FARMAKOLOGI SS0Fathiyah Safithri

Laboratorium Farmakologi Program Pendidikan Dokter Univ. Muhammadiyah Malang2007

SISTEM ADRENERGIK

Organisasi Divisi Simpatis

NeuronAdrenergik Perifer

Sintesa Katekolamin

TRANSMISI SINYAL

Release Norepineprine aksi potensial pada membran saraf depolarisasi kanal ion Na terbuka kanal Ca terbuka ion calsium masuk ke dalam neuron Peningkatan ion Ca intrasel vesicle kontak dengan membran saraf release NE secara eksositosis . Diduga release melibatkan mekanisme kontraktil dari sitoskeleton dan protein tubulin.

NEUROTRANSMISI ADRENERGIK-3456

varicositiesNTNTRRESEPTOR POST SINAPRESEPTOR PRE SINAP(-)Uptake 1

Uptake 2MetabolitesirkulasiPeningkatan second messenger

Pembukaan kanal ion

Kaskade biokimia

Respon farmakologi

Feedback controlOf noradrenaline releaseNE release involves Ca2+ influx2R activation inhibit Adenylat cyclase cAMP Ca2+ influx Uptake 1 inhibitors:Antidepressants, Cocaine,Amphetamine

Uptake 2 inhibitor:normetanephrine

Metabolism of noradrenaline

Degradation of catecholamines

DISTRIBUSI RESEPTOR SIMPATIS

Classification of adrenoceptors1896 Oliver and Schafer-adrenal extracts increase BP1913 Dale-adrenaline alone produced both vasodilation or vasoconstriction In combination with ergot derivative (a1 antagonist), adrenaline produced a decrease in BP (b2-mediated)1948 Ahlquist- postulated a and b based on agonist potency:Alpha: A>NA>>isoprenaline=isoproterenolBeta: Iso>A>NA

Adrenergic Receptor Family

RESEPTOR UNTUK NEROTRANSMITER ADRENERGIK BERDASARKAN JENIS ;alpha adrenergik reseptor alpha 1, alpha 2 dan alpha 3beta adrenergik reseptor beta 1, beta 2 dan beta 3Reseptor yang berespon pada saraf simpatis dengan urutan potensi (kekuatan efek) dimana NE > EPI >D> isoproterenol dinamakan sebagai alpha receptors.

Sedang reseptor yang berespon dengan urutan potensi dimana isoproterenol > EPI > NE >D dinamakan sebagai beta receptors. MENGAPA DISEBUT SEBAGAI ALPHA ATAU BETA

bAdr-R Subtypes b1Heart

b2 Smooth Muscle

b3Adipose Tissue(increase HR and contractility)(relaxation of smooth muscle in lung, uterus, blood vessels)(stimulation of lipolysis)

Myocardial b Adr Recept SignalingGasGaiAdenylateCyclaseAdenylateCyclase+_

MEKANISME FARMAKODINAMI NEROTRANSMITER ADRENERGIK NOR ADREEPINEPRNEDOPAMIN+ reseptor G-protein adenyllate siklase

G-protein Pospolipase pospolipid ATP

cAMP

Ca++IP3

DAG

OBAT-OBAT YANG BEKERJA PADA SISTEM ADRENERGIK

tyrosineTyrosin hydroksilase

Dopa

Dopa decarboksilase

Dopamine

Dopamine hydroksilae

NorepineprineVesicle

Norepineprine celah sinap

Vesicle

Reserpine

mitokondriaPhenylalanine

Alpha methylp Tyrosine

Carbidopa

disulfiram exocytosisMetabolitedifusiCarrier mediatedUptake Sintesa dan penyimpananNorepineprine padasaraf simpatis periper

tyrosineVesicle

MitokondriaMono amineoksidaseexocytosisMetabolitedifusiCarrier mediatedUptake 1Release , uptake danmetabolisme Norepineprine padaSaraf simpatis periperCocain beta adrenergik agonist ephedrine iproniazidAuto reseptor alpha 2

Uptake 2 cortico steroidbloker(-)Amphetamine difusiyohimbine

APLIKASI KLINIS OBAT YG BEKERJA PD SISTEM ADRENERGIK

Potency AGONIST ANTAGONIST

++++(+) DEXMEDETOMIDINE ATIPAMEZOLE++++ CLONIDINE YOHIMBINE+++ NOREPINEPRINE PENTHOLAMINE++ EPINEPRINE PHENOXYBENZAMINE++ DOPAMINE TOLAZOLINE+ ISOPROTERENOL LABETALOLPOTENSI OBAT PADA RESEPTOR ADRENERGIK

EFEK AGONIS ADRENERGIK

APLIKASI KLINIS AGONIS ADRENERGIK

ANTAGONIS ADRENERGIKALPHAPrazosin 1 >>>> 2Phenoxybenzamine 1 > 2(irreversible)Yohimbine 2 >> 1

BETAMetoprolol 1 >>> 2Propranolol 1= 2TimololButoxamine 2 >>> 1

EFEK ANTAGONIS ADRENERGIK

APLIKASI KLINIS ANTAGONIS ADRENERGIK

Terima kasih..

Main processes involved in adrenergic transmission1. Uptake of precursor tyrosine by carrier linked to Na+ uptake.2. DA transport into synaptic vesicles, conversion to DA.-Release of transmitter occurs when an action potential reaches the nerve terminal causing membrane depolarization. -Depolarization activates Ca2+ channels.-The increase in intracellular Ca2+ facilitates exocytosis of vesicles and release of transmitter.-NE activates post-and presynaptic receptors.-the action is finished by uptake of NE which is reused or broken down by MAO and COMT degradation enzymes.

-NE is released from nerve terminals during periods of nerve stimulation. Adrenergic fibers can sustain this activity for prolong periods if synthesis and uptake are not impaired.-Spike or action potential depolarizes nerve terminal membrane, causing opening of calcium channels.-Evidence by EM, also DBH is released which can be measured in the plasma as an index of sympathetic activity.

-Two enzymes-MAO and COMT--MAO-found in mitochondria of nerve terminals, some liver, some intestinal ephitelium. -MAO-effects oxidative deamination, amine becomes aldehyde.-COMT- widespread enzyme, found in both neural and non-neural tissue.-COMT-effects methylation on phenyl group.-In periphery the oxidative branch, catalyzed by ADH-aldehyde dehydrogenase predominates. Final metabolite is-VNMA- vanillilmandelic acid.-In CNS, reductive branch predominates,catalyzed by AR-aldehyde reductase. Final metabolite is MOPEG-3methoxy-4hydroxyphenylglycol.The level of transmitter in the tissues is maintained relatively constant despite the additional losses assumed to occur during enhanced sympathetic activity. One important level of homeostatic control is at biosynthetic pathway.-Oliver demonstrated that injection of rabbit adrenal extracts to dogs caused an increase in BP.-Dale-active principle had been identified as adrenaline.A produces two types of effects- vasodilation- b2 and vassoconstriction-a1. Dominant is vassoconstriction leading to increase in BP. Ergot derivatives cause a decrease in BP because they act as a1 antagonist.Vasoconstriction component disappeared and dilation unmasked (b2)