CLINICAL PHARMACOLOGY: CARDIOVASCULAIR SULANTO SALEH-DANU R., dr.,SpFK DEPT. OF PHARMACOLOGY and THERAPY DIV. OF CLINICAL PHARMACOLOGY FACULTY OF MEDICINE – GMU

HEART CARDIOVASCULAR VESSELS BLOOD DISTRIBUTION : OKSIGEN, NUTRIEN, WATER, ELEKTROLIT, VITAMIN, HORMON, MEDICINES etc,etc. to our organ and tssues. HEART PUMPING : OXYGEN and NUTRIEN to whole organ and tissues CARDIOVASCULAR VESSELS ‘ROAD’ / pipe for distribution Oxygen and Nutrient CARRYING and TRANSPORTING : Carbon dioxyde; metabolism production, metabolism residual - CONTRIBUTOR : immune sys - TERMOREGULATION BLOOD  CARRYING MATERIAL & “GARBAGES” from the body to out side .

HEART As a PUMP: pumping the blood to whole body Blood vessels : limited capacity HEART ELECTRICAL CONDUCTION SYST.: to maintain the heart rate and rhythm HEART MUSCLE (MYOCARDIUM) : need OXYGEN and other “food” for 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 39°C; 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/PENYAKIT CARDIOVASCULAR NEONATUS ? INFANTS ? CHILDREN ? PADA : NEONATUS ? INFANTS ? CHILDREN ? ADOLESCENS ?

HYPERTENSION

Hypertension SBP > 140 mmHg DBP> 85 mmHg Vital organs risk Heart Coronary factors Myocardium factors Stroke Multi infarct dementia Peripheral vascular disease Aortic aneurysm Renal failure CHD LVH Congestive heart failure Arrhythmia cordis Sudden death Disability R. Boedhi Darmojo, 2000, WHO-ISH, 1999

Goal Hypertension Therapy To 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 Hg JNC. VII, 03, WHO – ISH, 1999

Management Strategy Assessed The Patient Risk Profile Blood Pressure (mm Hg) Risk Factors & Disease History Grade I (mild) Grade II (moderate) Grade III (severe) SBP:140-159 160-179 > 180 DBP:90-99 100-109 > 110 I. No Other Risk Factors LOW RISK MED RISK HIGH RISK II. 1-2 Risk Factors V. HIGH RISK III. 1-2 Risk Factors or TOD or Diabetes HIGH IV. Associated Clinical Condition WHO – ISH, 1999

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  Strokes TIA (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 PHARMACOTHERAPEUTICS Fail non pharmacotherapy Low risk (during 6-12 mo) SBP > 150 mm Hg DBP > 95 mm Hg Med risk (during 3-6 mo) SBP > 140 mm Hg DBP > 90 mm Hg High & very high risk Must be direct pharmacotherapy

ANTIHYPERTENSIVE AGENTS (CLASSES)  DIURETICS β- BLOCKERS ACE-inhibitors CALCIUM CHANNEL BLOCKERS ARBs (angiotensine receptor blockers)  aldosterone receptors antagonists  α– adrenoceptor antagonists  central sympatholytic actions  arteriolar dilators  peripheral sympathetic inhibitors INITIAL PHARMACOTHERAPY

Pharmacotherapy based on : Efficacy, Safety, + Costly (WHO-ISH, 1999) Class of drug Compelling indication Possible indications Compelling C.I Possible C.I Diuretics Heart Failure ELDERLY Systalic hypertension Diabetes Out ß-Blockers Angina After M.I Tachyarrhythmia Heart Failure Pregnancy Diabetes Asthma & CoPD Heart Block (gr 2/3 AV) Phslipidemia Athletes, physically active patients Peripheral vascular disease Calcium antagonists Systolic hypertension Heart block Congestive heart failure ACE inhibitors LU Dysfunction After myocardial infarct Pregnancy Hyperkalaemia Renalartery stenosis (bilateral)  - Blocker Prostatic hypertrophy Glucose intolerance dyslipidemia Orthostatic hypotension Angiotensin II Receptor antagonist Ace – inhibitor cough Heart failure

Choice of initial drugs Diuretics β - blockers Calcium channel blocker ACE inhibitor AIIRA / ARB

Pharmacotherapy hypertension ( in Elderly ) Diuretic Calcium channel blocker (calcium antagonist) Amlodipine 2,5- 10 mg Felodipine 2,5- 20 mg Isradipine 5 - 20 mg Nicardipine 60 - 40 mg Nifedipine 30 –120 mg Nisaldipine 20 – 60 mg Dihydropyridines Non dihydropyridines Benzothiazepin (diltiazem) 120 – 360 mg Phenylalkilamine 50 – 100 mg (mibefrazil) Veropamil 90 – 180 mg

Evidence based and patient guided choice STEP CARE: RIGID VS LIBERAL Old New approach Some variation of : 1. Diuretic or β-blocker 2. Vasodilatation 3. Combination 4. Central agents Evidence based and patient guided choice ARB Diuretics ACEI β - blocker CCB

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 FAILURE DECOMPENSATIO CORDIS GAGAL JANTUNG Cardiac output is inadequate to provide the oxygen needed by the body SYSTOLIC 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 .

ACUTE H F/PULMONARY EDEMA CONGESTIVE HEART FAILURE ( C H F ) DECOMPENSATIO CORDIS GAGAL JANTUNG CONGESTIVE / CHRONIC Increased exertion Emotion Salt in diet Noncompliance etc. ACUTE H F/PULMONARY EDEMA

STRATEGY CHF PHARMACOTHERAPY NON-PHARMACOTHERAPY 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) NON-PHARMACOTHERAPY PHARMACOTHERAPY

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 diuretic 5. Give ACE inhibitor or ARB 6. Give digitalis (if systokic dysfunction with 3rd heart soundor atrial fibrillation present) 7. Give β-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 ACTION DRUGS USE IN CONGESTIVE HEART FAILURE DIGOXIN (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 β1 -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 PECTORIS CHEST PAIN NYERI DADA

DRUGS USED IN THE TREATMENT OF 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. ATHEROSCLEROTIC ANGINA = CLASSIC ANGINA = ANGINA OF EFFORT Type of ANGINA VASOSPASTIC ANGINA = REST ANGINA = VARIANT ANGINA = PRINZMETAL’S ANGINA UNSTABLE ANGINA = CRESCENDO ANGINA = ACUTE CORONARY SYNDROME

ANGINA PECTORIS impairment 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

INTRAMYOCARDIAL FIBER TENSION ... major determinant of coronary insufficiency : myocardial fiber tension ( the higher the tension, the greater the oxygen requirement )................. MYOCARDIAL OXYGEN REQUIREMENT INTRAMYOCARDIAL FIBER TENSION + EJECTION TIME + + + + + HEART FORCE PERIPHERAL RESISTANCE HEART RATE BLOOD VOLUME VENOUS TONE SYSTOLIC FACTORS DIASTOLIC FACTORS

Vasospasm may reduce supply Effort increases demand STABLE ANGINA Vasospasm may reduce supply Stenosis prevents increased supply Effort increases demand Symptoms: Crushing sensation in chest or neighbouring areas  Associated with effort Relieved by rest or nitroglycerin Diagnosis 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 = Prinzmetal’s angina Vasospasm reduces supply Symptoms Diagnosis -- angina pain at rest -- angina not effort-related -- often occurs on early morning -- exacerbated by smoking -- ST segment elevation during pain -- angina induced by ergonovine -- angoigraphy may not reveal coronary artery diseases -- exercise stress test of little value Variant 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 pectoris Vasodilators Cardiac depressants Nitrates Calcium blockers Beta-blockers Long duration Intermediate Short duration (Trevor,AJ; Katzung,BG; Masters,SB; 2005)

OBAT-OBAT YANG DIGUNAKAN PADA 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 DENGAN SILDENAFIL (dalam waktu 24 jam) atau TADALAFIL (dalam waktu 5-6 hari)

NON-DIHYDROPYRIDINE : CALCIUM CHANNEL-BLOCKING MEDICINES DIHYDROPYRIDINE : amlodipine felodipine nicardipine nifedipine nimodipine nisoldipine, etc. NON-DIHYDROPYRIDINE : bepridil diltiazem verapamil VASODILATATION

β-ADRENOCEPTOR-BLOCKING AGENTS obat-obat yang bekerja menghambat reseptor β 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

β – BLOKER AGENTS : Atenolol Carvedilol Labetalol Metopolol Nadolol Pindolol Propranolol Timolol, etc.

Adverse Drug Reactions Impaired/ failure organ Multiple disease state polypharmacy compliance Altered organ response Adverse Drug Reactions Altered drug concentration Homeostatic regulation

LONGTERM / UNCONTROLED OXYGEN CONSUMPTION ANGINA ATTACK LONGTERM / UNCONTROLED MYOCARD INFARCTION CARDIAC ARREST  DEATH

CARDIAC ARRHYTHMIAS ARITMIA 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 CLASSIFICATION ARITMIA CORDIS from ATRIUM :  SINUS BRADYCARDIA  SINUS TACHYCARDIA  MULTIFOCAL ATRIAL TACHYCARDIA  PREMATURE ATRIAL DEPOLARIZATION (PAT)  ATRIAL FLUTTER  ATRIAL FIBRILLATION ARITMIA 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 CORDIS CLASSIFICATION : 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 β-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

WASSALAMU'ALAIKUM W W

arterial blood pressure VASODILATOR systemic vascular resistance arterial pressure sympathetic nervous system outflow Sodium excretion renin release aldosteron venous capacitance heart rate angiotensin II systemic vascular resistance cardiac contractillity sodium retention plasma volume arterial blood pressure cardiac output