ANGINA PECTORISTHROMBOLITYCANTI ARRYTHMIAPROF MOCH ARIS WIDODO PhDDEPARTMENT PHARMACOLOGY AND THERAPYMEDICAL FACULTY BRAWIJAYA UNIVERSITY

RISK FACTORSSMOKINGOBESITYHYPERTENSIVMETBOLIC SYNDROME

ACUTECORONARYSYNDROME

ANGINAMIOCARD INFARCTARRYTMIA

ANGINA PECTORIS NYERI DADA YANG BERASAL DARI JANTUNG DAN SERING KALI MENJALAR SAMPAI UJUNG JARI DANKE BAHU

NYERI OLEH KARENA OLEH KARENA TIDAK SESUAINYA KEBUTUHAN JARINGAN OTOT JANTUNG DENGAN SUPLAI OKSIGEN OLEH CABANG CABANG ARTERIKORONARIA

PENYEBAB :

SUPLAI OKSIGEN DAN BAHAN MAKANAN BERKURANG OLEH ARENA PENYEMPITAN PEMBULUHDARAH KORONER OLEH PENYUMBATAN ATAU TERJADI VASOKONSTRIKSI KPORONER

KEBUTUHAN YANG MENINGKAT MISALNYA PADALATIHAN TAKHIKARDI PENINGKATAN PRELOADATAU AFTER LOAD.

ALIRAN DARAH KE ARTERI KORONARIA

TERJADI PADA FASE DASTOLE OLEH KARENA:

OTOT JANTUNG RELAKSASIKATUP AORTA MENUTUPTEKANAN DIASTOLE YANG CUKUP

SISTOLE

DIASTOLE

AORTA

ARTERI KORONARIA

VENTRIKEL KIRI

TYPE TYPE ANGINA PECTORIS:

ATEROSCLEROTIC ANGINA : ANGINA DE EFFROT, ATAU ANGINA KLASIK. TERKAIT DENGAN ATHEROMA, 90%PENYEBAB ANGINA, PENYEMPITAN MENYEBABKAN ISKEMIA DAN METABOLIT ACID RASA NYERI SPESIFIKNYERI HILANG SAAT IATIRAHAT.

VASOSPASTIK ANGINA = REST ANGINA = PRINZMEAL ANGINA = VARIANT ANGINA VASOSPASNE REVERSIBLE DAPAT TERJADI SAAT ISTIRAHAT – DAPAT MENJADI UNSTABLE ANGINA

UNSTABLE ANGINA CRESCENDO ANGINA = SINDEROMA KORONER AKUT, TERJADI [ENINKATAN FREKUENSI DAN DERAJAT SERANGAN OK BERKURANGNYA FLOW KORONERDISEBABKAN OLEH PLAK ATEROSKLEROSIS. TROMBUS RUPTURE PLAK DAN VASOSPASME PREKUSOR UNTUKMIOKARD INFARK.

THERAPY ANGINA PECTORIS

PENCEGHAN ANGINA PECTORISPENGENDALIAN FAKTOR RESIKOMODIFIKASI LIFE STYLE

PEMASANGAN STENT

PENGOBATAN DENGAN OBATANTI LIPIDANTI TROMBOSISANTI ANGINA

OBAT UNTUK ANGINA PECTORIS MENGHILANGKAN NYERI

VASODILATOR ARTERI KORONARIA

VASODILATOR PERIPERMENGURANGI PRELOAD DAN

AFTER LOAD

MENGURANGI BEBAN JANTUNG

SYSTEMIC CIRCUATION REDUCED AFTER LOAD

BETA BLOCKER BETA BLOKER SA NODE CA ANTAGONIST NITRATES NEGATIF INOTROPICS

VERAPRAMIL ARTERIAL RESISTANCE

VESSELS DILTIAZEM

NITRATES Ca ANTAGONIST

REDUCED PRELOAD VENOUS CAPACANCE

VESSELS

REDUCED VENOUS RETURN

OBAT OBAT UNTUK ANGINA

VASODILATOR CARDIAC DEPRESANT

NITRATES CALSIUM ANTAGONIS BETA BLCKER

SHORT DURATION

INTERMEDIATE

LONG DURATION

GOLONGAN CONTOH OBAT DURATION

VERY SHORT IMHALED AMYL 3-5 MENIT NITRIT

SHORT NITROGLICERIN 10-30 MENIT ISOSORBID DINITRAT

SUBLINGUAL

INTERMDIATE NITROGLYCERINE 4-8 JAM ISOSORBIDE DINIRAT

ORAL

LONG NITROGLICERIN 8-10 JAM TRANS DERMAL PATCH

KELOMPOK NITRAT

MEKANISME KERJA KELOMPOK NITRAT

GLYCERYL TRINITRAT DIHEPAR

GLYCERYL DINITRAT EFEK VASODILATASI

MONONITRAT METABOLIT TAK ADA EFEK

DENITRASI GTN DIDALAM OTOT POLOSMENYBABKAN MELEPASKAN NO STIMULATEGUANILATE SIKLASE MENINGKATKAN C GMPDEPOSPORILATION OF MYOSIN LIGHT CHAINKINASE RELAKSASI OTOT POLOS PEMBULUH DARAH VASODILATASI

NITRAT :KARDIOVASKULER: RELAKSASI OTOT POLOS

PEMBULUH RAH MENYABABKAN PENURUNAN PROLOADDAN MENGUANGI BEBAN JANTUNGM BESAR JANTUNGDAN MENURUNKAN OUT PT JANTUNG PENURUNA AFTERLOAD TERJADI OLEH KARENA DILATASI ARTRIOLE MENURUNKAM TAHANAN PERIPER, MENURUNKAN TEKAMAM DARAH.

NITRAT MENYEBABKAN REFLEK TAKIKARDI

EFEK RELAKSASI OTOT POLOS LAIN KECIL

EFEK SAMPING :

TAKIKARDI REFLEK KOMPENSASI HYPOTENSIORTHOSTATIK HYPOTENSI NYERI KEPALA BERDENYUT

INTERAKSI DENGAN SIDEFANIL

SIDEFANIL (VIAGRA) MENGHAMBAT POSPODIESTRASE ISOFORM. MENURUNKAN PEMECAHAN C GMP

+NITRAT MENINGKATKAN SINTESA C GMP

SINERGISTIK RALAKSASI PEMBULUH ARAH HYPOTENSION, HYPOREPERFUSION PADA ORGAN PENTING

CALCIUM ANTAGONIS

DERIVAT DYHYDROPYRIDINE NIFEDIPINE DILTIAZEMVERAPRAMIL

MEKANISME MENGHAMBAT KANAL KALSIUM TYPE L DIOTOT POLOS PEMBULUH DARAH DAN JANTUNG SEHINGGAINFLUK KALSIUM SAAT TERJADINYA AKSI POTENSIALMENURUN --- DILATAS PEMBULUH DARAH

EFEK FARMAKOLOGI RELAKSASO PEMBULUH ARAH HIPOENSI DAN PENURUNAN KONTRAKSI DAN FREKUENSIJANTUNG

KEGUNAAN : ANGINA, HYPERTENSI, TAKHIKARDI SUPRAVENTRIKEL, MIGRAIN DAN RAYNODE DISEASE

BETA BLOKER

MENGHAMBAT KONTRAKSI JANTUNG DENGANMENGHALNGI IKATAN LIGAND DALAM HALINI NOR ADRENERGIC ATAU NEROTRANSMITERBERIKATAN DENGAN RESEPTOR BETA 1

EFEK SAMPING BBETA BLOKER JUGA MENCEGAH IKATAN NEROTRANSMITER DENGAN RESEPTOR BETA 2 DENGAN AKIBAT BRONCHO KONSTRIKSI

BETA BLOKER

MENGHAMBAT KONTRAKSI JANTUNG DENGANMENGHALNGI IKATAN LIGAND DALAM HALINI NOR ADRENERGIC ATAU NEROTRANSMITERBERIKATAN DENGAN RESEPTOR BETA 1

EFEK SAMPING BBETA BLOKER JUGA MENCEGAH IKATAN NEROTRANSMITER DENGAN RESEPTOR BETA 2 DENGAN AKIBAT BRONCHO KONSTRIKSI

MIOCARD INFARCTACUTE CORONARY SYNDROMES

AND THROMBOLITYC

ANGINA UNSTABLE

CRESCENDO ANGINA

MIOCARD INFACRT

Stable plaque

rupture

thrombosss

Embolitroponin

restabilized

Gp Iib/IIIa

Intact endothelim

Anti aggregratoryVia prostacyclin

VasodilatoryVia nitric oxide

FibrinolyticVia tPA

Anti thrombotic Via thrombomedulin

Damaged vascular endothelium

Platelet adhesionPlatelet activation

Platelet aggregration

Clotting mechanism Formation of fibrin

Back bone of thrombus

Clinical sydrome ofAcute myocard infarct

Peripheral arterial thrmbosis

Platelet inhibitorPrevent AMITIA (aspirin)

Anticoagulant given Acutely to prevent Further formation ofFibrin (heparin)To prevent thrmboEmbolism (warfarin)

Fibrinolytic agentsFor clinical syndromesAMI and phripheralArterial thrombosis

EARLY PHASE AMIRUSH TO ICURAPID LYSIS PCIPAIN RELEIFASPRINBETA BLOCKERACE INHIBITORFUTUE STEM CELL

REPERFUSION

CHRONIC PHASESTATINASPIRIN /CLOPIDOGRELACE INHIBITORPCI / BYPASS

REMODELLINGPREVENT CHVACE INHIITORBETA BLOKERHYPERTENSI

PREVENT SUDDEDDEATHBETA LOCKER

ANTI PLATELET AGENTSTICLOPIDINE : thienoyridine derivat irreversibly inhibit the

binding of ADP to is receptor on the platelets side effects : neutropenia, thrombocytopenia

CLOPIDOGREL: same as above, lower myelotoxiciy, GI effects same as aspirin

DIPYRIDAMOLE: the effects same as aspirin, no longer use inhibit COX, dangerous interaction with adenosine

SULFINPYRAZOLE: same as dypyridamol

GYCOPROTEIN IIb/IIIa RECEPTOR ANTAGONIST: ABCIXICIMA: monoclonal antibody against IIb/IIIa receptorTIROFIBAN : Nonpeptida peptidomeric Iia/IIIb inibitorEFTIFIBATIDE : A synthetic cyclic heptapeptida

PLATELET INHIBITION

ASPIRIN

INHIBITION OF COX 1 inhibit synthesis of thombin side effect GI bleeding weak inhibition of COX2 weak anti inflamatory

ASPIRIN RESISTANCE

CLINICAL USE after MI, angina, after stroke after by pass surgery, diabetes, well treated hypertension

Primary prevention of aspirin only those at high risk group

drug interaction NSAIDS, warfarin, ACE inhibitor

ACUTE ANTI koagulant

HEPARIN oral : diberikan secara intra vena

WARFARIN: diberikan secara

FIBRINOLYTIC (THOMBOLYTIC) HERAPYGoal of therapy : reperfusion , early patency, salvage cardiac miocyte from cell death , improve remodeling, enhance electrical stability reduced long term mortalityGolden period: 1 hours - 7-12 hours reduced mortality rate and reduce infarct sizePrehospital fibrinolytic therapy is more better

ALTEPLASETpa, Tissue plasminogen activator a naturally occuring enzyme

that bind to fibrin convert plasminogen to plasmin very short half life intra venous side effect: hemorrhage contra indication CVA, postoperation

TENECTEPLASE: genetically enginered mutant of tPA decrease plasma clearance longer half life iv sigle bolus

RETEPLASE: deletion mutant of ateplase longer plasma clearance 10U+10U for 10 minute each 30 minute apart

STREPTOKINASE : no direct effect on plasminogen it work by binding to plasminogen to form a complex to convert plasminogen to plasmin dose 1.5 million unit in 100ml saline over 30 to60 minute

Contra indication of fibrinolyticsuspected aortic dissectionprevious history of hemorrhage stroke central nervous system damage within1 yearhead trauma / brain surgeryinternal bleeding within 6 weeksactive bleeding / bleeding disordermayor surgery within 6 weekstraumatic cardio respiratory resusitationpersistent serious hypertensionoral anticoagulant therapypeptic ulcer diseaseintracranial neoplasmacute pancraetitisPregnancy / within 1 week postpartumdementiatransient ischemic attack (TIA)infective endocarditisactive cavitating TBCadvanced liver diseaseintra cardiac thrombi

ANTI ARRYTHMIA DRUGS

OBAT ARITMIA JANTUNGCardiac cells undergo depolarization and repolarization to

form cardiac action potentials about sixty times per minute. The shape and duration of each action potential are

determined by the activity of ion channel protein complexes in the membranes of individual cells, and the genes encoding most of these proteins now have been identified.

Thus each heartbeat results from the highly integrated electrophysiological behavior of multiple proteins on multiple cardiac cells.

Ion channel function can be perturbed by acute ischemia, sympathetic stimulation, or myocardial scarring to create abnormalities of cardiac rhythm, or arrhythmias.

Available antiarrhythmic drugs suppress arrhythmias by blocking flow through specific ion channels or by altering autonomic function.

Mekanisme aritmia jantungWhen the normal sequence of impulse

initiation and propagation is perturbed, an arrhythmia occurs.

Failure of impulse initiation may result in slow heart rates (bradyarrhythmias)

Failure of impulses to propagate normally from atrium to ventricle results in dropped beats or "heart block"

These abnormalities may be caused by drugs or by structural heart disease

Three major underlying mechanisms have been identified: enhanced automaticity, triggered automaticity, and re-entry.

Enhanced Automaticity

Enhanced automaticity may occur in cells that normally display spontaneous diastolic depolarizationthe sinus and AV nodes and the His-Purkinje system. b Adrenergic stimulation, hypokalemia, and mechanical stretch of cardiac muscle cells increase phase 4 slope and so accelerate pacemaker rate,

acetylcholine reduces pacemaker rate both by decreasing phase 4 slope and by hyperpolarization (making the maximum diastolic potential more negative).

In addition, automatic behavior may occur in sites that ordinarily lack spontaneous pacemaker activity; e.g., depolarization of ventricular cells (e.g., by ischemia) may produce such "abnormal" automaticity.

Afterdepolarizations and Triggered Automaticity

Under some pathophysiological conditions, a normal cardiac action potential may be interrupted or followed by an abnormal depolarization If this abnormal depolarization reaches threshold, it may, in turn, give rise to secondary upstrokes that can propagate and create abnormal rhythms. These abnormal secondary upstrokes occur only after an initial normal, or "triggering," upstroke and so are termed triggered rhythms.

Na Ca K K NaNa-K ATP ase

0

+30

- 90

KONDUKSIADANYA BLOK AUTOMATISITYFREKUENSI

AKSI POTENSIAL DAN TERJADINYA ARRITMIA

INTRA SEL

Triggered Automaticity

Two major forms of triggered rhythms are recognized. In the first case, under conditions of intracellular Ca2+ overload (e.g., myocardial ischemia, adrenergic stress, digitalis intoxication, or heart failure), a normal action potential may be followed by a delayed afterdepolarization (DAD). If this afterdepolarization reaches threshold, a secondary triggered beat or beats may occur. In the second type of triggered activity, the key abnormality is marked prolongation of the cardiac action potential. When this occurs, phase 3 repolarization may be interrupted by an early afterdepolarization (EAD). When cardiac repolarization is markedly prolonged, polymorphic ventricular tachycardia with a long QT interval, known as the torsades de pointes syndrome, may occur. Congenital long QT syndrome, a disease in which torsades de pointes is common, can be caused by mutations in the genes encoding the Na+ channels or the channels underlying the repolarizing currents

Re-entry

Anatomically Defined Re-entry. Re-entry can occur when impulses propagate by more than one pathway between two points in the heart, and those pathways have heterogeneous electrophysiological properties. Patients with Wolff-Parkinson-White (WPW) syndrome have accessory connections between the atrium and ventricle With each sinus node depolarization, impulses can excite the ventricle via the normal structures (AV node) or the accessory pathway. However, the electrophysiological properties of the AV node and accessory pathways are different.

PENGOBATAN ARITMIA :

JENIS ARITMIAS DIIDENTIFIKASI

PENYEBAB YANG REVERSIBLE DIHILANGKAN

DINILAI KEPENTINGAN RISK DAN BENEFIT DARI TERAPI

ATRIAL ARITMIA DAN AV NODAL REENTRAN TAKIKARDIVERNTIKULAR ARITMIA ----- ANCAMAN SUDEN DEATH

PEMILHAN OBAT HARUS DIPAHAMI

FARMAKODINAMI OBAT OBAT ARITMIA

FARMAKOKINETIK OBAT ARITMIA

PENYAKIT YANG MENYERTAI ARITMIA

ARRITMIA JANTUNG

SUPRAVENTRIKULER VENTRIKULER

FOKUS ECTOPIK DI ATAS A-V NODE DI VENTRIKEL

HEMODINAMIK RINGAN BERAT COLLAPS

SUDDEN DEATH TIDAK ANCAMAN

CONTOH ATRIAL TAKIKARDI VES ATRIAL FLUTER VENT. TAKIKARDI

VEBNT FIBRILASI

PENYEBAB ARITMIA YANG REVERSIBEL

OBAT OBATANDIGITALIS ANTI ARRITMIATHEOPHILIN CATHECOLAMINETRISIKLIK ANTI DEPRESAN PHENOTHIAZINEANOREKSIAN OBAT ANAESTHESI

FAKTOR JANTUNGISKEMIA JANTUNG CHF

PENYAKIT LAINTHYROTOKSIKOSIS LUNG DISEASE

GANGGUAN METABOLIKASIDOSIS ALKALOSISHYPOKSIA HYPERKALEMIAHYPOMAGNESEMIA HYPOKALEMIA

ARRITMIA JANTUNG HILANG APABILA FAKTOR TERSEBUTDIPERBAIKI

DIAGNOSEPEMERIKSAAN ECG

DILAKUKAN MONITOR 24 – 72 JAMDILAKUKAN TEST EXERCISE PEMERIKSAAN ELEKTRO FISIOLOGIS PEMERIKSAAN 12 LEAD ECG ATAU OESOPHAGUS ECG

DIHILANGKAN PENYEBAB

DILAKUKAN TERAPI OBAT

DILAKUKAN TERAPI DEFIBRILASI

PEMASANGAN PACU JANTUNG

OBAT ARRITMIA JANTUNG :

I. SODIUM CHANNEL BLOKER : KELAS I a KELAS I bKELAS I c

II. BETA ADRENERGIK AGONIS

III PROLONGATION OF THE ACTION POTENTIAL

IV. A-V NODAL CALCIUM CHANNEL BLOCKER

LAIN –LAIN

DATA FARMAKOKINETIK OBAT ARITMIA YANG DIBERIKANSECARA INTRA VENA

OBAT LOADING MAINTENANCE THER. PLASMA CONC

LIDOCAIN 3-4 MG/KG 1-4 MG/MIN 1.5-5 UG/ML

BRETYLIUM 5-30 MG/KG 1-4MG/MIN -

PROCAINAMIDE 10-20 MG/KG 1-4 MG/MIN 4-10 UG/ML 20 MG/MIN

VERAPRAMIL 1-20 MG/KG

ADENOSIN 2-20 MG/KG

ESMOLOL 500 UG/KG(50UG/KG/MIN) 100-200 UG/KG

PROPANOLOL 1-5 MG

PENYAKIT DAN OAT OBAT YANG MENYEBABKAN PERUBAHAN FARMAKOKINETIK

CONGESTIVE HEART FAILURE ---- DISTRIBUSI OBAT

KELAINAN HEPAR ------- METABOLISME OBATBINDING PROTEIN

GAGAL GINJAL ------------------- EKSKRESI OBAT MENURUN

PENGOBATAN LAIN MISALNYA PHENO BARBITAL MENINGKATKAN METABOLISME OBAT

OBAT PILIHAN PENAALAKSANAN ARITMIA

ARITMIA ACUT KRONIS

ATRIAL FIBRILASI/ FLUTER DIGITALIS , VERAPRAMIL SAMA BETA BLOKER

AV NODAL ENTRY ADENOSINE , VERAPRAMIL QUINIDINE, PROCAINAMIDE AMIODARONE, FLECAINIDE

WOLF PARKINSON WHITE ADENOSINE, VERAPRAMIL KELAS Ic DAN Kelas 1aSYNDEROME BETA BLOKER

ATRIAL FIBRILASI DENGAN PROCAIN AMIDE PROCAINAMIDE , QUINIDINEPREEXCITEN VENRICULAER KELAS IcCOMPLEXES

AUTOMATIC ATRIAL A-V NODAL BLOKER VERAPRAMIL, KELAS IaTAKHIKARDI KELAS Ic

AKUT KRONISPREMATURE VENTRICULAR BEAT AND NO SUSTAINED VENTRIKULAR ARRITMIA ASYMPTOMATIC - - SYMPTOMATIC - BETA BLOKER

KELAS Ia/ Ic SUSTAINED VENTRK. TAKIKARDI LIDOCAIN KELAS Ia

PROCAINAMIDE KELAS Ic BRETYLIUM BETA BLOKER

VNTRIKULAR FIBRILASI LIDOCAIN - PROCAINAMIDE BRETYLIUM

WIDE COMPLEX TAKHIKARDI PROCAINAMIDE LIDOCAINE

ADENOSINE HINDARI VERAPRAMIL

NAROW COMPLEX TAKHIKARDI ADENOSINE VERAPRAMIL

KONTRA INDIKASI RELATIF OBAT ANTI ARRITMIA

NON CARDIACPENYAKIT GI QUINIDINEPROSTATISM, RETENSI URINEGLAUCOMA DYSOPYRAMIDEARTRITIS INFLAMASI MEXILETIN , TOCAINIDETREMOR LIDOCAINBRONCHO SPASM BETA BLOKER, PROPAFENONEPENY. PARU AMIODARONEPSIEN MUDA AMIODARONE, PRODCAINAMIDE

CARDIACCHF DYSOPYRAMIDE, FLECAINIDE,STENOSIS AORTA BETA ANTAGONIS, VERAPRAMIL,CARDIOMYOPATHI BRETYLIUM, KELAS 1 a dan IIIHYPERTENSI PU;LMONAL