Transcript 순환기약물강의자료.
허혈성 심질환의 약물치료 고려대학교 안암병원 순환기내과 흉통클리닉 안철민 Pathogenesis of Angina Myocardial O2 demand Myocardial O2 supply Initial Treatment • A = Aspirin Anti-anginal therapy • B = Beta-blocker Blood pressure • C = Cigarette smoking Cholesterol • D =Diet and Diabetes • E = Education & Exercise Definition of Successful Therapy • Elimination of chest pain • Return to normal activities • Good patient compliance minimal side effects of therapy, cost-effective • Goal must be modified according to clinical characteristics & preferences of each patient Gibbons et al. ACC/AHA practice guideline 2002 협심증의 치료 목적 • 사망률 및 이환율 감소 • 증상의 호전 • 운동능력 향상 aspirin, statin, β-blocker Nitrate, β-blocker Ca blocker Case 1 : 김O길(1358331) History Resting chest pain with stress, early in the morning HTN/DM (+/-) : 150/90 mmHg, Treadmill test : negative Provocation Test Discharge medication • Dx : vasospastic angina, CAD(1-VD) • Aspirin • Adalat 100mg 30mg 약물선택 변이형 협심증 1. 아스피린 (X) : 혈관확장성 PG합성장애 disgren (Triflusal) 2. 베타차단제 (X) : 2 수용체 차단 수용체로 인한 관동맥 수축 3. 질산염제제 4. 칼슘차단제 (amlodipine, verapamil, diltiazem, nifedipine, felodipine) Primary prevention of aspirin Results 총 사망률 10%↓ MI risk 44%↓ (50세이하) Nonfatal stroke, CHD, CV events ↓ Nonfatal & fatal MI,CHD death ↓ Major CV events 15%↓, MI 36%↓ All CV events ↓ Stroke 17% ↓ CV death 1.4% 0.8%↓ Ischemic stroke risk 1.4%↓ Am J Cardiol, 2006;98:746-750 2nd Prevention of aspirin - CV death 17% ↓ - AMI 34% ↓ - CVA 35% ↓ - All CV disease 35% ↓ 10년간 심혈관 질환의 발생 위험이 10% 이상인 고위험 환자군 의 대부분이 아스피린을 사용할 것을 권고하고 있으며 atherosclerosis가 증명된 환자는 어떤 사람이라도 복용하도록 함 : AHA recommendation Initial Tx: 160-325mg at 1st day Subsequent Tx: 75-160 mg/day • 64세 흡연하며 cholesterol 190mg/dl 이면서(HDL 50mg/dl) 혈압약 norvasc 5mg드시면서 130/80mmHg인 남자 환자 : 10+1+1+0+2 = 14 (10 year risk = 16%) • 70세 비흡연자로 콜레스테롤 수치 170mg/dl(HDL 45mg/dl) 를 보이며 혈압약을 드시면서 140/70mmHg로 유지되는 여자 환자 14+1+0+1+5 = 21 (10 year risk = 14%) 칼슘차단제 작용기전- antianginal drug • 심박수 감소, 심수축력 감소 혈압강하 심근산소요구량 감소 • 심박수 감소 이완기증가 관동맥관류 증가 칼슘차단제 분류 • Non- Dihydropyridine: HR↓, Contractility↓ (artery < cardiac) Verapamil (Isoptin®), Diltiazem (Herben®) • Dihydropyridine: vasodilation↑ (artery>cardiac) Nifedipine (Adalat®), amlodipine(Norvasc®), felodipine (Splendil®), Nicardipine (Perdipine®) 칼슘차단제 종류 NITRATES : HEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Pulmonary congestion Preload Ventricular size Vent. Wall stress MVO2 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload • Cardiac output • Blood pressure NITRATES : Preparation Preparation of agent Dose Nitroglycerin Ointment 0.5-2 inches Buccal or transdermal 1-3 mg Trandermal patch 0.4-1.2 mg/h for Oral sustained release 9.0-13.5mg Isosorbid dinitrate (isoket retard®) Oral 10-60mg Oral sustained release 80-120mg Isosorbid-5-mononitrate (imdur®, ismo®) Oral 20-30mg Oral sustained release 60-240mg Schedule 2-3 times/d 3 times/d 12-14hrs 2-3 times/d 2-3 times/d Once daily 2 times/d Once daily Case 2 : 임O수(557552) History : stable angina HTN : 160/100 mmHg, Treadmill(+) at stage III PTCA with stent Cypher 2.75X18mm, 2.75X18mm, Cypher 2.5X18mm Progress Note • Medication – Aspirin – Clopidogrel – Herben – Lipitor 100mg 75mg 180mg 10mg Plaque Rupture and Thrombus Formation Aspirin Ticlopidine , Clopidogrel Clopidogrel Acute STEMI CLARITY PCI-CLARITY 2005 2007 Occluded artery 36% D/MI/UR/ RI 20% NSTEMI / ACS PCI Post MI High Risk of Event COMMIT CURE CREDO CAPRIE CHARISMA 2005 2001 2002 1996 2006 Mortality Mortality D/MI/Stroke D/MI/Stroke 46 % 7% 20% 27% Vasc D/MI/Stroke 9% Vasc D/MI/Stroke Benefit in symptomatic patients D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia. Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther. 2006;4:7-15. HMG CoA Reductase Inhibitors: Statin • Mainstay of cholesterol-lowering therapy • Ideal condition 1. potent enzyme inhibition 2. preferential action & distribution in Liver 3. Optimal pharmacokinetics 4. good safety profile & low potential for drug interactions • LDL-C 18–55% & TG 7–30%, ↑ HDL-C 5–15% • Major side effects – Myopathy – Increased liver enzymes • Contraindications – Absolute: active liver disease, pregnancy, myopathy – Relative: use with certain drugs Statin의 약물상호작용 • Cimetidine(H2 Blocker)과 상호작용 없다. • Warfarin(혈액응고저해제)과 상호작용 없다. • Digoxin(심부전치료제)과 동시 투여시 digoxin농 도증가 (digoxin용량조절필요) • Erythromycin(macrolide계 항생제)과 동시 투여 시 혈중농도 40%증가 Pleiotropic Effects of Statins • Endothelial function (NO regulation) • Atherosclerotic plaque stabilization • Inhibition of LDL-C oxidation • Effects on VSMC growth • Platelet inhibition and anti-thrombosis • Reduced leukocyte adhesiveness • Effects on circulatory clotting factors • Reduced ischemia-reperfusion injury (cardiac and cerebral) • Enhanced angiogenesis Rosensen R et al. JAMA. 1998;279:1643-1650; Gotto AM et al. Curr Opin Lipidology. 2001;12:391-394; Maron DJ et al. Circulation. 2000;101:207-213; White CM. J Clin Pharmacol. 1999;39:111-118. LDL-Cholesterol Target “Very high risk group” 1. Diabetes with established CVD 2. Severe and poorly controlled risk factors and established CVD (Continued smoking, HTN) 3. Multiple risk factors of metabolic syndrome and CVD 4. Patients with acute coronary syndrome Lower LDL-C < 70mg/dL NCEP Report J Am Coll Cardiol 2004;44:720- Pharmacologic Therapy: Statins-Dose Response Response to Minimum/Maximum Statin Dose Fluvastatin 20/80 mg Pravastatin Lovastatin 20/80 mg 20/80 mg Simvastatin 20/80 mg Atorvastatin Rosuvastatin 10/40 mg 10/80 mg % Reduction in LDL-C 0 10 19 27 28 20 35 37 46 12 30 31 40 10 37* 50 “Rule of Six” 60 12 40 12 18 47 9 55 55 Adapted from Illingworth. Med Clin North Am. 2000;84:23. Rosuvastatin for active control study PI. Impact of Norvasc and Atorvastatin -Caduet Atorvastatin Negative Polarity Amlodipine Positive Charge Adherence Synergy effect Cost-effectiveness Case 3 : 신O대(1392580) History : dyspnea on exertion. 56/M, HTN/DM(+/+) : for 3 years Heavy smoker, alcoholics, 120/80mmHg Regional Wall Motion Akinetic whole anteroseptum and aepx - Global Function(%) : 22 % ~ 27 % Ischemic cardiomyopathy Unstable angina Coronary Angiogram Progress Note • Medication – – – – – – – – – Aspirin Clopidogrel Dilatrend Aprovel Lasix Aldactone Caduet Digoxin Amaryl-M 100mg 75mg 12.5mg 150mg 20mg 12.5mg 5/10mg 0.125mg 2-500mg BP BP BP 베타차단제 작용기전 • 심박수 감소 • 심수축력 감소 심근산소요구량 감소 • 혈압강하 • 심박수 감소 이완기증가 관동맥관류기 증가 Equivalent doses • • • • • Propranolol (pranol®) Metoprolol (betaloc®) Atenolol (tenormin®) Carvedilol (dilatrend®) Bisoprolol (concor®) 80mg 100mg 50mg 12.5mg 10mg Beta 1 selectivity: Bisoprolol > atenolol > metoprolol M.Gabriel Khan. Cardiac drug therapy. 6th ed. 베타차단제 적응증 1. 협심증 발작이 육체적 활동과 관계 있는 경우 2. 고혈압이 동반 3. 상심실성 빈맥이나 심실성 빈맥의 병력 4. 심근경색후 협심증 5. 불안이 심한경우 베타차단제 부작용 ACE inhibitor의 작용 • 혈압강하 • 단백뇨 감소 • 심부전 환자에서 전,후부하 감소 • 심근경색 환자에서 좌심실 기능의 개선 • 혈관 확장 Inhibtion < 20% ACE inhibitor ACE inhibitio n >90% Inhibtion < 20% HOPE Study (Usefulness of ACEi) Relative Risk Reduction of Cardiovascular Endpoints in high risk patients (angina, DM, HTN, PAOD) with normal LV Fx. Combined Cardiovascular Cardiovascular Myocardial endpoints mortality infarction Stroke -20% p <0.001 -22% p <0.001 -26% p <0.001 Ramipril n=4645 Placebo n=4652 -32% p <0.001 Weber et al. AJC 2002;89:suppl:27A Equivalent doses • • • • • • • • • Captopril (Capril) Enalapril (Lenipril) Lisinopril (Zestril) Perindopril (Acertil) Ramipril (Tritace) Cilazapril (Inhibase) Fosinopril (Monopril) Benazepril (Cibacen) Imidapril (Tanatril) 100mg 20mg 20mg 3mg 10mg 2.5mg 10mg 10mg 10mg M.Gabriel Khan. Cardiac drug therapy. 6th ed. Effects of Angiotensin II on AT1 and AT2 Receptors ANGIOTENSIN II AT1 AT1 RECEPTOR BLOCKER • VASOCONSTRICTION • INCREASED SYMPATHETIC TONE • ALDOSTERONE SECRETION • RENAL Na+ RETENTION • CARDIAC MYOCYTE PROLIFERATION • VASCULAR PROLIFERATION AT2 • VASODILATION • GROWTH INHIBITION • APOPTOSIS Angiotensin II receptor antagonist • AT 1 receptor를 선택적으로 block • Coughing등의 부작용이 작다. • 고혈압, 심부전등에 주로 사용 Profile of ARB Candesartan (Atacand) Irbesartan (Aprovel) Losartan (Cozaar) Valsartan (Diovan) Telmisartan (Micardis) Eprosartan (Teveten) Valsartan/Amlodipine(Exforge) 4~32mg 150~300mg 25~100mg 40~320mg 20~80mg 300~800mg 5/80~10/160mg I am tired !! Preload Afterload Heart I am a hill Stage C, D Drugs Recommendation for Routine Use Diuretics Digitalis ACE inhibitors β-blockers ALDOSTERONE INHIBITORS Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Retention Na+ Retention H2O Edema Excretion K+ Arrhythmias Excretion Mg2+ Collagen deposition Fibrosis - myocardium - vessels Case 4 : 김O선(1485079) History : Unstable angina, Lt main + 3VD EF 20~25%, Dilated cardiomyopathy 70/M, s/p Pneumonectomy Lt. CABG refuse, medical Tx Progress Note • • • • • • • • • • • • Aspirin Clopidogrel inhibase Digoxin Lipitor Ismo Dilatrend Lasix Aldactone Sigmart Molsiton Vastinan 100mg 75mg 1mg 0.125mg 10mg 20mg 6.25mg 20mg 12.5mg 5mg 4mg 35mg TP BP BP BP TP TP BP Other Anti-angina drug –metabolic agent Minimal hemodynamic effect • Potassium channel opener - Nicorandil : Sigmart® 5mg • Fatty acid oxidation inhibitor - Trimetazidine : Vastinan® 20mg,35mg • Direct NO donor - Molsidromine : Molsiton® 4mg Nicorandil : K+ATP Channel Opening Action 1. Microvascular Dilation 2. Ischemic preconditioning (Cardioprotective Effects) KATP Channel Opening Ca++ channel closing Hyperpolarization K+ Ca++ Ca++ sensitivity decrease Stored in SR Ther Res 1996;17:1155-60 Trimetazidine • Stable angina patients • Revascularization patients • Left ventricular dysfunction patients • Ischemic cardiomyopathy patients • Coronary artery disease patients with diabetes mellitus • Heart failure patients Thank you for your kind attention !!!