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

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Presentasi berjudul: "1 CLINICAL PHARMACOLOGY: CARDIOVASCULAIR SULANTO SALEH-DANU R., dr.,SpFK DEPT. OF PHARMACOLOGY and THERAPY DIV. OF CLINICAL PHARMACOLOGY FACULTY OF MEDICINE."— Transcript presentasi:

1 1 CLINICAL PHARMACOLOGY: CARDIOVASCULAIR SULANTO SALEH-DANU R., dr.,SpFK DEPT. OF PHARMACOLOGY and THERAPY DIV. OF CLINICAL PHARMACOLOGY FACULTY OF MEDICINE – GMU

2 2 CARDIOVASCULAR HEART VESSELS BLOOD - -DISTRIBUTION : 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 - TERMOREGULATION  PUMPING : OXYGEN and NUTRIEN to whole organ and tissues ‘‘ROAD’ / pipe for distribution Oxygen and Nutrient  CARRYING MATERIAL & “GARBAGES” from the body to out side.

3 3 HEART As a PUMP: pumping the blood to whole body Blood vessels : limited capacity ELECTRICAL CONDUCTION SYST.: to maintain the heart rate and rhythm HEART MUSCLE (MYOCARDIUM) : need OXYGEN and other “food” for the activity

4 4 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 DARAH RUTINE LENGKAP, KIMIA DARAH, dan EKG 1.. PROBLEM ? 1.. PROBLEM ? 2. OBJEKTIF ? 2. OBJEKTIF ? 3. PEMILIHAN TERAPI  NON FARMAKOLOGIK 3. PEMILIHAN TERAPI  NON FARMAKOLOGIK  FARMAKOLOGIK  FARMAKOLOGIK 4. PERESEPAN ? 4. PERESEPAN ? 5. INFORMASI, INSTRUKSI dan PERINGATAN-2 ? 5. INFORMASI, INSTRUKSI dan PERINGATAN-2 ? 6. MONITORING – EVALUASI INTERVENSI ? 6. MONITORING – EVALUASI INTERVENSI ?

5 5 HEART DISEASES  HYPERTENSION;  CONGESTIVE HEART FAILURE or DECOMPENSATIO CORDIS;  ANGINA PECTORIS ( CHEST-PAIN  ACUTE MYOCARDIAC INFARCTION);  CARDIAC ARRHYTMIAS.

6 6 KELAINAN/PENYAKITCARDIOVASCULAR PADA : NEONATUS ? INFANTS ? CHILDREN ? ADOLESCENS ?

7 7 HYPERTENSION

8 8 Hypertension SBP > 140 mmHg DBP> 85 mmHg Heart Vital organs risk Coronary factors Myocardium factors CHDLVH Congestive heart failure Arrhythmia cordis Sudden death Stroke Multi infarct dementia Peripheral vascular disease Aortic aneurysm Renal failure Disability R. Boedhi Darmojo, 2000, WHO-ISH, 1999

9 9 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

10 10 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: > 180 DBP: > 110 I. No Other Risk FactorsLOW RISKMED RISKHIGH RISK II. 1-2 Risk FactorsMED RISK V. HIGH RISK III. 1-2 Risk Factors or TOD or Diabetes HIGH RISKHIGHV. HIGH RISK IV. Associated Clinical Condition V. HIGH RISK WHO – ISH, 1999

11 11 CARDIOVASCULAR RISK FACTORS; MAYOR RISK FACTORS : Hypertension (as components of metabolic syndrome) Hypertension (as components of metabolic syndrome) Cigarette smoking Cigarette smoking Obesity ( BMI ≥ 30 ) Obesity ( BMI ≥ 30 ) Physical inactivity Physical inactivity Dyslipidemia Dyslipidemia Diabetes mellitus Diabetes mellitus Microalbuminuria or estimated GFR< 60 ml/min Microalbuminuria or estimated GFR< 60 ml/min Age >55 years – men; > 65 years for women Age >55 years – men; > 65 years for women Family history of premature CV disease Family history of premature CV disease

12 12 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

13 13 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

14 14 ANTIHYPERTENSIVE AGENTS (CLASSES)  DIURETICS  β - BLOCKERS  ACE-inhibitors  CALCIUM CHANNEL BLOCKERS  ARBs (angiotensine receptor blockers)  aldosterone receptors antagonists  aldosterone receptors antagonists  α– adrenoceptor antagonists  α– adrenoceptor antagonists  central sympatholytic actions  central sympatholytic actions  arteriolar dilators  arteriolar dilators  peripheral sympathetic inhibitors  peripheral sympathetic inhibitors INITIALPHARMACOTHERAPY

15 15 Pharmacotherapy based on : Efficacy, Safety, + Costly (WHO-ISH, 1999) Class of drug Compelling indication Possible indications Compelling C.IPossible C.I Diuretics Heart Failure ELDERLY Systalic hypertension DiabetesOut 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 Angina ELDERLY Systolic hypertension Peripheral vascular disease Heart blockCongestive heart failure ACE inhibitors Heart Failure LU Dysfunction After myocardial infarct Pregnancy Hyperkalaemia Renalartery stenosis (bilateral)  - Blocker Prostatic hypertrophyGlucose intolerance dyslipidemia Orthostatic hypotension Angiotensin II Receptor antagonist Ace – inhibitor coughHeart failurePregnancy Hyperkalaemia Renalartery stenosis (bilateral)

16 16 Choice of initial drugs  Diuretics  β - blockers  Calcium channel blocker  ACE inhibitor  AIIRA / ARB

17 17 Pharmacotherapy hypertension ( in Elderly ) Diuretic Calcium channel blocker (calcium antagonist) Dihydropyridines Non dihydropyridines Amlodipine2,5- 10 mg Felodipine2,5- 20 mg Isradipine mg Nicardipine mg Nifedipine30 –120 mg Nisaldipine20 – 60 mg Benzothiazepin (diltiazem) 120 – 360 mg Phenylalkilamine50 – 100 mg (mibefrazil) Veropamil90 – 180 mg

18 18 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 Diuretics β - blocker CCB ACEI ARB

19 19 Choice of the initial drugs  Should tailored to the patients, for example in gout do not administered thiazide in gout do not administered thiazide  In asthmatic patients do not give beta blocker. blocker.  In “blacks people” ACE inhibitor or beta-blockers are not very effective beta-blockers are not very effective

20 20 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.

21 21 CONGESTIVE HEART FAILURE ( C H F ) DECOMPENSATIO CORDIS GAGAL JANTUNG

22 22 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.

23 23 CONGESTIVE HEART FAILURE ( C H F ) DECOMPENSATIO CORDIS GAGAL JANTUNG CONGESTIVE / CHRONIC ACUTE H F/PULMONARY EDEMA   Increased exertion   Emotion   Salt in diet   Noncompliance etc.

24 24 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-PHARMACOTHERAPY PHARMACOTHERAPY

25 25 TREATMENT OF CHRONIC H F : 1.Reduce workload of the heart a. Limit activity, put on bed rest a. Limit activity, put on bed rest b. Reduce body weight b. Reduce body weight c. Control hypertension 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 3 rd heart soundor (if systokic dysfunction with 3 rd heart soundor atrial fibrillation present) atrial fibrillation present) 7. Give β- blocker (to patients with stable class II-IV HF) (to patients with stable class II-IV HF) 8. Give vasodilators 9. Cardiac resynchronization if wide QRS interval is present in normal sinus wide QRS interval is present in normal sinus rhythm. rhythm.

26 26 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) (Katzung,BG et al., 2007)

27 27 MECHANISM and SITE OF ACTION DRUGS USE IN CONGESTIVE HEART FAILURE 1.DIGOXIN (an alkaloid GLYCOSIDE / CARDIOTONIC)  increase myocardium contractility by increasing calcium penetration to  increase myocardium contractility by increasing calcium penetration to myocardium myocardium DOBUTAMINE ( SYMPATHOMIMETIC Group ) DOBUTAMINE ( SYMPATHOMIMETIC Group )  increase myocardium contractility by increasing production cAMP in  increase myocardium contractility by increasing production cAMP in bounding β 1 -receptor. bounding β 1 -receptor. 2.DIURETICs Group;  reducing afterload by reducing blood volume ( increase of urine excretion )  reducing afterload by reducing blood volume ( increase of urine excretion ) 3.Angiotensin Converting Enzym (ACE) – Inhibitors / ARBs: CAPTOPRIL; CANDESARTAN; dll. CAPTOPRIL; CANDESARTAN; dll.  the effect dilatation peripheral blood vessels  cause decreasing  the effect dilatation peripheral blood vessels  cause decreasing afterload afterload 4.HYDRALAZINE  relaxation of arteriole  decreasing afterload

28 28 HAL-HAL YANG PERLU DIPERHATIKAN PADA PENDERITA GAGAL JANTUNG: 1.INTERAKSI DIGOKSIN dengan - CALCIUM  POTENSIASI DIGOKSIN. - CALCIUM  POTENSIASI DIGOKSIN. - QUINIDIN ( golongan ANTIARITMIA CORDIS )  kadar DIGOKSIN - QUINIDIN ( golongan ANTIARITMIA CORDIS )  kadar DIGOKSIN meningkat ( ikatan dengan protein ) meningkat ( ikatan dengan protein ) 2.MAKANAN / NUTRISI : JANGAN diberikan yang memperberat kerja jantung atau yang BERINTERAKSI dengan OBAT-OBAT yang kerja jantung atau yang BERINTERAKSI dengan OBAT-OBAT yang digunakan. digunakan. 3.Untuk DIGOKSIN, salah satu sifat obat ini di akumulasi ditubuh, cara pemakaian harus memperhatikan besar obat yang diekresikan dalam pemakaian harus memperhatikan besar obat yang diekresikan dalam 24 jam. Waktu paruh panjang ( 40 - >160 jam ). 24 jam. Waktu paruh panjang ( 40 - >160 jam ).

29 29 ANGINA PECTORIS CHEST PAIN NYERI DADA

30 30 DRUGS USED IN THE TREATMENT OF ANGINA PECTORIS.  angina pectoris refers to a strangling or pressure-like pain  angina pectoris refers to a strangling or pressure-like pain caused by cardiac ischemia. caused by cardiac ischemia. The pain is usually located sub sternally but sometimes The pain is usually located sub sternally but sometimes perceived in the neck, shoulder, or epigastrium. perceived in the neck, shoulder, or epigastrium. Type of ANGINA   ATHEROSCLEROTIC ANGINA = CLASSIC ANGINA = ANGINA OF EFFORT   VASOSPASTIC ANGINA = REST ANGINA = VARIANT ANGINA = PRINZMETAL’S ANGINA   UNSTABLE ANGINA = CRESCENDO ANGINA = ACUTE CORONARY SYNDROME

31 31 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 CHEST PAIN (left side) and/or DYSPNEA, DYSPNEA, EPIGASTRIC PAIN EPIGASTRIC PAIN

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

33 33 STABLE ANGINA Effort increases demand Vasospasm may reduce supply Stenosis prevents increased supply 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

34 34 VARIANT ANGINA = vasospastic angina = Prinzmetal’s angina Vasospasm reduces supply Symptoms -- angina pain at rest -- angina not effort-related -- often occurs on early morning -- exacerbated by smoking Diagnosis -- 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.

35 35 Drugs used in angina pectoris VasodilatorsCardiac depressants NitratesCalcium blockersBeta-blockers Long duration Intermediate Short duration (Trevor,AJ; Katzung,BG; Masters,SB; 2005)

36 36 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 :  FARMAKOTERAPI : - GLYSERIL TRINITRAT spray 400 mcg/metered dose, sublingual, - GLYSERIL TRINITRAT spray 400 mcg/metered dose, sublingual, diulang tiap 5 menit sampai nyeri hilang/berkurang atau diulang tiap 5 menit sampai nyeri hilang/berkurang atau - GLYSERIL TRINITRATE tablet 300 – 600 mcg s.l. diulang tiap - GLYSERIL TRINITRATE tablet 300 – 600 mcg s.l. diulang tiap 3-5 menit sampai mencapai dosis max mcg atau 3-5 menit sampai mencapai dosis max mcg atau - ISOSORBIDE DINITRATE tablet 5 mg, diberikan s.l.. Diulang - ISOSORBIDE DINITRATE tablet 5 mg, diberikan s.l.. Diulang tiap 5 menit. Maksimum 3 tablet. 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)

37 37 CALCIUM CHANNEL-BLOCKING MEDICINES DIHYDROPYRIDINE :   amlodipine   felodipine   nicardipine   nifedipine   nimodipine   nisoldipine, etc. NON-DIHYDROPYRIDINE :   bepridil   diltiazem   verapamil VASODILATATION

38 38 β-ADRENOCEPTOR-BLOCKING AGENTS  obat-obat yang bekerja menghambat reseptor β serabut syaraf syaraf simpatis reseptor β serabut syaraf syaraf simpatis Pada angina hal-hal yang menguntungkan : - menurunkan heart rate - menurunkan heart rate - tekanan darah turun - tekanan darah turun - kontraktilitas otot jantung turun. - kontraktilitas otot jantung turun. kebutuhan oksigen otot jantung turun

39 39 β – BLOKER AGENTS : - Atenolol - Carvedilol - Labetalol - Metopolol - Nadolol - Pindolol - Propranolol - Timolol, etc.

40 40 Adverse Drug Reaction Impaired/ failure organ Multiple disease state polypharmacycompliance Altered organ response Altered drug concentration Homeostatic regulation Adverse Drug Reactions

41 41 OXYGEN CONSUMPTION ANGINA ATTACK LONGTERM / UNCONTROLED MYOCARD INFARCTION CARDIAC ARREST  DEATH

42 42 CARDIAC ARRHYTHMIAS ARITMIA CORDIS

43 43 ARITMIA CORDIS : malfunction of the electrical impuls conduction in the heart. 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)

44 44 ARITMIA CORDIS CLASSIFICATION ARITMIA CORDIS from ATRIUM :  SINUS BRADYCARDIA  SINUS BRADYCARDIA  SINUS TACHYCARDIA  SINUS TACHYCARDIA  MULTIFOCAL ATRIAL TACHYCARDIA  MULTIFOCAL ATRIAL TACHYCARDIA  PREMATURE ATRIAL DEPOLARIZATION (PAT)  PREMATURE ATRIAL DEPOLARIZATION (PAT)  ATRIAL FLUTTER  ATRIAL FLUTTER  ATRIAL FIBRILLATION  ATRIAL FIBRILLATION ARITMIA CORDIS from VENTRICLE :  VENTRICULAR TACHYCARDIA  VENTRICULAR TACHYCARDIA  VENTRICULAR FIBRILLATION  VENTRICULAR FIBRILLATION  VENTRICULAR PREMATURE DEPOLARIZATION  VENTRICULAR PREMATURE DEPOLARIZATION ARITMIA CORDIS conduction from Atrium  Ventricle:  A – V REENTRY  A – V REENTRY  W-P-W SYNDROME  W-P-W SYNDROME

45 45 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; the channel with intermediate kinetics; Ib : action shorten the APD in some tissue of the heart and dissociate from the channel with rapid kinetics; the channel with rapid kinetics; Ic : action have minimal effect on the APD and dissociate from the channel with slow kinetics; with slow kinetics; II : action is sympatholytic. Drugs with this action reduce β -adrenergic activity in the heart ; 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 ( I K r ); the rapid component of the delayed rectifier potassium current ( I K r ); IV : action is blockade of the cardiac calcium current. This action slows conduction in region where the action potential upstroke is calcium conduction in region where the action potential upstroke is calcium dependent, eg the sinoatrial and atrioventricular nodes; dependent, eg the sinoatrial and atrioventricular nodes; Others : the effect depress ectopic focal of the heart.

46 46 CLAS Ia : quinidine; procainamide; disopyramide (norpace) CLAS Ib : lidocaine (xylocaine); mexiletine; tocainide CLAS Ic : flecainide; indecainide; propafenone (rythmonorm); moricizine moricizine CLAS II : propranolol; esmolol; sotalol CLAS III: amiodarone; bretylium; dofetilide; ibutilide CLAS IV: verapamil; diltiazem Others : adenosine; digoxin; magnesium sulfate

47 47

48 48 VASODILATOR systemic vascular resistance arterial pressure Sodium excretion sympathetic nervous system outflow renin release angiotensin II arterial blood pressure sodium retention plasma volume cardiac output systemicvascular resistance resistance heart rate cardiaccontractillity venouscapacitance aldosteron


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