Download 신O대(1392580) - 고려대학교 의료원 흉통클리닉

허혈성 심질환의 약물치료
고려대학교 안암병원 순환기내과
안철민
Pathogenesis of Angina
Myocardial
O2 demand
Myocardial
O2 supply
Initial Treatment
• A = Aspirin and
Antianginal therapy
• B = Beta-blocker and
Blood pressure
• C = Cigarette smoking and
Cholesterol
• D = Diet and Diabetes
• E = Education and Exercise
Definition of Successful Therapy
• Elimination of anginal chest pain
• Return to normal activities
• Good patient compliance
 minimal side effects of therapy, costeffective
• Goal must be modified in light of the clinical
characteristics and preferences of each patient
Gibbons et al. ACC/AHA practice guideline 2002
협심증의 치료 목적
• 증상의 호전
• 운동능력 향상
Nitrate, β-blocker
Ca blocker
• 사망률 및 이환율 감소
aspirin, statin,
β-blocker
Case 1 : 김O길(1358331)
History
Resting chest pain with stress, early in the morning
HTN/DM (+/-) : 150/90 mmHg
Provocation Test
Discharge medication
• Dx : vasospastic angina, CAD(1-VD)
• Aspirin
• Ismo
• Herben
100mg
20mg
90mg
TP
BP
약물선택
변이형 협심증
1. 아스피린 (X)
: 혈관확장성 PG합성장애  disgren (Triflusal)
2. 베타차단제 (X)
: 2 수용체 차단   수용체로 인한 관동맥 수축
3. 질산염제제
4. 칼슘차단제 ( verapamil, diltiazem, nifedipine, felodipine,
amlodipine)
: 주의 - rebound spasm
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% ↓
AHA ecommendation :Anyone with atherosclerosis
Initial Tx: 160-325mg at 1st day
Subsequent Tx: 75-160 mg/day
Anti-anginal Drug
칼슘차단제 작용기전
• 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®)
Multiple Effects of Verapamil or Diltiazem
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
4- Others
•
Cardiac output
•
Blood pressure
NITRATES :CONTRAINDICATIONS
Previous hypersensitivity
Hypotension ( < 80 mmHg)
AMI with low ventricular filling pressure
1st trimester of pregnancy
WITH CAUTION:
ž Constrictive pericarditis
ž Intracranial hypertension
ž Hypertrophic cardiomyopathy
NITRATES : Preparation
Preparation of agent
Dose
Schedule
Nitroglycerin
Ointment
0.5-2 inches
2-3 times/d
Buccal or transdermal
1-3 mg
3 times/d
Trandermal patch
0.4-1.2 mg/h for 12-14hrs
Oral sustained release
9.0-13.5mg
2-3 times/d
Isosorbid dinitrate (isoket®)
Oral
10-60mg
2-3 times/d
Oral sustained release
80-120mg
Once daily
Isosorbid-5-mononitrate (imdur®)
Oral
20-30mg
2 times/d
Oral sustained release
60-240mg
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
– Ismo
– Lipitor
100mg
75mg
90mg
20mg
10mg
BP
BP
Plaque Rupture and Thrombus Formation
Inhibitors of Platelet Activation
 Aspirin
(Rhonal, Astrix , BASA)
 Ticlopidine (Clid)
Cilostazol (Pletaal)
Clopidogrel (Plavix)
 GP IIb/IIIa receptor blocker
- Abciximab (Reopro)
- Tirofiban (Agrastat)
- Eptifibatide (Integrilin)
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(duration of action on
HMG-coA & upregulation of LDL-R)
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: liver disease
– Relative: use with certain drugs
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
Norvasc
Crestor
Digoxin
Amaryl-M
100mg
75mg
12.5mg
150mg
20mg
12.5mg
5mg
10mg
0.125mg
2-500mg BP
약물선택
불안정형 협심증
1. Aspirin and ticlopidine, clopidogrel
- aspirin 80-324mg/day : 급성 심근경색증, 사망률
을 50% 감소
- ticlopidine 250mg bid : 심혈관계 사망률 47%,
심근경색증 46% 감소
2. Heparin
- 심근경색증과 불응성 협심증의 발생율을 80%정도 감소
- rebound pnenomenon (thrombin활성도 증가)에 유의
약물선택
불안정형 협심증
3. 베타차단제
반복적 허혈, 심근경색 감소
금기가 없는 모든 환자, 특히 고혈압, 빈맥이 동반시
심박수 50-60회/분
4. 질산제제
흉통의 빈도를 줄이고 좌심실 기능을 향상
초기는 경정맥 투여  24시간이상 흉통이 없으면 경구투여
5. 칼슘차단제
( verapamil, diltiazem, nifedipine, felodipine, amlodipine)
흉통의 빈도를 감소
사망률, 심근경색 ? 속효성 제제는 초기단독치료는 금물
베타차단제 작용기전
• 심박수 감소
• 심수축력 감소
심근산소요구량 감소
• 혈압강하
• 심박수 감소
이완기증가
관동맥관류기 증가
Beta-blockers
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
베타차단제의 부적절한 사용
1.
2.
3.
4.
5.
6.
7.
8.
천식, 만성폐쇄성 폐질환-금기
당뇨병 : 인슐린으로 인한 저혈당을 심화
심한 좌심실 기능장애
수축장애로 인한 울혈성 심부전
우울증
Raynaud’s phenomenon
말초혈관질환
서맥성 부정맥
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)
4~32mg
150~300mg
25~100mg
40~320mg
20~80mg
300~800mg
I am
tired !!
Preload
Afterload
Heart
I am a hill
Stage C, D
Drugs Recommendation for Routine Use : Class I
Diuretics
Digitalis
ACE inhibitors
β-blockers
DIGOXIN
Na-K ATPase
Na+
K+
Na-Ca Exchange
Na+
Myofilaments
K+ Na+
Ca++
Ca++
CONTRACTILITY
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
Ismo
Dilatrend
Lasix
Aldactone
Sigmart
Molsiton
Vastinan
100mg
75mg
1mg
0.125mg
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 !!!