for serotonin
are characterized, the first four have related
functions
All types are G-protein coupled receptor except
5-HT3 receptors nicotinic/GABAA family of
Na+,K+ channel proteins
Type

Distribution

Postulated Roles

5-HT1

Brain, instetinal nerves

Neuronal inhibition, behavioural


effects, cerebral vasoconstriction

5-HT2

Brain, heart, lungs, smooth muscle


control, GI system, blood vessels,
platelets

Neuronal excitation, vasoconstriction,


behavioural effects, depression,
anxiety

5-HT3

Limbic system, ANS

Nausea, anxiety

5-HT4

CNS, smooth muscle

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 Receptor Agonists (5-HT


RAs)
Contoh:

Buspirone 5HT1A agonis effective


nonbenzodiazepine anxiolytic
Sumatriptan and its congeners are agonists
effective in the treatment of acute migraine and
cluster headache attacks.

5-HT 1D/1B AGONIST (TRIPTANS)

5-HT analogues that are agonists on 5-HT1D/1B


showed effectiveness against migraine
The pathophysiology of migraine is still poorly
understood and controversial

5-HT Receptor Agonists (5-HT


RAs)
Terdapat 2 tipe utama nyeri kepala
migren:
Migren tanpa aura (migren umum): berat,
unilateral, nyeri kepala berdenyut 2-72
jam, diperberat aktivitas fisik, mual,
muntah, fotofobia, fonofobia. 85%
menderita migren tipe ini.
Migren dengan aura (klasik); nyeri kepala
didahului gejala neurologi aura
gangguan visual, sensorik,
bicara/motorik.

5-HT Receptor Agonists (5-HT RAs)


the pain of both types of migraine may be due to
extracranial and intracranial arterial dilation. This
stretching leads to release of neuroactive
molecules, such as substance P.
In migraine, evidence indicates the activation of
the trigemino-vascular system leading to dilation
& neurogenic inflammation (antidromic release of
proinflammatory peptides & neuropeptides)
Mechanism: 5-HTRAs stimulate 5-HT1D/1B
receptors in the intracranial vasculature &
sensory nerves of the trigeminal system leading
to:
Cerebral vasculature vasoconstriction
Inhibition of release of proiflammatory peptides
(kinins) & neuropeptides

5-HT Receptor Agonists (5-HT


RAs)
Eletriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan

Use: Acute treatment of attacks +/-aura, not for


prophylaxis
Not used in hemiplegic or opthalmogenic migraine
Not combined with ergotamine derivatives nor
selective serotonin reuptake inhibitors (SSRIs)
Contraindicated with coronary artery disease,
congenital heart disease, atherosclerosis, severe
hypertension or seizures
Not used in patients below 18 (or <12 for Zolmitriptan)

Safety in pregnancy/lactation not tested

5-HT RAs Adverse Effects &


Pharmacokinetics
Angina pectoris-like syndrome, arrhythmias, CA
spasm, MI, cerebral hemorrhage, stroke & increased
blood pressure in susceptible patients
Pharmacokinetics:
Mostly significant pain relief within 4 hours
Severe renal/hepatic impairment can affect their
biotransformation & clearance (dose reduction)
Average oral bioavailability, sumatriptan being the
lowest (14%)
Selective serotonin reuptake inhibitors (SSRIs) are
used as antidepressants (Details in Depression):
Fluoxetine, paroxetine, sertaline, citalopram

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,

Other 5-HT Antagonists


Ergot Alkaloids
Formed by fungus
several receptors (Dopamine, 5-HT, receptors).
Pharmacological actions
I. CNS
1. Stimulate Dopamine receptors &
decrease prolactin and parkinsonism.
2. Stimulation of cerebral vessels (5-HT2).
II. Smooth muscles
1. Vasoconstriction of blood vessels
2. Contraction of uterus
3. Nausea, vomiting, diarrhea

Other 5-HT Antagonists


Ergot Alkaloids
Types & uses
Migraine treatment :
Ergotamine & dihydroergotamine (5HT1 &
5HT2 )
M
igraine prophylaxis: Methysergide (5HT2)
P
ostpartum hemorrhage:
Ergometrine (Ergonovine)
E
ndocrine disorders (hyperprolactinemia) Parkinsonism
Bromocriptine (dopamine agonist).

Other 5-HT Antagonists


Ergot Alkaloids
They are of fungal origin & used as oxytocic
drugs, e.g., ergometrine (ergonovine) & Meergometrine
Ergotamine & dihydroergotamine have 5-HT1D
agonist activity, in addition to -adrenergic
stimulation & direct vasoconstriction
They are used in early-onset phase of migraine
Used in combination with caffeine
Adverse effects include nausea &
vasoconstriction that may lead to angina or
stroke
Methysergide: discussed later slide

Other 5-HT Antagonists


Ergot Alkaloids
Methysergide: Both antagonist on 5-HT
receptors & a partial agonist
Prophylactic migraine treatment
It takes 1-2 days for full effect,
Not used during acute attack
Chronic use should not exceed 6 months
without 3-4 weeks methysergide-free period
Its frequent side effects limit its use; retroperitoneal & pulmonary fibrosis, aortic/valular
fibrosis, insomnia, alopecia
Dose should be gradually tapered off for2-3
weeks to avoid rebound headache

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

Peran prostaglandin sebagai mediator lokal


PGS dan senyawa lain diproduksi dalam jumlah
kecil oleh semua jaringan.
They generally act locally rapidly metabolized
to inactive products at their sites of action

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.

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