*CLINICAL PHARMACOLOGY:CARDIOVASCULAIR

SULANTO SALEH-DANU R., dr.,SpFKDEPT. OF PHARMACOLOGY and THERAPYDIV. OF CLINICAL PHARMACOLOGYFACULTY OF MEDICINE GMU

*CARDIOVASCULARHEARTVESSELSBLOODDISTRIBUTION : OKSIGEN, NUTRIEN, WATER, ELEKTROLIT, VITAMIN, HORMON, MEDICINES etc,etc. to our organ and tssues.

CARRYING and TRANSPORTING : Carbon dioxyde; metabolism production, metabolism residual- CONTRIBUTOR : immune sys - TERMOREGULATIONPUMPING : OXYGEN and NUTRIEN to whole organ and tissues ROAD / pipe for distribution Oxygen and Nutrient CARRYING MATERIAL & GARBAGES from the body to out side .

*HEARTAs a PUMP: pumping the blood to whole body Blood vessels : limited capacityELECTRICAL CONDUCTION SYST.:to maintain the heart rate and rhythmHEART MUSCLE (MYOCARDIUM) :need OXYGEN and other foodfor the activity

*SEORANG ANAK PEREMPUAN 7 TAHUN,DIBAWA ORANG TUANYA UNTUK PERIKSA PADA SAUDARA KARENA ANAKNYA MENDERITA DEMAM KURANG LEBIH SEMINGGU; MENGELUH SENDI-2 NYA NYERI/SAKIT; KEJADIAN INI PERNAH DIALAMI BEBERAPA WAKTU YANG LALU; KADANG-KADANG BICARA TAK JELAS; TAK BISA BERGERAK/LEMAH PADA PEMERIKSAAN SUHU 39C; CHOREA, ERITEMA, ARTHRITIS.

UTK KONFIRMASI DILAKUKAN PEMERIKSAAN PENUNJANG : DARAH RUTINE LENGKAP , KIMIA DARAH, dan EKG

1.. PROBLEM ? 2. OBJEKTIF ? 3. PEMILIHAN TERAPI NON FARMAKOLOGIK FARMAKOLOGIK 4. PERESEPAN ? 5. INFORMASI, INSTRUKSI dan PERINGATAN-2 ? 6. MONITORING EVALUASI INTERVENSI ?

*HEART DISEASES

HYPERTENSION;

CONGESTIVE HEART FAILURE or DECOMPENSATIO CORDIS;

ANGINA PECTORIS ( CHEST-PAIN ACUTE MYOCARDIAC INFARCTION);

CARDIAC ARRHYTMIAS.

*KELAINAN/PENYAKITCARDIOVASCULAR PADA : NEONATUS ?INFANTS ?CHILDREN ?ADOLESCENS ?

*HYPERTENSION

*Hypertension SBP > 140 mmHg DBP> 85 mmHg Heart

Vital organs riskCoronary factorsMyocardium factorsCHDLVHCongestive heart failureArrhythmia cordisSudden deathStrokeMulti infarct dementiaPeripheral vascular diseaseAortic aneurysmRenal failureDisability R. Boedhi Darmojo, 2000, WHO-ISH, 1999

*Goal Hypertension TherapyTo achieve the maximum reduction in the total risk of cardiovascular/ target vital organ morbidity and mortality

Target: BP: SBP < 130 140 mm Hg DBP < 90 mm HgJNC. VII, 03, WHO ISH, 1999

*Management Strategy Assessed The Patient Risk ProfileWHO ISH, 1999

Blood Pressure (mm Hg)Risk Factors & Disease HistoryGrade I (mild)Grade II (moderate)Grade III(severe)SBP:140-159160-179> 180DBP:90-99100-109> 110I. No Other Risk FactorsLOW RISKMED RISKHIGH RISK

II. 1-2 Risk Factors MED RISKMED RISKV. HIGH RISKIII. 1-2 Risk Factors or TOD or DiabetesHIGH RISKHIGHV. HIGH RISKIV. Associated Clinical ConditionV. HIGH RISKV. HIGH RISKV. HIGH RISK

*CARDIOVASCULAR RISK FACTORS;

MAYOR RISK FACTORS :

Hypertension (as components of metabolic syndrome) Cigarette smoking Obesity ( BMI 30 ) Physical inactivity Dyslipidemia Diabetes mellitus Microalbuminuria or estimated GFR< 60 ml/min Age >55 years men; > 65 years for women Family history of premature CV disease

*Complications of hypertension

Brain StrokesTIA (transient ischemic attack)

Heart Left ventricular hypertrophy Coronary artery disease Myocardial infarction Heart Failure Arrhythmia

Kidney Renal failure

Retinopathy

Aneurysm (rupture) of the aorta

Peripheral artery disease

*When Starting PHARMACOTHERAPEUTICSFail non pharmacotherapyLow risk (during 6-12 mo)SBP > 150 mm HgDBP > 95 mm HgMed risk (during 3-6 mo)SBP > 140 mm HgDBP > 90 mm HgHigh & very high riskMust be direct pharmacotherapy

*ANTIHYPERTENSIVE AGENTS (CLASSES)

DIURETICS - BLOCKERS ACE-inhibitors CALCIUM CHANNEL BLOCKERS ARBs (angiotensine receptor blockers)

aldosterone receptors antagonists adrenoceptor antagonists central sympatholytic actions arteriolar dilators peripheral sympathetic inhibitorsINITIAL PHARMACOTHERAPY

*Pharmacotherapy based on : Efficacy, Safety, + Costly (WHO-ISH, 1999)

Class of drugCompelling indicationPossible indicationsCompelling C.IPossible C.IDiuretics Heart FailureELDERLY Systalic hypertensionDiabetes Out-BlockersAnginaAfter M.ITachyarrhythmiaHeart Failure Pregnancy DiabetesAsthma & CoPDHeart Block (gr 2/3 AV)PhslipidemiaAthletes, physically active patientsPeripheral vascular diseaseCalcium antagonistsAnginaELDERLY Systolic hypertensionPeripheral vascular diseaseHeart blockCongestive heart failureACE inhibitorsHeart FailureLU DysfunctionAfter myocardial infarctPregnancyHyperkalaemiaRenalartery stenosis (bilateral) - BlockerProstatic hypertrophyGlucose intolerance dyslipidemiaOrthostatic hypotensionAngiotensin IIReceptor antagonistAce inhibitor coughHeart failurePregnancyHyperkalaemiaRenalartery stenosis (bilateral)

*Choice of initial drugs

Diuretics - blockers Calcium channel blocker ACE inhibitor AIIRA / ARB

*Pharmacotherapy hypertension ( in Elderly )Diuretic

Calcium channel blocker (calcium antagonist)Dihydropyridines Non dihydropyridinesAmlodipine2,5- 10 mgFelodipine2,5- 20 mgIsradipine5 - 20 mgNicardipine60 - 40 mgNifedipine30 120 mgNisaldipine20 60 mgBenzothiazepin (diltiazem) 120 360 mgPhenylalkilamine50 100 mg(mibefrazil)Veropamil90 180 mg

*STEP CARE: RIGID VS LIBERALOldNew approachSome variation of :1. Diuretic or -blocker2. Vasodilatation3. Combination4. Central agentsEvidence based and patient guided choiceDiuretics - blockerCCBACEIARB

*Choice of the initial drugs

Should tailored to the patients, for example in gout do not administered thiazide

In asthmatic patients do not give beta blocker.

In blacks people ACE inhibitor or beta-blockers are not very effective

*

LIFE STYLE MODIFICATION FOR HYPERTENSION PREVENTION and MANAGEMENT

Lose weight if overweight

Limit alcohol intake to no more than 1 oz (30 mL) ethanol {e.g., 24 oz (720 mL) beer, 10 oz (300 mL) wine, or 2 oz (60 mL) 100-proof whiskey} per day or 0.5 oz (15 mL) ethanol per day for women and lighter weight people.

Increase aerobic physical activity (30 to 45 minutes most days of the week).

Reduce sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium chloride).

Maintain adequate intake of dietary potassium (approximately 90 mmol per day).

Maintain adequate intake of dietary calcium and magnesium for general health.

Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health.

*CONGESTIVE HEART FAILURE( C H F )

DECOMPENSATIO CORDIS

GAGAL JANTUNG

*CONGESTIVE HEART FAILUREDECOMPENSATIO CORDISGAGAL JANTUNGCardiac output is inadequate to provide the oxygen needed by the bodySYSTOLIC FAILURE : the mechanical pumping (contractility) and the ejection fraction of the reduced.

DIASTOLIC FAILURE : stiffening and loss of adequate relaxation plays a mayor role reducing the cardiac output .

*CONGESTIVE HEART FAILURE( C H F )DECOMPENSATIO CORDISGAGAL JANTUNGCONGESTIVE / CHRONICACUTE H F/PULMONARY EDEMAIncreased exertionEmotionSalt in dietNoncomplianceetc.

*

1. CORRECTION THE REVERSIBLE CAUSES;

2. INCREASING MYOCARDIAC CONTRACTILITY;

3. REDUCING CARDIAC PRELOAD (blood volume filling heart ventricle during diastolic phase);

4. REDUCING CARDIAC AFTERLOAD ( pressure needed for pumping the blood to the circulation systems ;Systolic phase)STRATEGY CHF NON-PHARMACOTHERAPYPHARMACOTHERAPY

*TREATMENT OF CHRONIC H F :

Reduce workload of the heart a. Limit activity, put on bed rest b. Reduce body weight c. Control hypertension

2. Restrict sodium intake

3. Restrict water

4. Give diuretic5. Give ACE inhibitor or ARB6. Give digitalis (if systokic dysfunction with 3rd heart soundor atrial fibrillation present)

7. Give -blocker (to patients with stable class II-IV HF)

8. Give vasodilators

9. Cardiac resynchronization if wide QRS interval is present in normal sinus rhythm.

*PHARMACOTHERAPY DIURETICS ALDOSTERONE RECEPTOR ANTAGONIST ACE inhibitors ANGIOTENSIN RECEPTOR BLOCKERS BETA blockers CARDIAC GLYCOSIDES / CARDIOTONIC VASODILATORS BETA AGONISTS, dopamine BIPYRIDINES NATRIURETIC PEPTIDE (Katzung,BG et al., 2007)

*MECHANISM and SITE OF ACTIONDRUGS USE IN CONGESTIVE HEART FAILUREDIGOXIN (an alkaloid GLYCOSIDE / CARDIOTONIC) increase myocardium contractility by increasing calcium penetration to myocardium DOBUTAMINE ( SYMPATHOMIMETIC Group ) increase myocardium contractility by increasing production cAMP in bounding 1 -receptor. DIURETICs Group; reducing afterload by reducing blood volume ( increase of urine excretion )

Angiotensin Converting Enzym (ACE) Inhibitors / ARBs: CAPTOPRIL; CANDESARTAN; dll. the effect dilatation peripheral blood vessels cause decreasing afterload

HYDRALAZINE relaxation of arteriole decreasing afterload

*

HAL-HAL YANG PERLU DIPERHATIKAN PADA PENDERITA GAGAL JANTUNG:

INTERAKSI DIGOKSIN dengan - CALCIUM POTENSIASI DIGOKSIN. - QUINIDIN ( golongan ANTIARITMIA CORDIS ) kadar DIGOKSIN meningkat ( ikatan dengan protein ) MAKANAN / NUTRISI : JANGAN diberikan yang memperberat kerja jantung atau yang BERINTERAKSI dengan OBAT-OBAT yang digunakan.

Untuk DIGOKSIN, salah satu sifat obat ini di akumulasi ditubuh, cara pemakaian harus memperhatikan besar obat yang diekresikan dalam 24 jam. Waktu paruh panjang ( 40 - >160 jam ).

*ANGINA PECTORISCHEST PAINNYERI DADA

*DRUGS USED IN THE TREATMENTOF ANGINA PECTORIS.

angina pectoris refers to a strangling or pressure-like pain caused by cardiac ischemia. The pain is usually located sub sternally but sometimes perceived in the neck, shoulder, or epigastrium.

Type of ANGINA ATHEROSCLEROTIC ANGINA = CLASSIC ANGINA = ANGINA OF EFFORT VASOSPASTIC ANGINA= REST ANGINA= VARIANT ANGINA= PRINZMETALS ANGINA UNSTABLE ANGINA= CRESCENDO ANGINA= ACUTE CORONARY SYNDROME

*ANGINA PECTORISimpairment oxygenation of the heart muscle Imbalancing the supply to the need of oxygen of the heart muscles (myocardium) CHEST PAIN (left side) and/or DYSPNEA, EPIGASTRIC PAIN

*... major determinant of coronary insufficiency : myocardial fiber tension ( the higher the tension, the greater the oxygen requirement )................. MYOCARDIAL OXYGEN REQUIREMENTINTRAMYOCARDIAL FIBER TENSIONDIASTOLIC FACTORSBLOOD VOLUMEVENOUS TONESYSTOLIC FACTORSPERIPHERAL RESISTANCEHEARTRATEHEARTFORCEEJECTIONTIME++++++

*STABLE ANGINAEffortincreasesdemandVasospasm may reduce supplyStenosis preventsincreased supplySymptoms:Crushing sensation in chest or neighbouring areas Associated with effort Relieved by rest or nitroglycerinDiagnosis Possible resting ECG changes during exercise stress test : - ST segment elevated or depressed - arrhythmias - decreased BP - ischaemic myocardium revealed by thallium-201 or MIBI imaging Angiography shows coronary artery disease

*VARIANT ANGINA = vasospastic angina = Prinzmetals anginaVasospasm reducessupplySymptoms-- angina pain at rest-- angina not effort-related-- often occurs on early morning-- exacerbated by smokingDiagnosis-- ST segment elevation during pain-- angina induced by ergonovine-- angoigraphy may not reveal coronary artery diseases-- exercise stress test of little valueVariant angina, in which vasospasms is the primary cause of coronary insufficiency,is must less common than stable angina. However, vasospasms is often a contributing factor in both stable and unstable angina.

*Drugs used in angina pectorisVasodilatorsCardiac depressantsNitratesCalcium blockersBeta-blockersLong durationIntermediateShort duration(Trevor,AJ; Katzung,BG; Masters,SB; 2005)

*OBAT-OBAT YANG DIGUNAKANPADA SERANGAN ANGINA (ANGINA PECTORIS)AIMS : mengatasi nyeri dada atau mencegah timbulnya nyeri dada menghambat progresi dari atherosclerosis memperbaiki prognosis

SERANGAN AKUT : NON-FARMAKOTERAPI : segera diistirahatkan begitu serangan nyeri muncul, baringkan pada tempat yang aliran udara baik. FARMAKOTERAPI : - GLYSERIL TRINITRAT spray 400 mcg/metered dose, sublingual, diulang tiap 5 menit sampai nyeri hilang/berkurang atau - GLYSERIL TRINITRATE tablet 300 600 mcg s.l. diulang tiap 3-5 menit sampai mencapai dosis max 1.800 mcg atau - ISOSORBIDE DINITRATE tablet 5 mg, diberikan s.l.. Diulang tiap 5 menit. Maksimum 3 tablet.

HINDARI PEMAKAIAN PREPARAT NITRATE BERSAMA-SAMA DENGANSILDENAFIL (dalam waktu 24 jam) atau TADALAFIL (dalam waktu 5-6 hari)

*CALCIUM CHANNEL-BLOCKING MEDICINES

DIHYDROPYRIDINE :

amlodipine felodipine nicardipine nifedipine nimodipine nisoldipine, etc.

NON-DIHYDROPYRIDINE :

bepridil diltiazem verapamil

VASODILATATION

*

-ADRENOCEPTOR-BLOCKING AGENTS

obat-obat yang bekerja menghambat reseptor serabut syaraf syaraf simpatis

Pada angina hal-hal yang menguntungkan : - menurunkan heart rate - tekanan darah turun - kontraktilitas otot jantung turun.

kebutuhan oksigen otot jantung turun

*

BLOKER AGENTS :

Atenolol Carvedilol Labetalol Metopolol Nadolol Pindolol Propranolol Timolol, etc.

*Adverse Drug Reaction Impaired/ failure organMultiple disease statepolypharmacycomplianceAltered organ responseAltered drug concentrationHomeostatic regulationAdverse Drug Reactions

*OXYGEN CONSUMPTION

ANGINA ATTACK

LONGTERM / UNCONTROLED

MYOCARD INFARCTION

CARDIAC ARREST DEATH

*CARDIAC ARRHYTHMIASARITMIA CORDIS

*ARITMIA CORDIS : malfunction of the electrical impuls conduction in the heart.ARITMIA CORDIS :

1. DECREASING THE HEART RATE SINUS BRADYCARDIA

2. INCREASE THE HEART RATE SINUS or VENTRICULAR TACHYCARDIA; ATRIAL or VENTRICULAR PREMATURE DEPOLARIZATION; ATRIAL FLUTTER)

3. INCOORDINATION / AUTONOM OF THE IMPULS CONDUCTION (ATRIAL FIBRILLATION; MULTIFOCAL ATRIAL TACHYCARDIA; VENTRICULAR FIBRILLATION)

4. NEW PATHWAY OF THE ELECTRICAL CONDUCTION (A V REENTRY; W-P-W / Wolff-Parkinson-White SYNDROME)

*ARITMIA CORDIS CLASSIFICATIONARITMIA CORDIS from ATRIUM : SINUS BRADYCARDIA SINUS TACHYCARDIA MULTIFOCAL ATRIAL TACHYCARDIA PREMATURE ATRIAL DEPOLARIZATION (PAT) ATRIAL FLUTTER ATRIAL FIBRILLATIONARITMIA CORDIS from VENTRICLE : VENTRICULAR TACHYCARDIA VENTRICULAR FIBRILLATION VENTRICULAR PREMATURE DEPOLARIZATION ARITMIA CORDIS conduction from Atrium Ventricle: A V REENTRY W-P-W SYNDROME

*PHARMACOTHERAPY ARITMIA CORDISCLASSIFICATION : I; II; III; IV dan Unclassified ) :

Ia : action prolong the action potential duration (APD) and dissociate from the channel with intermediate kinetics;Ib : action shorten the APD in some tissue of the heart and dissociate from the channel with rapid kinetics;Ic : action have minimal effect on the APD and dissociate from the channel with slow kinetics;

II : action is sympatholytic. Drugs with this action reduce -adrenergic activity in the heart ;

III : action is manifest by prolongation of the APD. Most action block the rapid component of the delayed rectifier potassium current ( IKr );

IV : action is blockade of the cardiac calcium current. This action slows conduction in region where the action potential upstroke is calcium dependent, eg the sinoatrial and atrioventricular nodes;

Others : the effect depress ectopic focal of the heart.

*CLAS Ia : quinidine; procainamide; disopyramide (norpace)

CLAS Ib : lidocaine (xylocaine); mexiletine; tocainide

CLAS Ic : flecainide; indecainide; propafenone (rythmonorm); moricizine

CLAS II : propranolol; esmolol; sotalol

CLAS III: amiodarone; bretylium; dofetilide; ibutilide

CLAS IV: verapamil; diltiazem

Others : adenosine; digoxin; magnesium sulfate

*

*VASODILATORsystemic vascularresistance

arterial pressureSodium excretionsympathetic nervous system outflowrenin releaseangiotensin IIarterial blood pressuresodium retentionplasma volume cardiac outputsystemic vascular resistanceheart ratecardiac contractillityvenous capacitancealdosteron