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CLINICAL PHARMACOLOGY: CARDIOVASCULAIR

CLINICAL PHARMACOLOGY: CARDIOVASCULAIR. SULANTO SALEH-DANU R., dr.,SpFK DEPT. OF PHARMACOLOGY and THERAPY DIV. OF CLINICAL PHARMACOLOGY FACULTY OF MEDICINE – GMU. DISTRIBUTION : OKSIGEN, NUTRIEN, WATER, ELEKTROLIT, VITAMIN, HORMON, MEDICINES etc,etc.

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CLINICAL PHARMACOLOGY: CARDIOVASCULAIR

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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 – GMU

  2. 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 .

  3. 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

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

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

  6. KELAINAN/PENYAKIT CARDIOVASCULAR PADA : NEONATUS ? INFANTS ? CHILDREN ? ADOLESCENS ?

  7. HYPERTENSION

  8. Hypertension SBP > 140 mmHg DBP> 85 mmHg Heart Vital organs risk 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

  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. Management Strategy Assessed The Patient Risk Profile WHO – ISH, 1999

  11. 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

  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. 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. ANTIHYPERTENSIVEAGENTS (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

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

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

  17. 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

  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 ARB Diuretics ACEI β - blocker CCB

  19. 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

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

  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. 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

  24. STRATEGY CHF • 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

  25. 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.

  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)

  27. 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

  28. HAL-HAL YANG PERLU DIPERHATIKAN PADA • PENDERITA GAGAL JANTUNG: • INTERAKSI DIGOKSINdengan • - CALCIUM POTENSIASI DIGOKSIN. • - QUINIDIN ( golongan ANTIARITMIA CORDIS )  kadar DIGOKSIN • meningkat ( ikatandengan protein ) • MAKANAN / NUTRISI : JANGAN diberikan yang memperberat • kerjajantungatau yang BERINTERAKSI dengan OBAT-OBAT yang • digunakan. • Untuk DIGOKSIN, salahsatusifatobatinidiakumulasiditubuh, cara • pemakaianharusmemperhatikanbesarobat yang diekresikandalam • 24 jam. Waktuparuhpanjang ( 40 - >160 jam ).

  29. ANGINA PECTORIS CHEST PAIN NYERI DADA

  30. 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

  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 DYSPNEA, EPIGASTRIC PAIN

  32. ... 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

  33. 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

  34. VARIANT ANGINA = vasospastic angina = Prinzmetal’s angina Vasospasm reduces supply Symptoms Diagnosis -- ST segment elevation during pain -- angina induced by ergonovine -- angoigraphy may not reveal coronary artery diseases -- exercise stress test of little value -- angina pain at rest -- angina not effort-related -- often occurs on early morning -- exacerbated by smoking 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. 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)

  36. OBAT-OBAT YANG DIGUNAKAN PADA SERANGAN ANGINA (ANGINA PECTORIS) AIMS :  mengatasinyeri dada ataumencegahtimbulnyanyeri dada  menghambatprogresidari atherosclerosis  memperbaiki prognosis SERANGAN AKUT :  NON-FARMAKOTERAPI : segeradiistirahatkanbegituserangan nyerimuncul, baringkanpadatempat yang aliranudarabaik.  FARMAKOTERAPI : - GLYSERIL TRINITRAT spray 400 mcg/metered dose, sublingual, diulangtiap 5 menitsampainyerihilang/berkurangatau - GLYSERIL TRINITRATE tablet 300 – 600 mcg s.l. diulangtiap 3-5 menitsampaimencapaidosis max 1.800 mcg atau - ISOSORBIDE DINITRATE tablet 5 mg, diberikans.l.. Diulang tiap 5 menit. Maksimum 3 tablet. HINDARI PEMAKAIAN PREPARAT NITRATE BERSAMA-SAMA DENGAN SILDENAFIL (dalamwaktu 24 jam) atau TADALAFIL (dalamwaktu 5-6 hari)

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

  38. β-ADRENOCEPTOR-BLOCKING AGENTS • obat-obat yang bekerjamenghambat reseptorβserabutsyarafsyarafsimpatis Pada angina hal-hal yang menguntungkan : -menurunkan heart rate - tekanandarahturun - kontraktilitasototjantungturun. kebutuhanoksigenototjantungturun

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

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

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

  42. CARDIAC ARRHYTHMIAS ARITMIA CORDIS

  43. 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)

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

  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; 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.

  46. 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

  47. WASSALAMU'ALAIKUM W W

  48. 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

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