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عروقی-دارو درمانی بیماریهای قلبی
درهای پر فطاری خى -دار
هذرس:دکتر خیراهلل غالهی
Pharmacotherapy of hypertensionKheirollah Gholami, Pharm.D.
27/2/139018/5/2011
•
•
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•
•
•
•
2
• Hypertension is termed the ―silent killer‖ because most
patients do not have symptoms.
• The primary physical finding is elevated BP.
ی خىعالئن پرفطار
یب لبس ثی ػش كذا فش ی ؿد. فشد silent killerیچ ػالشی ذاسد ث ی دی ث آ ی خدشفـبس
دس چىبح شخ ای ـى ی ؿد. اجش ثؼوی اص افشاد ث ب افضایؾ فـبس خ ػالئی ث ػشدسد سا ـب
ی دذ اب ث ثیبسی ػالز داس فش ی ؿد و اوثش ثیبسا، آ ػالز سا داؿش ثبؿذ بذ دشؿی
اػشثب ی ثبؿذ، اوثشا ػالشی ذاسذ فمي ثب اذاص ی خسی دشخسی دس دیبثز. ػالز داؿش دس دشفـبسدشادسا
یشی فـبس خ شخ ی ؿذ ث ی دی خشبن ی ثبؿذ.
• The diagnosis of hypertension cannot be made based on one elevated BP
measurement. The average of two or more measurements taken during two or more
clinical encounters should be used to diagnose hypertension.
چگگی تطخیص
ثبس یب ثیـشش دس 2ش فـبس خ ثد ؿخق یؼز. حذال یه ثبس اذاص یشی فـبس خ ثبال ثد آ دی ثش د
فشد ـخق ی خد شح یب د سص خشف یب د فش خشف ثبیذ فـبس خ اذاص یشی ؿد سب دشفـبس
ؿد.
3
Clinical Evaluation of Patients with HTN
• All patients with HTN should have the following measured prior to initiating therapy: – 12-lead ECG– spot urine albumin-to-creatinine ratio; creatinine– blood glucose and hematocrit;– serum potassium, calcium; and a fasting lipid panel.– For patients without a history of CAD, noncoronary
atherosclerotic vascular disease (referred to as CAD risk equivalents), LVD, or diabetes, it is important to estimate a 10-year risk of fatal CHD or nonfatal MI using Framingham Risk scoring.
ثیبسی ػالز ذاسد صب ثشای اسصیبثی ثبیی فشد دشفـبس خ چ وبس ثبیذ ادب داد ث خلف چ ای
ؿشع آ ـخق یؼز؟
فش ی ؿد. lead-12وب اص فشد شفش ؿد و ث آ ECGاثشذا ثبیذ یه
شفش ؿد. وشاسیی، لذ خ، بسوشیز، دشبػی، وؼی urine albumin-to-creatinine ratio چی
دشفبی چشثی فشد ثبیذ اذاص یشی ؿد.
WHO report Hypertension has been listed as the first cause of death worldwide
• Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ, Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347–1360. RV.
صادر هی کذ guidelineسازهاى ایی ک در هرد پرفطار خی
WHO كحجز ی وذ. ای ی خ)ػبصب ثذاؿز خبی( یىی اص شاوضی اػز و دسثبس دشفـبس
شي اسفبلبر ػبصب دشفـبس خی سا ای ػب شي دس دیب ی داذ. ب س و ی دای ای ػب
لجی ػشلی اػز و اوثشا بؿی اص دشفـبس خی ی ثبؿذ.
4
Leaders in Hypertension
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)
World health organization (WHO)
European Society of Hypertension (ESH)
European Society of Cardiology (ESC)
International Society of Hypertension (ISH)
JNC (joint national committee on prevention, detection, evaluation and treatment of
high blood pressureیبثی دسب دشفـبس ( ویش ای اػز دس آشیىب و ثشای دیـیشی، سدیبثی، اسص
ثیش ی دذ guidelineػب یه ثبس 4ؿشع وشد ش 1980یب 1976ی یؼذ. اص guidelineخی
ثد اػز. ـشی آ دس سا اػز. 2003و آخشی آ ػب
ESH (European society of hypertension)
ESC (European society of cardiology)
ISH (international society of hypertension)
كحجز ی وذ و اوثشا ؿجی ؼشذ اب بی سفبر داسذ ث خلف دشفـبسی خای شاوض دسثبس
اسدبیی ب دس ثؼوی لؼز ب ثب آشیىبیی ب فشق ی وذ.
i
( systemic vascular resistanceز ػیؼش ػشق )(* مبcardiac outputفـبس خ ; ثشذ لجی )
5
o
ثش د لجی ; سؼذاد هشثب لت * مذاس خی و اص لت خبسج ی ؿد.
ثب سخ ث ای فش داسب ثب سأثیش ثش ثش د لجی یب مبز ػشلی فـبس خ سا سغییش ی دذ.
Blood Pressure
Diastolic Pressure
Systolic Pressure
Hypertension
Diastolic pressure فـبس دبییsystolic pressure .فـبس ثبال ی ثبؿذ
6
- elevation of systolic/diastolic pressure above 140/90 mm Hg
- most common cardiovascular disease
Essential
HYPERTENSION
Secondary
Unknown etiology
80-90% of all cases
Treatment mainly symptomatic
Known etiology
Treat to eliminate
cause of the disease
ییب دشفـبس essential hypertension(primary hypertension)داسذ دچبس ی خ% وؼبی و دشفـبس90
% ثبلی بذ 10خق یؼز. دسب آ ب ؼال ػالشی اػز. ث ـب ـی خخ ای ؼشذ ػز دشفـبس
( فش ی ؿد.secondary hypertensionثبی ) ی خو ی سا ػز سا سؼیی وشد دشفـبس
Epidemiology
Approximately 31% of the population (72 million Americans) have high BP (≥140/90 mm Hg)
Prevalence increase with age
Before 45 men>women
45-54 women slightly > men
>55 women>men
Mexican Americans (20.7%) <non-Hispanic whites (28.9%) <non-Hispanic blacks (33.5%)
Age ≥60 years prevalence in 2000 65.4%, in 1988 57.9%
اپیذهیلژی
ؼشذ. ی خ% اص خؼیز آشیىب دچبس دشفـبس31جك آبس آشیىب
ی خػبی دشفـبس 55% وؼبی و دس ػ 90ثب افضایؾ ػ افضایؾ دیذا ی وذ یؼی ی خشفـبسؿیع د
ی ؿذ. ی خػبی دچبس دشفـبس 75ذاسذ ثب سػیذ ث ػ
55ػبی دس خب ب وی ثیـشش اػز ثبالی 45-54ثیـشش اص خب بػز. ی خػب دشفـبس 45دس آلبیب صیش
ی ؿذ. آب ثیـشش اص آلبیب دچبس ػب خب
7
% ثد اذ 58، 1988ثدذ، ی خؼیز دس ی خػب دس آشیىب دچبس دشفـبس 60% اص افشاد ثبالی 65، 2000ػب
ثب زؿز صب اػز. احشبال یه دی ػذ ی آ افضایؾ صی اػز و دشفـبسی خو ـب دذ ؿیع ثیـشش
شذ.خاغ دچبس آ ؼ
% اكال ی داذ. اص وؼبی و 30داسذ اص آ غ اذ ی خ% اص وؼبی و دشفـبس70سب 2000جك آبس ػب
% اص افشاد دشفـبس خ وشش ی ؿذ.34ی یشذ سب لشاس % سحز دسب59ؼشذ سب آدچبس
BP Control Rates
Trends in awareness, treatment, and control of high
blood pressure in adults ages 18–74
National Health and Nutrition Examination Survey,
Percent
II
1976–80
II
(Phase 1)
1988–91
II
(Phase 2)
1991–94 1999–2000
Awareness 51 73 68 70
Treatment 31 55 54 59
Control 10 29 27 34
.
USA
27
Canada
13
England
6
France
24
Adapted from G. Mancia / L. Adapted from G. Mancia / L.
RuilopeRuilope
< 140/90 mmHg
MarquesMarques--Vidal P et al. J Vidal P et al. J Hum HypertensHum Hypertens 19971997
Percentages of Patients whose Hypertension is Controlled
Percentages of Patients whose Percentages of Patients whose Hypertension is ControlledHypertension is Controlled
Finland Spain
20
Germany Scotland
< 160/95 mmHg
Australia
19
India
9
20.5
17.522.5
> 65 years
USA:USA: JNC VI. JNC VI. Arch Intern MedArch Intern Med 19971997
Canada:Canada: Joffres Joffres et al. et al. AmAm J J HypertensHypertens 2001 2001
England:England: Colhoun et al. J Hypertens 1998Colhoun et al. J Hypertens 1998
France:France: Chamontin et Chamontin et al. al. AmAm J J HypertensHypertens
19981998
%، 20%، اػذبیب 20%، فالذ 13% وشش ی ؿذ. دس وببدا 27ای حبز دس سب دیب خد داسد، دس آشیىب سب
%. 6%، ایغ 24% ، فشاؼ 5/22%، آب 5/17%، اػىبسذ 9%، ذ 9اػششایب
8
یب چشثی ثبالی خ ؼشذ. ثشاػبع آخشی دشفـبسی خصاسر ثذاؿز اػال وشد یه ػ شد ایشا جشال ث
شبیح، ثی سخی ث وشش فـبس خ چشثی خ ثبال خت ؿذ ثیبسی بی لجی ػشلی ثب اص ثی ثشد سصا
یی ایشای ثی 6/6یؼششی ػز شي یش دس وـس ثبؿذ. فش، ؿب 369ػب ػش اص شیك شي صدب 3136
% ی 34ؼشذ. دس ایشا سب prehypertensionیی فش دچبس 12ؼشذ. دشفـبسی خػبی دچبس 25 -64
لشف % وؼبی و داس24% اص وؼبی و االع داسذ داس اػشفبد ی وذ سب 25داسذ دشفـبسی خداذ
ی وذ وشش ی ؿذ.
دشفـبس خی ثب ػ، خغ، ص، دشفبی چشثی دیبثز دس اسسجبى اػز.
9
Approximately 25% or 6.6 million Iranians aged 25-64 years had hypertension; additionally 46% or 12 million Iranians aged 25-64 years had prehypertension.
Among hypertensive patients, 34% were aware of their elevated BP
25% were taking antihypertensive medications;
only 24% had BP values <140/90 mm Hg
Hypertension associated with age, male gender, obesity, central obesity, hypercholesterolemia, and diabetes
10
Hypertension ىی اص خد ثشخبی ی زاسد بذ ػىش غضی، ػىش لجی، بسػبیی ویی، ػاسم فیضیطی
بسػبیی چـی وسی. ـى ذاؿش ثذ لشف داس، زسا ی ثبؿذ فشد ث شس صب دچبس ای ـىالر
ی ؿد.
Secondary Causes of Hypertension
• Diseases Chronic kidney disease
Cushing’s syndrome
Coarctation of the aorta
Obstructive sleep apnea
Parathyroid disease
Pheochromocytoma
Primary aldosteronism
Renovascular disease
Thyroid disease
د وذ: ـىالر ویی، ػذس وؿی، ثیبسی بیی و ی ساذ دشفـبس خی ثبی ایدب
Pheochromocytoma ب دشفـبس خی دسب ی ؿد.، ثیبسی بی سیشئیذی ... و ثب دسب ای ثیبسی
11
Secondary Causes of Hypertension cont..
Drugs Associated with Hypertension in Humans
Prescription drugs
Adrenal steroids (e.g., prednisone, fludrocortisone, triamcinolone)
Amphetamines/anorexiants (e.g., phendimetrazine, phentermine, sibutramine)
Antivascular endothelin growth factor agents( bevacizumab, sorafenib, sunitinib)
Estrogens (usually oral contraceptives)
Calcineurin inhibitors (cyclosporine and tacrolimus)
Secondary Causes of Hypertension cont.
Decongestants (phenylpropanolamine and analogs)
Erythropoiesis stimulating agents (erythropoietin and darbepoietin)
Non-steroidal antiinflammatory drugs,
Cyclooxygenase-2 inhibitors
Others: venlafaxine, bromocriptine, bupropion, buspirone,
carbamazepine, clozapine, desulfrane, ketamine, metoclopramide
Situations: β-blocker or centrally acting α-agonists (when abruptly discontinued); β-blocker without α-blocker first when treating pheochromocytoma
Secondary Causes of Hypertension cont..
Street drugs and other natural products
Cocaine and cocaine withdrawal
Ephedra alkaloids (e.g., Ma-huang), “herbal ecstasy,”
other phenylpropanolamine analogs
Nicotine withdrawal, anabolic steroids, narcotic withdrawal, methylphenidate, phencyclidine, ketamine, ergotamine and other ergot-containing
herbal products, St. John’s wort
12
ثبی ؿذ: دشدیض، آفشبی ب، ػیجسشای، اػششط ب، ی خ بػث دشفـبسداسبیی و ی ساذ ث
... )دغ حشب دسثبس فـبس adult coldػیىػذسی، سبوشیع، دوظػشبز ب ث خلف دس افشاد دیبثشی،
خ شین ػؤا ؿد(
Secondary Causes of Hypertension cont…
Food substances
Sodium
Ethanol
Licorice
Tyramine-containing foods if taking a monoamine oxidase inhibitor
ثبی ی ؿذ: ػذی، اى، ؿیشی ثیب غزابی حبی سیشای سی خدشفـبغزابیی و ثبػث
Risk factors for cardiovascular complications in hypertensive subjects
Age (> 55 for men, 65 for women)
Hypertension
Cigarette smoking
Dyslipidemia
Microalbuminuria or estimated GFR <60 mL/min
Family history of premature CVD (men <55 or women <65)
Obesity (BMI >30 kg/m2)
Diabetes mellitus
Physical inactivity
Hypertension 2003;42:1206.
اػز. ػ، اػشؼب دخبیبر، دیغ دشفـبسی خیىی اص سیؼه فبوشسبی ایدبد وذ ی ـىالر لجی ػشلی
ػبی فر 65ػبی بدس خباد لج اص 55یذیذی، سبسیخچ ی خبادی ث خلف اش دذس خباد لج اص
ثبؿذ، دیبثز ػذ سحشن اص دیش سیؼه فبوشسب ی ثبؿذ. BMI>30وشد ثبؿذ، اهبف ص ث خلف اش
13
Classification of Hypertension
7th report of
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
JNC 7
JNC 7
Primary Goal: morbidity and mortality – Target organ disease
• Heart, brain, kidney, periphery, eyes
Surrogate Goal: Treat to a target BP– <140/90 mm Hg for most
– <130/80 mm Hg for Diabetes or Chronic Kidney Disease (CKD)
14
JNC :پرفطار خی را ایي گ طبق بذی هی کذ
80 -89 دیبػش 120 -139دیبػشیه جیؼی ی ثبؿذ. ػیؼش 80ػیؼشیه صیش 120فـبس خ صیش
prehypertension خد ذاؿز وؼی و دس ای شح لشاس داسد دسب 2003ی ثبؿذ. ای غز لج اص ػب
، 90 -99 دیبػش 140-159سیی ثشای ا الص یؼز ش ای و ثیبسی بی صی ای داؿش ثبؿذ. ػیؼش دا
stage I اػزstage II 100 دیبػش ثبالی 160ػیؼش ثبالی .
ػیؼش ث د داس ثشای وشش فـبس خ یبص داسذ چ ش داسی هذ فـبسخ بیشب stage IIاوثش ثیبسا
دبیی ی آسد. mm5 دیبػش سا حذد mm10سا
. دس دسب ثبیذ ث داسد 90 یب دیبػش ثبالی 140فـبس ػیؼش ثبالی دغ ث وؼی دشفـبس خ فش ی ؿد و
لغ سػیذ. ثبیذ ث شین ؽ صد وشد و ثب سػیذ فـبس خ ث ای مذاس جبیذ داس سا cut off pointصیش ای
وشد داس ثبیذ ثشای یـ لشف ؿد. دس وؼبی و دیبثشی ؼشذ یب بسػبیی ویی داسذ فـبس خ ثبیذ ث
ثشػذ. 80 130صیش
سب ای دػشساؼ ب ثشای وبؾ شي یش ی ثبؿذ. شچ فـبس خ ثیبس دبیی سش ثبؿذ احشب شي یش
وشش اػز.
ؼز یب ؟ ی خثبؿذ آیب دچبس دشفـبس 95 دیبػشؾ 135ػیؼشؾ اش وؼی فـبس خ
اػز. ی خث ؼز شوذا اص فـبس خ ب ثبالسش اص حذ شب ثبؿذ ثیبس دچبس دشفـبس
ؼشذ صب ی خ( اػال وشد وؼبی و دچبس دشفـبسAmerican heart association) AHA 2007ػب
ثبؿذ. 80 120ؼشذ ثبیذ فـبس خـب صیش left ventricular dysfunctionدچبس
15
For persons over age 50, SBP is a more important than DBP as CVD risk
factor.
Starting at 115/75 mmHg, CVD risk doubles with each increment of
20/10 mmHg throughout the BP range.
Persons who are normotensive at age 55 have a 90% lifetime risk for
developing HTN.
Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be
considered prehypertensive who require health-promoting lifestyle
modifications to prevent CVD.
JNC 7: New Features and Key
Messages
JNC 7: New Features and Key Messages (Continued)
Thiazide-type diuretics should be initial drug therapy for most, either
alone or combined with other drug classes.
Certain high-risk conditions are compelling indications for other drug
classes.
Most patients will require two or more antihypertensive drugs to
achieve goal BP.
If BP is >20/10 mmHg above goal, initiate therapy with two agents,
one usually should be a thiazide-type diuretic.
هطرح ضذ است: JNC 7در
سب ثبالسش 20ػب فـبس ػیؼش سش اص فـبس دیبػش ی ثبؿذ. لشی ػیؼش اص حذ شب 50دس افشاد ثبالی
ثشاثش ی ؿد. 2سب ثبال ثشد اىب شي یش 10د دیبػش ث
ای 2011شح ؿذذ. اجش دس مبالر ػب دشفـبسی خسیبصیذب ث ػا ای والع داسیی دس دسب
هع صیش ػا سفش اػز.
16
• cardiac output (ß-blockers, Ca2+ channel blockers)
• plasma volume (diuretics)
• peripheral vascular resistance (vasodilators)
MAP = CO X TPR
PharmacotherapyNon-pharmacological
TREATMENT OF HYPERTENSION
• Restriction of salt
intake
• Reduction of body
weight
درهاى
ثبیذ ادب ؿد. life style modification اػز شػیذ 90/140اش ص فـبس خ ث
% اص بسػبیی بی 50% اص ػىش بی لجی 20 -25% اص ػىش بی غضی، 35 -40اش فـبس خ وشش ؿد
احشمبی لت وبؾ ی یبثذ.
ث س وی:
خد داسد و یچ ث ثیبس سكی ؿد ه دا دس ض ذاؿش ثبؿذ. دس غزابی خشف آ لذس ه
لز دچبس وجد ه دس ثذ ی ؿی. حشی اش یه ػب ه خسد ـد وی ب آ لذس دس رخیش
وشد ػذی ل ؼشذ و دچبس وجد آ ی ؿی ش آ و اخشالالر فیضیطیىی خد داؿش
ثبؿذ.
.ی ػجضیدبر دس سطی غزایی صیبد ؿد
ؿد ث خلف اص جیبر و چشة اػشفبد ؿد.مذاس چشثی و
10 ییشش خی فـبس خ سا وبؾ ی دذ. 5-20% وبؾ ص
،یی شش خی فـبس خ سا وبؾ 8 -14اهبف وشد ی ػجضیدبر ث سطی غزایی وبؾ چشثی
ی دذ.
یی شش خی فـبس خ سا وبؾ ی دذ. 8 – 9وبؾ ػذی
یی شش خی فـبس خ سا وبؾ ی دذ. 4 -9ایؾ فؼبیز ثذی افض
داس دس وشش فـبس خ ی ساذ ؤثش ثبؿذ. 2بی ادب سب ای وبسب ث اذاص
17
Sites of action of drugs that relax vascular smooth muscle
Angiotensin II receptorantagonistsLosartanValsartan
Ca2+-channel blockers
DihydropyridinesVerapamilDiltiazem
K+-channel activators
MinoxidilDiazoxide
Activators of theNO/guanylate cyclase pathway
HydralazineNitroglycerinNitroprusside
a-AdrenoceptorantagonistsPrazosinTerazosin
K+
Ca2+
NO
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT)
Objective: Compare amlodipine, doxazosin and lisinopril to chlorothalidone
• Prospective, double-blind, randomized trial
• 42,448 patients with hypertension for 4 to 9 yrs
• Mean age was 67 yrs
• Atenolol, reserpine, or clonidine allowed as add-on if BP was not controlled, then hydralazine
• Primary Endpoint: nonfatal MI + CHD death
JAMA 2002;288:2981-97
ALLHAT
• ALLHAT was designed as a superiority study with the hypothesis that amlodipine, doxazosin, and lisinopril would be better than chlorthalidone
• It did not prove this hypothesis because the primary end point was not different between chlorthalidone, amlodipine, and lisinopril.
• None of analyses demonstrated superior CV event reductions with lisinopril or amlodipine versus chlorthalidone.
• Overall, thiazide-type diuretics remain unsurpassed in their ability to reduce CV morbidity and mortality in most patients.
18
• A new analysis looking at 10-year mortality and morbidity data from the landmark Antihypertensive and Lipid-Lowering Treatmant to Prevent Heart Attack Trial(ALLHAT) would appear to confirm the previous trial conclusions.
• Medscape medical news.november 19,2009
Therapeutic algorithm of hypertension treatment (JNC 7)
19
Reaching BP improvement at specific patients
• when monotherapy doesn´t reduce BP to intended value adminastration of other drug should start .
• For most patients combination of 2 and more antihypertensives is necessary .
• If the BP is higher by 20/10 mm Hg than intended value, therapy should be started with combination of 2 antihypertensives.
Risk of cardiovascular diseases
• relationship between BP and CVD (cardiovascular disease) risk is continual, consistent and not dependent on other risk factors
• the higher BP, the higher risk of heart failure, stroke, renal diseases
• each increase of systolic BP by 20 and diastolic BP by 10 mm Hg doubles the risk of CVD
20
Clinical disorders resulting from hypertension
• Congestive heart failure
• Cerebral hemorrhage
• Renal failure
• Retinopathy
• Dissecting aneurysm
• Hypertensive crisis
• ACE inhibitors
• ATII antagonists
• Diuretics
• -adrenoceptor
blockers
• a1-adrenoceptor
blockers
• Ca2+ channel blockers
MONOTHERAPY
• Centrally acting
antihypertensives
• Guanethidine
• Minoxidil
• Hydralazine
Drugs used only in
combination
PHARMACOTHERAPY OF HYPERTENSION
ثشای وشش فـبس خ اسد ثبصاس ؿذ اذ خشف ؼشذ. اشص ثیـشش 2008سب 1950داسبیی و اص ػب
ثشبثالوشب ث آس 2007ب لشف ی ؿذ. اص ػب ARBب، سیبصیذب CCBب، ACEI ی داسب
بس ثیبسی بی صی ای لجی ػشلی حزف ؿذ اذ. ش ایى ثیhypertensionشدش اص خي ا دسب
( اػشفبد ی ؿذ.adjunctداؿش ثبؿذ یب ثیبس هشثب لت ثبالیی داؿش ثبؿذ. ثشبثالوشب ث ػا خي د )
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Treatment
The final goal of antihypertensive therapy is reduction of mortality and morbidity to CVS and renal diseases.
Primary goal is reduction of systolic BP. We want to reach BP less than 140/90 mm Hg (Torr), or less than 130/80 mm Hg among diabetic patients and patients with kidney diseases
Benefit of BP reductionIn clinical studies during antihypertensive therapy the followings
were recorded:
35-40% incidence reduction of stroke 20-25% incidence reduction of myocardial infarctionMore than 50% reduction of heart failure incidence
It is assumed that among patients at first stage of hypertension (140-159/90-99 mm Hg) and with other cardiovascular risk factors, permanent reduction of BP by 12 mm Hg during 10 years prevents one death from 11 treated patients
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Nonpharmacological treatment
Change of life-style:
• intake of Sodium chloride ≤ 5 – 6 g per day (ideally to 1.5 g/day =3.8gram salt)
• prevention of obesity – dietetic modification
• alcohol ... ≤ 30 g per day
• smoking – stop
• physical activity
• psychical relaxation
Nonpharmacological treatment
• Hypertension is two to three times more likely in overweight than in lean persons.
• More than 60% of patients with hypertension are overweight
• As little as 10 pounds of weight loss can decrease BP significantly in overweight patients.
• Abdominal obesity is associated with the metabolic syndrome, which is a precursor to diabetes, dyslipidemia, and, ultimately, CV disease.
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Nonpharmacological treatment
• Diets rich in fruits and vegetables and low in saturated fat lower BP in patients with hypertension
• Most people experience some degree of SBP reduction with sodium restriction.
• The Dietary Approaches to Stop Hypertension (DASH) eating plan is a diet that is rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat
Optimal Dietary Strategies for Reducing Incident Hypertension
In humans, excessive dietary sodium intake is etiologically related to the epidemics of prehypertension and hypertension. Moreover, excessive dietary sodium intake has been associated with left ventricular hypertrophy and alterations in the structure and function of large arteries and renal vascular beds, in part, independent of the effect of sodium on blood pressure.
There is also evidence that dietary sodium may affect arteriolar stiffness and, ultimately, systolic and pulse pressures. However, this is not true in all patients and may be related to not only genetic variations and how sodium is handled by the kidneys but also other dietary nutrients that may, in part, offset the effects of dietary sodium.
Optimal Dietary Strategies for Reducing Incident Hypertension. Weir, Matthew R.; Anderson, Cheryl A.M. hypertension. (54), October 2009, pp 698-699
The study by Zhang et al suggests that another important environmental determinant of hypertension is dietary animal protein intake.
The authors analyzed data from a prospective study of 87 293 nurses followed for 14 years and provide interesting new information that a diet with a higher net acid load was independently associated with increased risk of incident hypertension.
This association remains significant after controlling for dietary factors, such as sodium, magnesium, calcium, folate, protein, and potassium. Thus, we may have 1 more important factor to consider when treating hypertension: diet-dependent net acid load.
Zhang L, Curhan GC, Forman JP. Diet-dependent net acid load and risk of incident hypertension in United States women. Hypertension. 2009;54:751–755.
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In the study by Hedayati et al, dietary potassium deficiency was independently associated with increased blood pressure in a multiethnic, population-based cohort study. The association was stronger in blacks than nonblack counterparts and was independent of demographics, estimated glomerular filtration rate, and cardiovascular risk factors.•
Additional evidence about the role of potassium comes from research by Xie et al, which suggests that potassium deficiency increases serine-threonine (with-no-lysine [K]) kinase (WNK-1) expression, which may create an imbalance between the activity between the renal outer medullary potassium channel (ROMK) and the sodium epithelial channel, which results in greater sodium retention. Perhaps the ratio of dietary sodium:potassium may be relevant as a dietary maneuver to reduce blood pressure.•
•Hedayati SS, Minhajuddin A, Moe OW, Huang C. Dietary potassium deficiency is independently associated
with increased BP in a multi-ethnic population-based cohort [abstract]. J Am Soc Neph. 2008;19:90.
•Xie J, Wu T, Huang I, Cleaver O, Huang C-L. Role of WNK1 kinase in cardiovascular development and BP control
in mice [abstract]. J Am Soc Neph. 2008;19:65.
• The study by Zhang et al adds important new information to the literature about diet and incident hypertension.
• Despite the study’s limitations (blood pressure was self-reported and not directly measured) and the use of food frequency questionnaires to estimate dietary intake, the large number of participants who were health professionals indicates that these results are likely trustworthy. Thus, we have one more dietary consideration (ie, protein intake) for preventing and controlling prehypertension and hypertension.
• Optimal Dietary Strategies for Reducing Incident Hypertension. Weir, Matthew R.; Anderson, Cheryl A.M. hypertension. (54), October 2009, pp 698-699
• Currently, total protein intake for US adults is above recommended levels, and typical US diets are composed of more animal than plant protein. In a nutrient-dense diet, plant foods can provide sufficient amounts of all of the essential amino acids and are likely to supply alkali and reduce the net acid load of the total diet.
• To reduce net acid load in the diet, Zhang et al suggest reducing dietary intake of animal protein and increasing intake of fruits and vegetables. This suggestion is not new, but now we have one more reason to adhere to this sound advice.
Optimal Dietary Strategies for Reducing Incident Hypertension. Weir, Matthew R.; Anderson, Cheryl A.M. hypertension. (54), October 2009, pp 698-699
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Selection of pharmacotherapy
• Results gained in clinical studies show that BP reduction with using following antihypertensives –inhibitors of angiotensin converting enzyme(ACEI), blockers of angiotensin receptors(ARB), betablockers (βB), calcium channel blockers(Ca2+B) a diuretics, can reduce complications of hypertension.
• Base of medical treatment of uncomplicated hypertension in the first stage should be according to JNC 7 thiazide diuretics alone, or in combination with other antihypertensives in the second stage of hypertension.
Development of antihypertensive therapy. DHP indicates dihydropyridine;
ETa, endothelin A receptor blocker; VPI, vasopeptidase inhibitor.
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Development of fixed-dose combinations for antihypertensive therapy.
ACE indicates angiotensin-converting enzyme; CCB, calcium channel
blocker; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor.
Antihypertensive Agents
• Primary Agents– Supported by Outcomes data:Diuretics
ACE Inhibitors
Angiotensin Receptor Blockers (ARBs)
Calcium Channel Blockers (CCBs)
Beta-blockers
• Alternative AgentsAlpha-blockers, Arterial vasodilators, Centrally acting
agents, Reserpine
Advantages of thiazide diuretics
• According to more studies thiazide diuretics are considerably the most effective
• They increase antihypertensive effectivity of combined treatment
• They proved to reach BP normalisation
• Are less expensive than other antihypertensives
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Diuretics
Diuretics 1. carboanhydrase inhibitors (acetazolamid) – not used in the
treatment of hypertension
2. loop diuretics (furosemide, etacrynic acid, bumetanide) –strong short-lasting effect; ability to excrete to 25 % of Na+ from filtrate
• block active reabsorption of Na+, Cl-, K+ from
ascending limb of Henle´s loop
• at treatment of hypertension is rarely used only
furosemide in low dosage – if simultaneously is very
much reduced G filtration;
they aren´t suitable for long-lasting application
3. thiazide diuretics (hydrochlorothiazide, chlorthalidone)
• block reabsorption of Na+ and Cl- from distal tubulus• effect is weaker than loop diuretics – they excrete about 5 % from Na+ filtrate• most suitable diuretics for long–lasting treatment of hypertension • effect also in vessel wall (↓ volume of Na and ↓ reactivity to norepinephrine; regression of mediahypertrophy)• the most used is hydrochlorothiazide – daily dose12,5 – 25 mg
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4. K-sparing diuretics (spironolactone (aldosterone antagonist), amiloride, triamterene)
• at hypertension only assistant drugs to combinations
– to correct hypokalemia
5. other diuretics
• osmotic (mannitol, sorbitol)
Diuretics are suitable mainly for older patients and at simultaneous chronic heart failure
Serum half-life of most antihypertensive agents does not correlate with the hypotensive duration of action
Diuretics lower BP primarily through extra renal mechanisms.
Side effects of thiazide-type diuretics
• include hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual dysfunction.
• Many of these side effects were identified when high-doses of thiazides were used in the past (e.g., hydrochlorothiazide 100 mg/day).
• Current guidelines recommend limiting the dose of hydrochlorothiazide or chlorthalidone to 12.5 to 25 mg/day, which markedly reduces the risk for most metabolic side effects.
• Loop diuretics may cause the same side effects, although the effect on serum lipids and glucose is not as significant, and hypocalcemia may occur
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ADVERSE EFFECTS OF THIAZIDES
Hypokalemia
Hyperuricemia
Hyperglycemia
Dyslipidemia
Hypomagnesemia
Hyponatremia
Adverse effects
All dose dependent except for Dyslipidemia
ثؼش ث دص ؼشذ اص ػاسم سیبصیذب بیذوبی، بیذضی، بیذشوؼی، بیذشاسیؼی، بیذشالیؼی ا
یی ش سب 5/12شچمذس لشف داس ثبالسش سد ثذسش ی ؿذ. اشص سكی ی ؿد یذسوشسیبصیذ
یی ش خد ذاؿز 50یی ش دس سص لشف ؿد دس كسسی و دس زؿش لشف بی وشش اص 25حذاوثش
sexualث دی وبؾ دص لشفی دیذ ی ؿذ. ػاسم سب ای ػاسم دس ثیبسا دیذ ی ؿذ اب اال
dysfunction .دیغ یذیذی اثؼش ث دص یؼشذ
From katzung pharmacology book
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The Choice of Thiazide Diuretics; Why Chlorthalidone May Replace Hydrochlorothiazide?
• When the Multiple Risk Factor Intervention Trial was begun, either chlorthalidone or HCTZ, both at doses of 50 or 100 mg daily, could be used. In 6 clinics, chlorthalidone was chosen; in 9, HCTZ was used. After some 7 years, the Multiple Risk Factor Intervention Trial Policy Advisory Board recommended that all of the subjects be given chlorthalidone at a maximal dose of 50 mg/d, because the trend of mortality was unfavorable in the 9 clinics using HCTZ compared with the favorable trend in the 6 clinics using chlorthalidone.
• Surprisingly, the first definite evidence for a significant difference in the antihypertensive efficacy of HCTZ and chlorthalidone was published just 5 years ago, in Hypertention journal. Their review concluded that, “chlorthalidone is about 1.5 to 2.0 times more potent as HCTZ, and the former has a much longer duration of action.”
• Norman M. Kaplan (Hypertension. 2009; 54:951-953.) The Choice of Thiazide Diuretics; Why Chlorthalidone May Replace Hydrochlorothiazide?
• The first published trial of the 24-hour ambulatory blood pressure monitoring comparing the 2 drugs appeared only 3 years ago, again in Hypertension journal and from the same investigators.
• They found a greater lowering of systolic blood pressure with 25 mg of chlorthalidone than with 50 mg of HCTZ in a crossover trial of 30 stage 1 hypertensives (average baseline office blood pressure: 143/93 mm Hg) with 8-week periods of drug intake and a 4-week washout period between. The daytime ambulatory blood pressure monitoring was a statistically insignificant 3.3-mm Hg mean difference, but the nighttime mean difference was a highly significant 7.1-mm Hg lower blood pressure with chlorthalidone. Of further interest, the falls in serum potassium were similar during the 8-week periods of HCTZ or chlorthalidone intake, averaging 0.5 mEq/L.
• Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47:352–358.
Norman M. Kaplan (Hypertension. 2009; 54:951-953.) The Choice of Thiazide Diuretics; Why Chlorthalidone May Replace Hydrochlorothiazide?
Chlorthalidone is the preferable diuretic for initial and subsequent therapy of hypertension, starting with 12.5 mg/d and increasing to _25.0 mg/d with or without other antihypertensive drugs.
even in low doses, potent diuretics, such as chlorthalidone, can lower serum potassium enough to cause cardiac arrest.18 In view of the strong evidence that small doses of the aldosterone blockers spironolactone and eplerenone can protect vulnerable patients and significantly reduce blood pressures resistant to _3 drugs, a logical way to provide maximal antihypertensive efficacy and to prevent hypokalemia might be a combination of chlorthalidone and spironolactone 12.5/25.0 mg/d, although there are no trials in which the 2 drugs were given as combination. Both are inexpensive but unfortunately not available in a single tablet.
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Diuretics effective as second-line therapy for hypertension
Diuretics, when given as second-line therapy to treat hypertension, reduce blood pressure (BP) to about the same extent as when they are used as first-line treatment.
The BP-lowering effect of diuretics depends on the dose used but is independent of the type of first-line agent used.
Lisa Nainggolan.Diuretics Effective as Second-Line Therapy for Hypertension. www.medscape.com october 2009 heartwire
Eplerenone
Aldosterone antagonist
its propensity to cause hyperkalemia is greater than with the other potassium sparing agents, and even spironolactone
Contraindicated in patients with
impaired kidney function
type 2 diabetes with proteinuria
Gynecomastia occurs rarely
اػز. ای داس آشبیؼز آذػشش ی ثبؿذ eplerenone دیسسیه خذیذی و دس دیب خد داسد
Gynecomastia وششی ی دذ، دس ثیبسا دیبثشی بسػبی وییcontraindicate اػز وال خیی داسی
خبجی جد اػز.
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Beta Blockers
• The 2006 United Kingdom guidelines recommend a β-blocker only after other primary antihypertensive agents (thiazide-type diuretics, CCBs, ACE inhibitors, or ARBs) have been used.
• These findings also call in question the validity of results from prominent prospective, controlled clinical trials evaluating antihypertensive drug therapy that use β-blocker –based therapy, especially atenolol, as the primary comparator
Beta Blockers Cont
β-Blocker therapy in patients without compelling indications still has a prominent role in the management of hypertension
Using a β-blocker as a primary antihypertensive agent is optimal when a thiazide-type diuretic, ACE inhibitor, ARB, or CCB cannot be used as the primary agent.
Using a β-blocker in a young patient with hypertension that is thought to have high adrenergic drive, as evidenced by an elevated heart rate, may still be clinically reasonable
β-Blockers still have an important role as an alternative add-on agent to reduce BP in patients with hypertension but without compelling indications
Beta Blokers
• Meta-analyses data evaluating β-blockers and their ability to reduce CV events have limitations.
• Most studies that were included used atenolol as the β-blocker studied.
• Thus it is possible that atenolol is the only β-blocker that does not reduce risk of CV events as well as the other primary antihypertensive drug classes.
• it is acceptable to extrapolate these findings to the β-blocker drug class in general
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Renin-angiotensin-aldosterone system
Inhibitors of AC enzyme• block the change of angiotensin I to angiotensin II and at the
same time inactivation of bradykinin
• vazodilation in both resistant and capacity vessels
• accented indication:
- hypertonic people with heart failure (vasodilating therapy
of cardial insuficiency), also after myocardial infarction
- hypertonic people with DM and different forms of diabetic
nephropathy starting with microalbuminuria
(nephroprotective effect of ACEI)
• excessive initial fall in BP → postural hypotension or syncope; treatment should be started in bed from the lowest doses
• reaction of airways is often strong and irritating cough
→ intollerance of the whole group → replacement to AT1 receptor blockers
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• they are administered as “prodrug“, to effective substance are changed in liver
• effect to reduce BP is in the whole group similar; they differ only in pharmacokinetic dependent from structure
→ division to hydrophilic (“blood“) and lipophilic (“tissue“)
ACEI
• hydrophilic act only inside vessels and in endothelium; lipophilic also on the outer side of vessels (on “adventicial“ angiotensinconvertase) and in myocardial interstitium → probably more effectively at regression of left ventricule hypertrophy andvessel media
• all ACEI – are contraindicated in gravidity!
• Typical hydrophilic ACEI: captopril (prototype substance – has SH-group; Tensiomin)enalapril (Enap, Ednyt), lisinopril (Dapril, Diroton)
• Typical lipophilic ACEI:perindopril (Prestarium)trandolapril (Gopten)quinapril (Accupro)
• traditionally the most prescribed in our country is enalapril (Enap) – must be administered 2 x per day
• A regimen including an ACE inhibitor with a thiazide-type diuretic is considered first-line in recurrent stroke prevention base on proven benefits from the PROGRESS trial showing reduced risk of secondary stroke.
• In combination with β-blocker therapy, evidence shows that ACE inhibitors further reduce CV risk in coronary disease, and in patients post-MI.
• These benefits of ACE inhibitors occur in patients with atherosclerotic vascular even in the absence of left ventricular systolic dysfunction or heart failure, and have the potential to reduce the development of new-onset type 2 diabetes.
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• When higher doses are used, twice daily dosing is needed to maintain 24-hour effects with enalapril, benazepril, moexipril, quinapril, and ramipril.
• The absorption of captopril, but not other ACE inhibitors, is reduced when given with food.
Adverse effects of ACE Inhibitors
• Hypotension
• Renal
insufficiency
• Cough
• Hyperkalemia
• Hyperreninemia
• Ageusia
• Skin rash
• Proteinuria
• Neutropenia
• Angioedema
ب شثى ث وبدشدشی ی ثبؿذ. وبدشدشی اثشذا و اسد ثبصاس ؿذ لشف ACEI خیی اص ػاسم روش ؿذ ثشای
ثبس 3یی ش 50ثبس دس سص ثد و ػاسم صیبدی داؿز اشص حذاوثش مذاس سكی ؿذ 3یی ش 150بی
صیبد دیذ ی ؿد. )احؼبع خبن دـز ی دس سص ی ثبؿذ. اب ػبسه ی ػشف ی خـه حشی ثب دص و
وشد. ای switchخد ی وذ( ثب لغ وشد داس ؼال ای ػبسه سب ی ؿد ی سا ث داسی دیشی
داسب ث دی بس آذػشش ثبػث افضایؾ دشبػی ی ؿذ ثبیذ شالت ػبیش داسبیی و بیذشوبی ی دذ
ثد.
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Angiotensin Receptor Blockers
• ARBs directly block the angiotensin II receptor subtype 1 receptor that mediates the known effects of angiotensin II in humans: vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus.
• Because they do not block the angiotensin II receptor subtype 2 receptor, the beneficial effects of angiotensin II receptor subtype 2 stimulation (vasodilation, tissue repair, and inhibition of cell growth) remain intact when ARBs are used
• the ELITE (Evaluation of Losartan in the Elderly) studies show that losartan is not superior to captopril in left ventricular dysfunction when compared head-to-head.
• One outcome study, the VALLIANT, also showed that an ARBs can reduce CV events in patients post-MI with left ventricular dysfunction, but would be used mostly as an alternative to an ACE inhibitor for this use
• ARBs have been compared head-to-head with CCBs. The MOSES demonstrated that eprosartan reduces the occurrence of recurrent stroke more than nitrendipinedoes in patients with a past medical history of cerebrovascular disease
• ARBs may have cerebroprotective effects that may explain CV event reductions
• the VALUE (Valsartan Long-term Use Evaluation) trial, showed that valsartan-based therapy is equivalent to amlodipine-based therapy for the primary composite outcome of first CV event in patients with hypertension and additional CV risk factors
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• ARBs have a fairly flat dose–response curve, suggesting that increasing the dose above low or moderate doses is unlikely to result in a large degree of BP lowering.
• The addition of low doses of a thiazide-type diuretic to an ARB significantly increases anti hypertensive efficacy
• Similar to ACE inhibitors, most ARBs have long enough half-lives to allow for once-daily dosing
• ARBs have the lowest incidence of side effects compared to other antihypertensive agents
• ARBs should not be used in pregnancy
ب ؼشذ و ؿبخق آ ب صاسسب ی ثبؿذ. داسبی خثی ؼشذ.ARBدػش دیش داسبی سد اػشفبد
Calcium Channel Blockers
• Both dihydropyridine CCBs and nondihydropyridine CCBs, are first-line agents for hypertension.
• Newer data shows that CCBs are likely to be as effective at lowering CV events as other agents.
• In ALLHAT there was no difference in the primary outcome between chlorthalidone and amlodipine
• Dihydropyridine CCBs are very effective in older patients with isolated systolic hypertension.
• All CCBs (except amlodipine and felodipine) have negative inotropic effects.
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CCB
• Immediate-release nifedipine has been associated with an increased incidence of adverse CV effects, is not approved for treatment of hypertension
• Other side effects with dihydropyridines include dizziness, flushing, headache, gingival hyperplasia, and peripheral edema.
• Dizziness, flushing, headache, and peripheral edema, occur more frequently with all dihydropyridines than with the nondihydropyridines because they are less-potent vasodilators
Logical Combinations
Kieran McGlade Nov 2001 Department of General Practice QUB
Diuretic -blocker CCB ACE inhibitor a-blocker
Diuretic - -
-blocker - * -
CCB - * -
ACE inhibitor - -
a-blocker -
* Verapamil + beta-blocker = absolute contra-indication
ب ث خلف سادبی ثب ثشبثالوشب CCB آفبثالوشب داد ؿذ. اب ACEI ی یذ دیسسیه ب ثب ثشبثالوشب،
ذ چ ى اػز ثن لجی دذداد ـ
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Triple Fixed-Dose Combination Therapy: Back to the Past
Henry R. Black
Black Hypertension.2009; 54: 19-22
Fix dose combination داس یىی 3ث ثیبسی و لشاس اػز یـ داسب سا لشف وذ وه ی وذ ث خبی
لشف وذ )ػ داس دس یه لشف ی ثبؿذ(.
All of the combinations reduced MSDBP to ˂ 90
mm Hg but failed to lower mean sitting (MS) diastolic
blood pressure ( MSSBP) to ˂ 140 mm Hg. The only
regimen that reduced MSSBP to ˂140 mm Hg and
MSDBP to ˂ 90 mm Hg was the triple combination.
Advantages of a Fixed-Dose Combination as
Antihypertensive Therapy :
o Simplification of the regimen
o Improved adherence
o Reduced pill burden
o Potential for reduced cost with reduced copay, and
individual components may cost less
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Masked hypertension
• Measuring blood pressure in the office is normal but patient have elevated home or ambulatory blood pressure.
• Obara, Taku; Ohkubo, Takayoshi; Asayama, Kei; Metoki, Hirohito; Imai, Yutaka. Defenition of masked hypertension. Journal of Hypertension. 25(7):1511-1512, July 2007.
خد mask hypertension خش لجال ثیبس لشی اسد ت دضؿه ی ؿذ فـبس خؾ ثبال ی سفز اب اشص
ثشػىغ اػز یؼی ثیبس دس ت دضؿه فـبسؽ دبیی ی ثبؿذ ثیش ثبال ی سد و خیی خشبن اػز ،داسد
ی ؿد ػاسم ثؼیبس صیبدی ی ساذ داؿش ثبؿذ. اشص ثیبسی بی ؿبیغ ث ػىش ب سا ث detectچ
ای هع سثي ی دذ.
لی کاتی ک بایذ داست:ب طر ک
ػالز ذاسد. ی خدشفـبس
ػالج ذاسد اب دسب داسد.
داس لشی ؿشع ؿذ ثبیذ ثشای یـ اػشفبد ؿد.
یىی اص ثششی سا بی وشش دشفـبس خی وشش غیشداسیی ی ثبؿذ. افضایؾ فؼبیز، و وشد ص، و وشد
بیبرلشف چشثی ػذی، ػذ اػشؼب دخ
اػشفبد اص دسب بی داسیی فش ؿذ.
دس افشادی و ػب ؼشذ یچ 90 فـبس دیبػشیه ث صیش 140ذف، دبیی آسد فـبس ػیؼشیه ث صیش
80 130ؼشذ ذف صیش ثیبسی صی ای ذاسذ. اش دچبس ثیبسی دیبثز یب بسػبیی ویی یب ثیبسی بی دیش
ی ثبؿذ
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بیواری ایسکویک قلبی
هذرس: دکتر ضرام عال
Ischemic Heart Disease (IHD)
(Anginal syndrome)
by:
Dr. Shahram Ala(Pharm.D, BCPS)
Ischemia
Injury
Infarction
Death
CHF
Irreversible
Reversible
Intermediate
آظی كذسی شید ی شػیذ خ اوؼیظ داس ث ثبفز بی لجی اػز. لشی ث یه ثبفز خ اوؼیظ داس شػذ
فش ی ؿد آغبص ی شدد. دس ادا ischemiaذ سخشیت ػی و ث آ ػ بی آ ؿشع ث شد ی و
وـیذ ی ؿد، كذ ی ثیذ یه ػشی اص injuryاش ؼب دسب ـد یؼی خ ث ثبفز ثششدد ث
بذ ؿد ؼال یشوذسی ب، ظی ب اد دیش داخ ػی اص ثی ی سذ. سب ایدب اش خ اوؼیظ داس سػ
ischemiaی ؿد ی یشد. جحث فؼی سب شح infarctػ ثشی شدد اب اش ادا دیذا وذ ػ
injury .داخ ػ بی لجی ی ثبؿذ
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Signs and symptoms
• Quality
• Location
• Duration
• Precipitating factors
• Nitroglycerin relief
• Radiation
ز آ فـبسذ اػز ىب ی سی لفؼ ػی ی ثبؿذ. ویفی سشی ػالز آظی كذسی احؼبع فـبس ػی
دلیم ی ثبؿذ. ؼال ثب سالؽ 30ثبی سب 30ػي لفؼ ػی اص خبؽ ؿشع ی ؿد سب صیش شد ذسؾ آ
وبسبی اشطی ثش ثیـشش ی ؿد ػب ثب یششیؼشی خة ی شدد. ؼال سیش وـیذ ی ؿد ث دـز،
ػز ساػز فشد، ث ی دی دس سـخیق آ اؿشجببر صیبدی ى اػز دیؾ شد، دذا، دػز چخ بی د
آیذ. اجش ای ػالئ سیذیه اػز ى اػز دس ػبذا، ؼشبدا افشاد دشفـبس خ ای ػالئ ث هح دیذ
ـد.
ز، دس الغ آ لذس و لت یبص داسد اوؼیظ ث آ ثشػذ اػ demand supplyػز اكی آظی ػذ سؼبد ثی
ث آ اهبف ؿد یب ث سبیی ػز آظی ثبؿذ ث vasospasmسأی ی ؿد. اب دس وبسؽ ى اػز
دالوشی و اسفبق ی افشذ. سدغ؛ دس وبسؽ variantآظی
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Phatophysiology
• Imbalance of oxygen supply and demand
• Abnormality of coronary vascular tone (vasospasm)
• Platelet aggregation or thrombus formation
Foam Cell Formation
+
LDL
Oxidative
Stress
Oxidized LDL Macrophage
Foam Cell
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Development of Atherosclerotic
Plaques
NormalFatty streak
Foam cells
Lipid-rich plaque
Lipid core
Fibrous cap
Thrombus
Angina
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LDLی ثبؿذ. hyperlipidemia hypertensionػز ثؼیبسی اص ـىالر لجی خیی اص ثیبسی بی دیش
شا ی ؿد ثب فـبس اسد )ایشیبی( ػی ی ؿذ و و ای ػ ب hypertension خلكب لشی ثب
سـىی ی ؿد و و ثضسشش ی ؿد. Foam cellsدش اص یذیذبیی ی ؿذ و لشی ثب اوؼیظ اوؼیذ ؿد
اص حذی زؿز دبس ی ؿذ سـىی ی ؿد. بی و حد آ Foam cellsب سا ثخسذ LDLلشی بوشفبطب
ثبػث ایدبد خش خی ی ؿد ؼیش سي ثؼش ی شدد. ثؼش ؿذ ؼیش سػي خش یب آسشاػىشص
ثبػث ایدبد اػذبػ شػیذ خ اوؼیظ داس ث ثبفز ػو لت ی ؿد.
Angina Pectoris
• Chronic stable Angina
• Unstable Angina
• Prinzmetal (Variant) Angina
Chronic stable angina
ع آژیي اصلی جد دارد:س
1. Chronic stable angina ،ای ػالئ سمشیجب د ب دس فشد ثبثز اػز فشد ی داذ وی لجؾ دسد ی یشد :
چمذس ی وـذ، چس خة ی ؿد چ وبس وذ و دسدب وشش ؿد.
2. Unstable angina.ای ع لشی اػز و ای ػالئ ثبثز جبؿذ :
46
3. Prinzmetal (variant) angina
Diagnostic Procedures
• Physical examination
• Quality of pain• Location• Precipitating factors
• Nitroglycerin relief• ECG• Laboratory data
رش ای تطخیصی آژیي
چیضی ـخق ی ؿد اب ویفیز ىب دسد، چ س ثذسش یب ثشش ی ؿد physical examinationؼال دس
خضئی ی سا آظی سا S-Tداؿش ثبؿذ یب سغییشار T invert حظ ایدبد آظی و ECG)یششیؼشی( اص سی
اش دس حظ ایؼىی شفش ECGسـخیق داد. داد بی آصبیـبی ث ػذی دشبػی سغییشار خبكی ی وذ.
ؿد ثیـششی ایز سا داسد.
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Special Diagnosis
• Exercise tolerance test (ETT)
• Myocardial imaging
• Holter monitoring
• Angiography
ک تطخیص قطعی را هطخص هی کذ Special diagnosisای رش
ETT - (exercise tolerance test سؼز سصؽ: سحز شالجز، دس لت فشد ثب سحشن صیبد ایؼىی ایدبد ؿد. دس )
ای حبز سغییشار اس لجی، خؼش ؿذ یب سغییش فـبس فشد یؼی ثجز ثد سؼز ػشیؼب ثبیذ لغ ؿد.
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- Myocardial imaging دس وؼبی و ؼجز ث سؼز سصؽ سح ذاسذ یب ی ساذ حشوز وذ. سبی اػى :
شد یب ثبال ث demandیب دثسبی سؼز ادب ی ؿد و ثب سؽ بی دیش ثال ثب ددبی سذؾ لت ایدبد ؿد
ثب دیذیشیذا سؼز، ػشلی و ایؼىیه یؼشذ ـبدسش ؿذ ایؼىی خبكی ایدبد ؿد سب ثشا دشفیط
یوبسد سا اذاص شفز. لشی و سبی ث فشد داد ی ؿد لؼز بیی و دشفیط بػت داسد دخؾ ی ؿد
لؼز بیی و دشفیط ذاسد ـخق ی ؿد.
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Holter
Holter monitoring
Holter monitoring - ػبػز ادب ی دذ 24: ث ثذ فشد دػشبی ك ی ؿد ش وبسی و فشد دسECG ثجز
ثشسػی ی ؿد ث خلف ای سؽ ثشای ایؼىی بی خبؽ ث وبس ی سد و ECGی ؿد ثؼذ اخشالالر
بی ؼ سدیبثی ی ؿد.ثب سؽ
50
51
Angiography - ؿد سب دیذ ؿد ی سي ػىغ شفش: ثششی سؽ سـخیق آظی دبیذاس اػز و دلیمب اص داخ
آیب سی یب آسشاػىشص خد داسد یب . ؼال اص ؿشیب فسا فشد ؿیبس )ى اػز یه هذاهشاة ث فشد
داد ؿذ ثبؿذ( اسد ی ؿذ اد حبخت دس حظ دیبػش ث فشد سضسیك ی ؿد اص ػشق اكی لت دس
ث و left anterior descending (LAD)اػز. LADؿد خلكب سي اكی لت و حب سذؾ ػىغ ثشداسی ی
ػو ث چخ خ ی سػبذ.
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Heart rate
Contractility
Systolic wall force
Oxygen supply:Coronary blood flow
Atherosclerosis
Vasospasm
• Oxygen content of atrial blood
• (Hgb, Hct, ABG)
• Treatment Overview
Oxygen Demand
ث هشثب لت، Demandی ثبؿذ. oxygen demand supplyدغ ث س وی اخشال اكی، ػذ سؼبد ثی
contractility systolic wall force )ثؼشی داسد )ای اسد یبص ػو لت سا افضایؾ ی دذoxygen
supply ث خشیب خ وشش )اثؼش ث آسشاػىشص اصاػذبػ( ثؼشی داسد. یضا سػیذ اوؼیظ ث
یضا ثی بصبی خ ؿشیبی یض ثؼشی داسد.
سا ثیـشش ثب ثشب Heart rate contractility سا افضایؾ داد. supplyد یب سا و وش demandدغ ثشای دسب یب ثبیذ
سا ثب سػبذ خ ثشش خجشا Oxygen supplyو ی وذ سب لت وذسش ثضذ. Ca2+ channel blockerثالوشب
ـبد ی بیذ. ب سي ب سا Ca channel blockerی وذ. ثب یششار ب اصاػذبػ سا و ی وذ ثب
stentآسشاػىشص ایدبد ؿذ ؼال ثشـز دزیش یؼز فمي ثبیذ خی دیـشی آ سا شفز. ثب صد
زاؿش ثشای ثبص ؿذ ؼیش ی ثبؿذ.
NitratesMechanisms of Action
• Venous vasodilation/pre-load reduction
• Arterial dilation/after-load reduction
• Coronary arterial vasodilation
• Enhancement of coronary collateral flow
• Antiplatelet and antithrombotic effects
ـبد وشد سیذ ؿشیب ػ ثبی دسب، یششار ب ی ثبؿذ. ای داسب فایذ ثؼیبس صیبدی داسذ، اص خ
(preload after load ؿشیب بی وششی سا ـبد ی وذ حشی خلز آشی دالوشی ،)ش د و ی ؿد
داسذ.
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یترات ای هجد در بازار
س سدیض ی ؿد. ث س ؼ ی ػش ثب 2ثبس سب سصی 3و ثؼش ث فشد اص سصی 4/6 6/2یششوبشی
Caثبس داد ؿد دس ای یب یه ثشب ثالوش یب 2ػبػز ی ثبؿذ. اش سصی 8سب 4یششوبشی دیػش سؾ
channel blocker سدیض ی ؿد. ىش ای و خد داسد nitrate free period .اػزcGMP ثب اهبف وشد
ی ؿد. یه ذر اػشفبد اص ای داس ثبػث و ؿذ ش ػفیذسی ی ؿد دغ ثبیذ ش ػفیذسی فؼب
nitrate free period زاؿش ؿد سبregenerate 7ظش 12كجح، 7ؿد ش اثش ذاسذ. ث س ؼ
ثؼبصد.یشد ثذ ی ساذ ش ػفیذسیػبػز یششار 12دس كسسی و فشد ذ. ؿت سدیض ی ؿ
ش لز فشد احؼبع دسد لجی وشد یششیؼشی سا صیش صثب ی زاسد. اش وؼی لشف یششیؼشی صیش صثبی
اؽ صیبد ؿذ یبص ث یششار بی الی اثشسش داسد. ش دبف یششیز ؼبد یه ػذد لشف اػز. بوضی دص
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دلیم اػز اش ثؼذ اص ای ذر خاة شفز چب 5دص ث فبك 3 صیشصثبی یب اػذشی آ یششیؼشی
دس ای افشاد خد داسد. MIدسد لجی ادا داؿز حشب ث دضؿه شاخؼ ؿد چشا و احشب
ؿت اص سی دػز ثشداؿش ؿذ. 7اثش داسذ. ای ب ثبیذ ػبػز 10یششار بیی و ث كسر دبد ؼشذ
)ای داس دس سئیذ یض اػشفبد ی ؿد
یؼشی ی یششار داسد، اثشؽ ؿجی یشش ش ایضػسثبیذ دی یششار دػش دیشی اص یششار بػز. د
اثشؽ ثیـشش اػز. ایضػسثبیذ یششار شبثیز ایضػسثبیذ دی یششار اػز.
55
ISMN
• Metabolite ISDN
• No FPE, AB: 100%
• QD
4/0ذاسد )ثشخالف یشش یؼشی و صیش صثبی آ First pass effectداسی خذیذی اػز و اسد ثبصاس ؿذ.
یی ثبیذ لشف وشد(. اثش آ ث ای اػز و یه ثبس دس سص 4/6سب یی اػز ی آؼش سؾ آ سا
وفبیز ی وذ.
Nicorandil
• Tab: (Ikoral)®
• nitrate derivative of nicotinamide
• vasodilator. potassium-channel opener
• 5-10mg/BD
• SE: headache, quetaneous vasodilatation and flushing, nausea, vomiting, dizziness, and weakness, myalgia, skin
rashes, and oral ulceration
اصدیالسس ی Potassium channel opener، ـشك یششاس ی یىسی آیذ اػز. Nicorandilدیش داسی
لشف ی ؿد. ؿجی یششار ب ى اػز ػشدسد داؿش ثبؿذ. داسی یی ش د ثبس دس سص 10سب 5ثبؿذ.
بیػیذی دس ی سد ثد اػز و اذیىبػی بی دیشی داسد.
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Beta blockers
• Propranolol (Indral)® Tab:10,20,40 mg
• Atenolol (tenormine)® Tab: 50,100 mg
• Metoprolol (Metoral)® tab:50mg
• Carvedilol (Kredex)® Tab:6.25 ,12.5m, 25 mg
Beta adrenergic blockers
• Mechanism of action• Judging therapeutic end point
• Contraindications• ISA• Abrupt withdrawal
اػشفبد ی ؿذ. MI CHFس آظی، سا وبؾ ی دذ. داسبی ثؼیبس خثی ؼشذ و د demandثشب ثالوشب
Propranolol ،atenolol ،metoprolol carvedilol دس ای دػش لشاس داسذ. سب صبی ی سا آ ب سا ادا داد
ـد. 90وشش اص ییب فـبس خ ػیؼش 60و هشثب لت ثیبس وشش اص
ثیبسا آػی غ لشف: وؼبی و فـبسؿب خیی دبیی ی افشذ
ای داسب جبیذ ث یىجبس لغ ؿذ چ ى اػز دسدبی آظیی ثذسشی دیؾ آیذ.
57
سا ثالن ی وذ وبسثشدبی دیشی غیش اص آظی یض داسد ث وبؾ 2- ثشب 1-دشدشا چ ثشب
یض داسی ثؼیبس فیذی اػز و خی ثؼیبسی اص آسیشی بی MIاهشاة شصؽ دػز. دس آظی حشی ثؼذ اص
لجی سا ی یشد.
58
اػشفبد ی ؿد. ی خآس ثیـشش ثشای دشفـبس
خلز بی خة دشدشا ث هذ آسیشی ثد سا داسد. ثالوشی اػز و 1-شسا ثشب
59
ثشب ثالوش اػز خبكیز آشی اوؼیذای یض داسد. اشص ث دجب Ca channel blockerوبسدی آفب ثالوش،
خبیضیی ای داس ثب ثمی ؼشذ.
Calcium Channel Blockers• Myocardial & vascular effects
Diltiazem, Verapamil
• Perdominant vascular effects
Nifedipine, Nimodipine, Amlodipine
• Selective vascular effects
Cinnarizine
ب ؼشذ. دیشیبص Ca channel blockerسا و ی وذ، demandسا صیبد supplyدػش دیش داسب و
سادبی ثیـشش سی لت ػشق ؤثش ؼشذ. یفذیذی، یدیذی آدیذی اخشلبسا سی ػشق ؤثش ؼشذ
ػیبسیضی اشخبثی سی ػشق اثش ی زاسد.
60
ثبالیی داسد first pass effectثبس اػشفبد ی ؿد. حشب ثبیذ ثب غزا لشف ؿد چ 3سب 2سادبی سصی
یی ش(. اص سشی ػاسم آ ثشادی وبسدی، وبؾ فـبس خ 5یی ش اػز ی آذؾ 40)لشكؾ
ػز اػز.یج
61
یفذیذی، دی یذسدشیذیی اػز و ثیـشش سی ػشق ؤثش اػز ـبدی ػشلؾ ثبػث ػشدسد سپذؾ لپت پی
ثپب یپه ؿد. ث پی دیپ فشپ پی ؿپد وپ حشپب MIؿد. ای سذؾ لت ى اػز حشی دش ث آظی
ثشبثالوش یب سادبی خسد ؿد. وؼبی و ثب خسد یششار ػشدسد ی یشپذ سشخیحپب اص یفپذیذی اػپشفبد ىپذ
آؼش سؾ وشش دیذ ی ؿد. عچ ػشدسدؿب خیی سـذیذ ی ؿد. ػاسم ثب
62
دشیذیی اػز و ؼال سصی یه ثبس خاة ی دذ ػاسهؾ اص ( سد خذیذ دی یذسnorvascآدیذی )
یفذیذی وشش اػز.
Side effects of CCB
Nifedipine Diltiazem Verapamil
Angina(MI) Bradycardia Bradycardia
Dyspnea Rash Constipation
Flushing Hypotension Hypotension
Headache
Hypotension
Palpitation
Edema
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New treatment
Ranolazine
• Does not have any appreciable effects on :
• Arterial resistance vessels,
• inotropic state of the myocardium,
• coronary blood flow.
• BP or HR ,
• myocardial oxygen supply or demand
• Inhibition of : fatty acid oxidation
late sodium current (Ina)
calcium overload during ischemia,
• Trimetazidine-Perhexiline
درهاى ای جذیذ آژیي
Ranolazine سی ػشق، فـبس خ، هشثب لت، ث سبصی اسد ثبصاس داسیی وـس ؿذ اػز. اثشیdemand
supply ذاسد. ای داس ثؼذ اص ایؼىی و ػ ب خشاة ی ؿذ اثش داسد. بس اوؼیذاػی اػیذ چشة سا ادب
ی دذ. لت وض لشف ی وذ چشثی و ثشای اػشفبد اص چشثی اوؼیظ ثیـششی الص داسد. دس
ساالصی، لت اص اػیذبی چشة ث ػز لشف وض ؿیفز دیذا ی وذ دسشید ـىالر ػ ایؼىی ثب داد
ca over loadػذی داخ ػ over loadوشش ی ؿد. اص شف دیش وبب بی ػذی ػشیغ سا ی ثذد
حی ایؼىی ca over loadو ی ؿد ـىالر دس ػی وبؾ ی یبثذ. دغ اص سشی اثشاسؾ وبؾ
یض خد داسد. trimetazidine perhexilineشي ػی ی ثبؿذ. اص ای سد
64
ACEI & ARB
• Anti ischemic effect
• Anti inflammatory
• Inhibition of rupture of
atherosclerotic plaque
Improvement of endothelial function
ب اثشار هذایؼىی هذ اشبثی داسذ حشی خی دبس ؿذ دالن بی ARBب ACEIاشص فش ی ؿد
ی ـیذ سا ی یشد. ث ی دی ى اػز دس ؼخ ثیبس آظی و فـبس ثبال آسشاػىشص و خش سی آ
ذاسد وبدشدشی یب صاسسب دیذ ؿد.
• Endothelin receptor blockers
• Ivabradine (inhib. SA node current)
• Testosterone
• Stem cell therapy
• Therapeutic angiogenesis
Endothelin receptor blockers ،Ivabradine ،testosterone ،stem cell therapy therapeutic
angiogenesis ؼشذ.یض شح
65
Variant AnginaClinical presentation:• Vasospasm
• At rest• Often in the morning
• ECG (ST elevation)
• Rapid & complete occlusion of the coroner
• Transient arrhythmias
• No hemodynamic factors alters
Variant angina یب آظی خاب، آظیی اػز و ثیـشش اصاػذبػ دس آ دخی اػز سب آسشاػىشص. خای
دبی ؿذیذ لفؼ ثذ فـبس چشثی خ ثبال دس حبی و دس آظیشافی ا چیضی ـبذ ی ؿد یىذفؼ دس
STیه ECGػی ث خلف ب كجح دیذا ی وذ. حشی دس حبز اػششاحز ى اػز دیذ ؿد. دس
elevation دیذ ی ؿد یهT invert سي ى اػز یىذفؼ ػشیغ ثؼش ؿد فشد آسیشی بیی داؿش .
ثبؿذ.
66
Variant Angina• Ergonovin stimolation test
• management:CCB, Nitrates, ASA
Beta blockers?
اػز و اسد سي ؿذ اسی سضسیك ی ؿد، ergonovin stimulation testسؽ سـخیلی ای آظی
سحشیه سػذشسبی آفب ػشسی ثبػث س ؿذ یه دفؼ سي ؿذ ػالئ ؿجی آظی ی دذ. ػذغ ػشیؼب
.یششیؼشی سیذی ی دذ ػالئ وشش ی ؿد
، یششار ب هذ دالوز ب )سب سشجصی دس آ CCBsظی داسبی ـبد وذ سي ی ثبؿذ، دسب بی ای آ
و 2-ثالوشب اػشفبد ی ؿذ چ فش ی ؿد سی ثشب 1-حظ اهبف ـد(. اب ثشبثالوشب ث خلف ثشب
شق سا ثیـشش ی وذ.ـبدی ػشق ی دذ ی ـیذ )حشی آس( سی ػ
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Silent Myocardial Ischemia
• Asymptomatic post infarction patients
• In patients with angina
• Totally asymptomatic person(Diabetics)
Diagnosis
Holter Monitoring
ETT
• Management:• Beta blockers,CCB, Nitrats, ASA
د ع آظی دیش خد داسد:
Silent myocardial ischemia خیی خشبن اػز، فشد اكال احؼبع دسد ی وذ ی ػ بی لجی شسجب :
دیبثشیه ى اػز ث خد آیذ. یب فاك ثی آظی ب یب دس افشاد infarctionسخشیت ی ؿذ. ثؼذ اص
، یششار ب CCBی ثبؿذ. دسب آ بذ ثمی ؿب ثشب ثالوشب، holter monitoring ETTسـخیق آ
هذدالوز بػز.
Angina: Syndrome X
Typical, exertional angina with positive exercise stress test
Anatomically normal coronary arteries
Reduced capacity of vasodilation in microvasculature
Long term prognosis very good
Calcium channel blockers and beta blockers effective
X Syndromeدس ای افشاد : افشادی و دسد لجی داسذ ی دس آظیشافی یچ سي شفش ای دیذ ی ؿد .micro
vascular ػشق سیض داخ ػو لت( دخی اػز. ای حبز خیی خشبن یؼز چ سي بی اكی خ سػب(
ب ثشب ثالوشب دس ای افشاد اذیىبػی داسد.CCBدسیش یؼشذ.
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Unstable Angina
• Increase in severity,duration of chest pain
• ST depression at rest or with pain
• continuing pain after recovery from MI
Management:(Nitrate,BB,CCB,ASA,Heparine)
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Unstable angina آظی بدبیذاس(: آظی دبیذاسی اػز و ى اػز یه دفؼ خش ای ایدبد ؿد یب دالن ثششوذ(
ؿذ. اش ای stableؼیش ثؼش ؿد. فشد دس ش حبشی دسد داسد. ای افشاد ثبیذ دس ثیبسػشب ثؼششی ؿذ سب
اػز. دس ای اسد اسد سي ی ؿذ PTCAی سد. دسب ب ثب صد MIآظی دسب ـد ثیبس ث ػز
ثب ثب ی فـبسذ سب سي ثبص ؿد ی اش ث ب سؽ ؼی ادا داد ؿد دثبس سي س ی ؿد ث
زاسی ـىالسی داسد ى اػز ػ stent ثؼش ـد. اجش ی زاسذ سب دثبس stentی دی دسؼیش
اػشفبد وذ. plavixادب ی دذ لج ثؼذ اص آ ثبیذ آػذشی PTCAب سی آ سا ثیشذ. دغ وؼبی و
Stenting
ASA + Ibuprofen ?
ی اػز و آػذشی یچ ب جبیذ ثب ثشف خسد ؿد. چشا و ثشف ث خبیی و لشاس ىش ای و الص فش ؿد ا
اػز آػذشی ثچؼجذ شل ی ؿد آػذشی ثذ اثش زاؿش دفغ ی ؿد. اجش دس ای دػش، فبیه اػیذ
2 خسد ؿد یب ایى ثشفػبػز ثؼذ اص ثشف ثبیذ 8اكال اثش هذدالوشی ذاسد. دغ ثشای اثش هذ دسدی آػذشی
ػبػز ثؼذ اص آػذشی لشف ؿد.
70
ثب اذشاص لشف ؿد ث فش فؼبؾ سجذی ی ؿد اثش ذاسد. اب دشدشاص ساثذشاص ای Plavixاش
ـى سا ذاسذ.
CABG
ادب ؿد. سي بیی اص ػبفئیذ دب یب ؿشیب دؼشبی CABGدس بیز اش ثب ای ب خاة ذاد ثبیذ ثشای ثیبس
چخ یب ساػز شفش ی ؿد سي خذیذی ثشای ثیبس ایدبد ی ؿد.
71
سکت قلبی
هذرس:دکتر فریبرز فرساد
MYOCARDIAL INFARCTION
Fariborz Farsad Pharm D BCPS Rajaie Heart Center
4
ػب دیؾ دچبس اؼذاد ؿشیب لت غض 3500یه ت خبت: شخللب لت دیذ اذ و یه ؿبضاد لشی
ثد اػز.
72
50% Coronary Heart Disease1% Congenital Heart Defects
1% Rheumatic Fever/
Rheumatic Heart
Disease
4% Congestive Heart Failure
2% Atherosclerosis
4% High Blood Pressure
22% Other
Coronary Heart Disease: Despite Advances, Still the #1 Killer
Percentage Breakdown of Deaths From Cardiovascular Diseases
United States: 2001 Mortality, Final Data
16% Stroke
American Heart Association1998 Heart and Stroke Facts: Statistical Update
اكی شي ی ثبؿذ. یىی اص ػ coronary heart diseaseآبس دلیمی دس سد ایشا خد ذاسد اب اكال
Acute Coronary Syndromes
Acute Coronary Syndrome
No ST Elevation ST Elevation
Unstable Angina Myocardial Infarction
Non Q MI Q wave MI
Non ST Elevation MI
Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.
بیذ ی ؿد و داسای د acute coronary syndromeاشص ای ؼب ث ػا یه ػذس شح اػز
ی ثبؿذ. STEMI non-STEMIؤف ی
73
Myocardial infarction
Most often due to a ruptured coronary plaque and later
platelet aggregation/thrombosis leading to an interruption
in blood flow and oxygen supply.
Critical condition requiring urgent need for aggressive
medical management.
Unstable Angina – Also part of the clinical spectrum of
acute coronary syndrome
ثبؿذ. ای سشجص و ث ػا یه خش سمی ی ؿد یه سشجص ؿىبف سشجص ی MIش سدیف ا دس ثحث
اػز و ػشق وشش سا ؼذد ی وذ ثب اؼذادؽ ثبػث لف ی ؿد. ای ب لف ruptureخسد دچبس
.ای اػز و ث آ ػىش ی لجی یذ
Myocardial Infarction
The prevalence of MI in the U.S. in 2002 was 7.6 million.1
The prevalence, although currently higher in men than women, increased 30% in women from 1989 to 1996.
Death rates were also higher among young African Americans.
Myocardial infarctions are identified in as many as 50-75% of sudden cardiac arrest victims.2,3,4
Within 6 years of a recognized heart attack, 7% of men and 6% of women will experience sudden death.1
1 American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex.: American Heart Association; 2002.2 Myerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6th ed.
Philadelphia: WB Saunders Co; 1997:chapter 24. 3 Lombardi G. JAMA. 1994;271:678-683.4 Bigger JT. Circulation. 1984;69:250-258.
endبی افششالی خد داسد شي ببی )ایؼز لجی( ػىش لجی ی ثبؿذو ثحث ػذ ای و دس سـخیق
product شدی آ ب شي ی ثبؿذ. ایؼز لجی یه اخشال اىششفیضیطیه ی ثبؿذ و سیش بی احشوبس سا
داسد. اب ػىش لجی یه اخشال ىبیىی اػز و ثب سشجص ثبػث شي افشاد ی ؿد.
74
ی ثبؿذ؛ ث ای ؼب و ی ثبیؼز دس اػشع لز ث شین golden timeآ چ دس ػىش ی لجی ایز داسد
دس ػىش لجی یه ػبػز ا ی ثبؿذ ث سذسیح ثب افضایؾ صب، شي Golden timeسػیذی ؿد سب دبر یبثذ.
یش افضایؾ ی یبثذ.
PATHOPHYSIOLOGY
Atheroma (plaque) rupture &
thrombosis
rupture of an unstable, lipid-rich atheromatous
plaque in epicardial artery; activating platelet
adhesion, fibrin clot formation and coronary
thrombosis
SpasmSecondary to emotinal stress & drug abuse
ػیش سـىی آسش دالن بی آسشاػىشص و بؿی اص بیذشیذیذی اػز ػیش شظش ای داسد دس د ی دد
دغ ؿـ صذی افشاد ث خد ی آیذ اب افشادی خد داسذ و دس ػی دبیی سش ثب ای ـى اخ ی ؿذ.
سشجص، ثحث اػذبػ )ثبی ث اػششع بی ػبفی ػء لشف اد( ثش دبسی دس اسیطی آ ػال
شح اػز.
75
Plaque Formation and Morphology
Smoking, high BP, toxins etc cause damage to the vascular endothelium.
LDL and fibrin pass through and collect in the sub-endothelium.
Monocytes adhere to the damaged endothelium, migrate to the sub-endothelial space and engulf LDL – FOAM CELLS.
SMC migration and CT formation.
Two main types of plaque:
Atheromatous (athere: gruel, oma: tumour)
Fibrous (like atheroma but with connective tissue cap)
FoamCells
FattyStreak
IntermediateLesion
Atheroma FibrousPlaque
ComplicatedLesion/Rupture
From FirstDecade
From ThirdDecade
From FourthDecade
Endothelial Dysfunction
Atherosclerosis Timeline
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).
76
یشد ث خلف دس افشادی و ػبثم فبیی داسذ ػ افشاد دس ای دس ثشخی افشاد ای ػیش ػشیغ سش كسر ی
فر وشد ثبؿذ دس ؼ ثؼذ acute coronary eventػبی ثش اثش 60اش ایز ثؼیبسی داسد. اش دذسی دس
آ ػب صدسش ای اسفبق ثیفشذ. اش دذس بدس فشدی ش د دچبس ـى لجی ثبؿذ ثب 15اشظبس ی سد و
ث سذسیح سدغ داؼیش ی چشثی یه دالن، آسشاػىشص سا دس خذاس ػشق ثیـششی اشظبس ای ـى دس ا ی سد.
ایدبد ی وذ. سب صبی و فشد فؼبیز ذاسد خشی ا سا سذیذ ی وذ اب اش ای فؼبیز دس حص ی لت ادب
دس خذاس ظبش ی ؿد دبسیی ؿد یؼی unstableسج ؿذ خب stabilityؿد دالن آسشاػىشص اص حبز
هبیؼ ی سشجسیه سی آ ػاس ی ؿد. لشی هبیؼ ثیؾ اص د ػ ػشق وشش سا شفز حبدث ی اكی
اسفبق ی افشذ.
داذ. آ چ و ی acute coronary eventدس حب حبهش ػال ثش بیذش یذیذی، اشبة سا یض خضء اسیطی
ی ؿد ػیز ب fatty streakثبػث بدبیذاس ؿذ دالن خغ ؿذ اوؼیذ ؿذ یذیذ ث خد آذ
77
ػ بی اشبثی ؼشذ و ث سذسیح ثب سشفی ب دس خذاس ػشق ـؼز ی وذ. حشی ث اػ ی اشبة یه
ی لشاس ثیشذػ اص ثیبسا ی ساذ سحز داسدسب
NEJM 1/14/99: Atherosclerosis: An Inflammatory Disease
Inflammation & MI Pathophysiology
Atherosclerosis Timeline
Phase I: InitiationLDL-C plays a major role in initiating the development of atherosclerotic plaque.
Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co;
2001:995-1009;
Libby P. J Intern Med. 2000;247:349-358.
Media
Intima
Phase II: ProgressionDisease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly.
LDL-C
Phase III: ComplicationExtensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.
Lumen Unstable
Stable
S2
78
Coronary Artery Anatomy
Left Main CA
Circumflex
Left Anterior Descending CA
Right CA
Marginal Branch
LAD supplies: Anterior and anterolateral LV, 2/3
septum, medial anterior RV, lower 1/3 posterior
RV
Circumflex supplies: Posterolateral LV,
sometimes inferior LV, may also supply posterior
left bundle and A-V node.
RCA supplies: Anterior RV, upper ½ (basal)
posterior wall, posterior 1/3 septum, posterior left
bundle, inferior LV, usually AV and proximal HIS
bundle via AV nodal branch.
SA node? RCA 55%, LCA
45%, dual 10%
AMI Localization
Anterior: V3, V4
Septal: V1, V2
Inferior: II, III, AVF
Lateral: I, AVL, V5, V6
I
II
III
aVR
aVL
aVF
V1
V2
V3
V4
V5
V6
چ كسر اػز. ث MIثؼش ث ای و دس ػ سي وشش ح لع سشجص ودب ثبؿذ ـخق ی وذ و دیـبذ
.ثبؿذیب ثب لت lateralی ساذ دس لذا، خف،
79
Acute MI - Risk Stratification
The GUSTO Pyramid - 30 Day Mortality Model
Age (31%)
Systolic Blood Pressure (24%)
Killip Class (15%)
Heart Rate (12%)
MI Location (6%) Prior MI (3%)
Age x Killip (1.3%) Height (1.1%)
Diabetes (1%) Time-to-Rx (1%)
Smoker (0.8%) Weight (0.8%)
Accel t-PA (0.8%)
Prior CABG (0.8%)
HTN (0.6%)
HXCV Disease
(0.4%)
Lee et al. Circulation 1995;91:1659-1668
Major Risk Factors for Heart Disease
Modifiable Nonmodifiable Emerging Risk Markers
High blood pressure Family history Homocysteine
Abnormal cholesterol levels Age Elevated lipoprotein (a) levels
Diabetes Gender Clotting factors
Cigarette smoking Markers of inflammation (CRP)
Obesity
Physical inactivity
Grundy SM, et al. Circulation. 1998; Grundy SM. Circulation. 1999
Braunwald E. N Engl J Med. 1997; Grundy SM, et al. J Am Coll Cardiol. 1999
فـبس سا ثبػث ی ؿذ. ثؼوی اص آ ب ث وشش mortalityسیؼه فبوشسبیی خد داسد و ش وذا یضای اص
خ، دیبثز، سشن ػیبس، وبؾ ص افضایؾ فؼبیز ی ساذ سحز اكالح لشاس ثیشذ اب ثؼوی دیش ث زوش
ثد ػبثم خبادی غیش لبث سغییشذ. ؼئ ای و اشص دس غشثبشی ثیبسا شح اػز بسوشبی خذیذ ی
clotting factor ،homocysteineشح یؼز( دس وبس فمي ثشای سبسئیذ آسسشیز CRPثبؿذ. اشبة )
ثبؿذ. اجش ثبیذ سخ داؿز و یه فبوشس acute coronary eventیذدشسئی ب ی ساذ ـب دذ ی ثشص
ث سبیی الن لشاس شفش ی ؿد.
80
Diet
Central obesity .چبلی خشبن ی ثبؿذ. دس آلبیب چبلی ث ؿى ػیت دس خب ب ث ؿى الثی ی ثبؿذ
غزابی ثؼیبس چشة سیؼه بساحشی ثبالیی داسذ دغ اكالح سطی غزایی ایز داسد.
81
Metabolic Syndrome
Group of abnormal physical findings related to the body’s metabolism – closely linked to insulin resistance
Excessive body fat – especially abdominal
Elevated triglycerides
Elevated blood pressure
Elevated fasting glucose
Low HDL cholesterol level
ثحث لذ خ HDL، وبؾ LDLضایؾ سشی یؼشیذ، افضایؾ ػذس شبثیه ثب دػ ای اص بسوشب اص خ اف
شا اػز
Cardiac Angiography
82
MSCT
83
اص ظش ایؼىی ـب ی دذ. لشی ثیبس سا شح اػز و ثب لت سا CT angioدسغشثبشی بی خذیذ ثحث
دس یه حص غبیؼی لشاس ی دی مغ ث مغ ػىغ ی یشد دس بیز دع آ سا ـب ی دذ و
یضا ای 0-200سا ـب ی دذ و ی ساذ دیؾ آی ثشص بساحشی لجی ثبؿذ. اص ca storingاص شش
شا وذ خشبن اػز. 400ثبال اػز ثبالی 200-400ص سیؼه و اػز، ا
Myocardial Infarction Clinical presentation
Diagnosis of Acute MI
History
• Classic symptoms: intense, oppressive chest
pressure radiating to left arm
• Other symptoms:
chest heaviness, burning
radiation to jaw, neck, shoulder, back, arms
nausea, vomiting
diaphoresis
dyspnea
lightheadedness
• Symptoms may be mild or subtle
84
MIعالهت ضاسی
-late nightب دس MIؿب ػالز آ دسد ی ثبؿذ ث ی دی دش ػش كذا اػز )داؿش دسد خة اػز(. اوثش
early morning اسفبق ی افشذ. دسد لجی دسدpost sternum اػز فـبسذ، و ی ساذradial ثبؿذ ث ػز
دػز چخ دـز. بی البر دسد ث كسر ػصؽ )ثیـشش دس خب ب( اػز.
ـؼش اػز. شین آظی دس حبی ی آ سا شین سب ث حب سدشث ىشد، اكالحب ابس فیی سی ػی
وشد ی ساذ دس یه خب ثـیذ ث خد ی دیچذ. MIو دسد داسد دس یه م ـؼش اػز اب شیوی و
شیوی و چی دسدی داسد ثبیذ ثی حشوز ثبذ.
اهشاة ثیبسای و دچبس دسد ی ؿذ ث سدبسی بؿی اص دیبثز یه ػشی ػالئ ػی ث ػشق
ثد داسذ و ى اػز سـخیق اؿشجب داد ؿد. ثیبس آظی ای اهشاة سا ذاسد.حب احؼبع ثذ
perforativeی ساذ شا سع ثبؿذ و ـب دذ ی اشـبس دسد ث بك دیش لت اػز ی ساذ حبز
ادیىبسدی، افز یب افضایؾ فـبس خ غیشاخشلبكی اػز. داؿش ثبؿذ. ػالئ دیش ث افضایؾ هشثب لت یب ثش
سغییش ىب سغییشی دس ؿذر دسد ایدبد ی وذ اب دس آظی ثبػث سغییش ی ؿد. MIدس
85
Gold Standard: chest pain
Quality - "squeezing," "griplike," "pressurelike," "suffocating" and "heavy”; or
a "discomfort" but not "pain." Angina is almost never sharp or stabbing, and
usually does not change with position or respiration.
Duration - anginal episode is typically minutes in duration. Fleeting discomfort
or a dull ache lasting for hours is rarely angina
Location - usually substernal, but radiation to the neck, jaw, epigastrium, or
arms is not uncommon. Pain above the mandible, below the epigastrium, or
localized to a small area over the left lateral chest wall is rarely anginal.
Provocation - angina is generally precipitated by exertion or emotional stress and
commonly relieved by rest. Sublingual nitroglycerin also relieves angina, usually
within 30 seconds to several minutes.
Diagnosis of Acute MI
Physical Examination
• Tachycardia or bradycardia
• Extrasystoles
• S3 or S4, mitral regurgitation murmur
• Lung rales
• Hypertension or hypotension
• Pallor, distress
Myocardial Infarction - Gross
86
ؿذ اػز ػ م دیذ ی ؿد: acute coronary eventدس ػو ی یوبسدی و دچبس
-Qیه لؼز شد اذ ث اكالح ىشسیه ؿذ اذ. سظبش اىششیىی آ دبسطیه اػز و سحز ػا .1
wave .ؿبخش ی ؿد
خي ایضاىششیه ثبالسش لشاس شفش ؿذ اػز. ج آ ؼجز ث damage injuryم ی دیش دچبس .2
ؿبخش ی ؿد. ST-elevationاػز ث ػا
م ی آخش ایؼىیه اػز و ػ بیؾ بیذوؼیه ؼشذ اوؼیظ ث آ ب ی سػذ. .3
سـخیق داد ؿد دسب آ ثؼیبس ساحز اػز ی MIای ػ سظبش دس اىششوبسدیشا ثبیذ دیذ ؿد. اش
دلیم یه اىششوبسدیشا ثشای ثیبس زاؿش ؿد. 5خیق آ دؿاس ی ثبؿذ ث ی دی فش ی ؿد ش سـ
87
Cardiac Markers
Enzymes Elevation
-- TROP
88
0 1 2 3 4 5 6 7 8
Cardiac troponin-no reperfusion
Days After Onset of STEMI
Mu
ltip
les o
f th
e U
RL
Upper reference limit1
2
5
10
20
50
URL = 99th %tile of
Reference Control Group
100
Cardiac troponin-reperfusion
CKMB-no reperfusion
CKMB-reperfusion
Cardiac Biomarkers in STEMI
Alpert et al. J Am Coll Cardiol 2000;36:959.
Wu et al. Clin Chem 1999;45:1104.
Cardiac Markers
Myoglobin
Nonspecific
Rapid-release kinetics
Useful for its negative
predictive accuracy in
the early hours after
symptom onset
Useful marker for
reperfusion
Inflammatory Markers
indicate plaque or
systemic
inflammation
associated with ACS
CRP identifies
patients with unstable
angina at high risk for
adverse cardiac
events
Cardiac Markers
CK-MB Isoforms
Improved sensitivity
compared with CK-
MB
Only one form in the
myocardium
CK-MB2 > 1U/L or
CK-MB2/CK-MB1 >
1.5
Troponins
Troponin I/Troponin T
Increased sensitivity
compared with CK-MB
Detect minimal
myocardial damage
Useful in risk
stratification
Biphasic release kinetics
89
لشی ػ دچبس ىشص ی ؿد ادی داخ خ آصاد ی شدد. ث دجب بسوشی ؼشی و فمي دس لت ه
MI فمي دس ظبش ؿد. بسوشی و صدسش ظبش ی ؿد یثی اػز ی غیش اخشلبكی ی ثبؿذ. سشدی
MI ثبال ی سد. اشص سشدی ث د كسر ویفی وی اذاص شفش ی ؿد. ثشای اذاص یشی ویفی دس ثبی
. ثش ای اػبع س اسفبق ثیفشذ ـذاس دذ اػزشین لش ی خی اص ا سی ویشی لشاس ی یشد لشی سغییش
ثبیذ ثیبسوشب ثبؿذ. MIؿد. یىی اص صایبی ـخق سؼشیف خذیذی اص افبسوشع یوبسد داد ی
No
release Tn release
Acute Coronary Syndromes
Non Q MIUA Q wave MI
CK release
UA STEMINSTEMI
Acute Coronary Syndromes
Platelet rich
Thrombin rich
Pain
ST elevation
CK riseSTEMI
NSTEMIPain
No ST elevation
CK rise or Tn rise
Pain
No ST elevation
No CK rise
No Tn rise
UA
90
ST Segment Elevation (Infarction)
ST Elevation MI ،non ST Elevation MIث ػ ؿى ی ساذ ظبش ؿد. acute coronary eventدغ
unstable angina اص اسد اسطاغ ی ثبؿذ. دس سب ای اسد دسد خد داسد ی خ سبیض آ ب و ST
elevation دسSTEMI اػز دس حبی و دس د ع دیش ای افضایؾ دیذا ی وذ چی سشدی دسSTEMI
ؿبذ افضایؾ آ یؼشی. unstable anginaافضایؾ ی یبثذ ی دس
، non STEMI unstable anginaثحث ػذ سشجص اػز دس حبی و دس STEMIطیه دس اص ظش اسی
platelet flow شح اػز.
یص گیری:پ
Primary prevention secondary prevention داسد خد دیـیشی ع د
91
دس. داسد خد فبوشس سیؼه ی اػز یفشبد اسفبق acute coronary event ص primary prevention دس
secondary prevention، MI ؿد ی دیـیشی آ دذد لع اص اػز افشبد اسفبق.
.ثبؿذ ی غزایی سطی داسیی غیش بی دسب اص یىی
Poly unsaturated and mono unsaturated fat (PUFA & MUFA) ثبیذ سصا وبشی اص% 20 و داسذ خد
MUFA چی ثبؿذ داؿش وششی saturated fat و اػز سغی چشثی، سشی بػت. ؿد سأی MUFA اص
.اػز ثششی Canola oil اػبع ای ثش. ثبؿذ ثیـشش اص آ
92
ثی داسد اثش هذ اشبanti-inflammatory 3-اب ،9 6 3 اببی یب اص. ثبؿذ ی omega 3 دیش ثحث
شین ثشای دغ pro-aggretory اػز pro-inflammatory 6 اب و حبی دس اثش هذ سدغ دالوشی ،
شین دس دغ داسد LDL سی خشة شاث ای ثش ػال omega3ثبیذ سخ داؿز و اػز بػت3 اب فمي لجی
ی ثبیذ اػشفبد ؿد و فمي یذش سشی یؼشیذی داؿش ثبؿذ.بی
FDA سا ب ى ؼال regulate سشویت ب 3-اب اص اب. وذ ی omacor وشد ؼشفی داس ؿج ػا ث سا
ی لشاس اػشفبد سدثشای وبؾ سشی یؼشیذ سص دس ثبس چبس سب ػ و 3-اب طالسیی بی وذؼ. اػز
.یشذ
93
وبسثشد ای دیـیشی ثشای و ب آ اص سب د. ؼشذ ب اػشبسی یشذ ی لشاس اػشفبد سد و دیش سشویجبر اص
وبؾ سا LDL %60-%70 ثشاذ داسیی اش. اػز ؿذ اهبف rosuvastatin اآل ثد simvastatin لجال داسذ
.دذ ی وبؾ %69 سا Rosuvastatine 40 mg ،LDL ؿد ی حؼة الیی داسی دذ
UAیب nonSTEMI دیشی STEMIخد داسد. یىی acute coronary eventوال د ع
ی ؿذ. اخشالف ثش ػش سشجسیه recurrent MI ای دچبس وشد فر ی وذ ی ػذ MIػذ ای ث حن
platelet rich ثد عacute coronary event خد داسد. یه اخشال سشجسیه یه اؼذاداػز. دس ایدب
ثبؿذ. primary indicationی ساذ PCIداسی الیی، سشجیشیه اػز. سؽ الیی یؼز چ STEMIدس
آشی سشجسیه ب ؼشذ. anti-plateletداسی الیی non STEMI UAی دس
94
Paradigm of Reperfusion Rx for Acute MI
Acute Coronary Occlusion
Myocardial Necrosis
LV Dysfunction
Death
Thrombolysis
Primary PCI
Recurrentinfarction
Antithrombotic
Therapy
Braunwald, E. Circulation 1989;79:441-4.
Class I
Benefit >>> Risk
Procedure/ Treatment SHOULD be performed/ administered
Class IIa
Benefit >> Risk
Additional studies with focused
objectives needed
IT IS REASONABLE to perform
procedure/administer treatment
Class IIb
Benefit ≥ Risk
Additional studies with broad objectives
needed; Additional registry data would
be helpful
Procedure/Treatment
MAY BE CONSIDERED
Class III
Risk ≥ Benefit
No additional studies needed
Procedure/Treatment SHOULD
NOT be performed/administered SINCE
IT IS NOT HELPFUL AND MAY BE
HARMFUL
should
is recommended
is indicated
is useful/effective/ beneficial
is reasonable
can be useful/effective/ beneficial
is probably recommended or indicated
may/might be considered
may/might be reasonable
usefulness/effectiveness is unknown
/unclear/uncertain or not well established
is not recommended
is not indicated
should not
is not useful/effective/beneficial
may be harmful
Applying Classification of ACC/AHA Guideline
Recommendations
Fibrinolysis is generally preferred
Early presentation (≤ 3h from symptom onset and delay to invasive strategy)
Invasive strategy not an option (cath lab not available, no vasc access, lack of skilled PCI lab)
Delay to invasive strategy (door-to-balloon) — (door-to-needle) > 1 hr; med contact to balloon >90)
Invasive strategy generally preferred
Skilled PCI lab available with surgical backup
(med contact to balloon < 90 min)
High risk from STEMI (cardiogenic shock,
Killip class ≥3)
Contraindication to lysis (including increased
bleeding/ICH risk)
Late presentation (>3 hrs)
Diagnosis in doubt
2007 ACC/AHA guideline considerations
Antman et al. ACC/AHA 2004 STEMI Guidelines: JACC 44: 671,2004. Circulation 110: 588,2004
95
ACC/AHA 2007 STEMI Focused Update: Acute Medical Therapy
General treatment
measures
Aspirin, nitrates, oxygen, analgesics (morphine)
Infarct size limitation β-blockers (not for acute use in patients
with evidence of heart failure)
Reperfusion Thrombolysis (goal < 30 min) or primary PCI (goal < 90
min)
Anticoagulant and antiplatelet therapy
UFH or enoxaparin or fondaparinux
Clopidogrel 75 mg/d added to aspirin for patients undergoing fibrinolysis; 300 mg loading dose for patients <75 y
If PCI: clopidogrel, GP IIb/IIIa inhibitors
Antman E, et al. J Am Coll Cardiol 2007:. doi:10.1016/j.jacc
2007 UA/NSTEMI Guidelines
Risk Stratification
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
Initial Evaluation - Risk Stratification
12-lead ECG within 10 min for all patients with chest pain or
symptoms suggestive of ACS
Early risk stratification by symptoms, physical findings,
ECG, cardiac markers
Cardiac markers, Troponins and CK-MB, for initial
assessment
Use of risk stratification models (TIMI, PURSUIT, GRACE)
can be useful to assist in decision making for treatment
options
I IIa IIb III
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
96
Risk Scores
TIMI GRACE Future
His
tory
AgeHypertensionDiabetesSmoking↑cholesterolFamily historyHistory of CAD
Age Continuous assessment
Pre
se
nta
tion
Severe anginaAspirin within 7 daysElevated markersST segment deviation
Heart rateSystolic BPElevated markersHeart failureCardiac arrestElevated markersST segment deviation
New markers
Electronic health records
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
TIMI Risk Score For UA/NSTEMI7 Independent Predictors
1. Age > 65 years
2. > 3 CAD Risk Factors
( chol, FHx, HTN, DM, cigs)
3. Prior CAD (cath stenosis >50%)
4. ASA in last 7 days
5. > 2 Anginal events < 24 hours
6. ST deviation
7. Elevated Cardiac Markers
(CK-MB or Troponin)Number of Predictors
0
5
10
15
20
25
30
35
40
45
0/1 2 3 4 5 6/7
% D
ea
th / M
I / R
eva
sc
Antman et al JAMA 2000;284: 835. www.timi.org
Early invasive strategy (angiography within 24-48 hrs) for
stabilized patients with an increased risk for clinical
events (See list)
Early invasive strategy for patients with refractory angina,
hemodynamic instability, or electrical instability
Early invasive strategy not recommended for patients with
extensive co-morbidities or those who don’t consent to
revascularization
I IIa IIb III
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
Select a Strategy: INV vs. CONS
97
Algorithm for Patients
with UA/NSTEMI Managed by
an Initial Invasive Strategy
Proceed to Diagnostic Angiography
ASA (Class I, LOE: A)
Clopidogrel if ASA intolerant (Class I, LOE:
A)
Diagnosis of UA/NSTEMI is Likely or Definite
Invasive Strategy
Initiate A/C Rx (Class I, LOE: A)
Acceptable options: enoxaparin or UFH (Class I, LOE: A)
bivalirudin or fondaparinux (Class I, LOE: B)
Select Management StrategyProceed with an
Initial Conservative
Strategy
A
B
B1
B2
Prior to Angiography
Initiate at least one (Class I, LOE: A) or
both (Class IIa, LOE: B) of the following:
Clopidogrel
IV GP IIb/IIIa inhibitor
Factors favoring admin of both clopidogrel and
GP IIb/IIIa inhibitor include:
Delay to Angiography
High Risk Features
Early recurrent ischemic discomfort
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
14.5
24.2
16.914.8
0
5
10
15
20
25
30
TnT - TnT +
(%)
CONS INV
Death, MI, Rehosp ACS at 6 Months
p=NS
*
Morrow DA. JAMA 2001;286:2405-2412; Cannon CP. N Engl J Med. 2001;344:1879-87.
15.3
26.3
15.6 16.4
0
5
10
15
20
25
30
No ST chg ST chg
p=NS
*
Benefit of Invasive Strategy by Troponin and ST Δ’s
P<0.001 P<0.001
Early Invasive Strategy – Acute Medications
Immediate aspirin
Upstream treatment with clopidogrel or a
GP IIb-IIIa inhibitor before angiography*
Unfractionated / LMW heparin
Bivalirudin / Fondaparinux
Omit upstream GP IIb-IIIa, if bivalirudin used and
clopidogrel load 6 hrs before cath
Upstream treatment with both clopidogrel and GP IIb-IIIa
inhibitor before angiography*
I IIa IIb III
* Class IB: Hold clopidogrel for 5-7 days if CABG is planned
98
Algorithm for
Patients with
UA/NSTEMI
Managed by an
Initial Invasive
Strategy
Proceed to Diagnostic Angiography
ASA (Class I, LOE: A)
Clopidogrel if ASA intolerant (Class I, LOE: A)
Diagnosis of UA/NSTEMI is Likely or Definite
Invasive Strategy
Initiate A/C Rx (Class I, LOE: A)
Acceptable options: enoxaparin or UFH (Class I, LOE: A)
bivalirudin or fondaparinux (Class I, LOE: B)
Select Management StrategyProceed with an
Initial Conservative
Strategy
A
B
B1
B2
Prior to Angiography
Initiate at least one (Class I, LOE: A) or
both (Class IIa, LOE: B) of the following:
Clopidogrel
IV GP IIb/IIIa inhibitor
Factors favoring admin of both clopidogrel and GP
IIb/IIIa inhibitor include:
Delay to Angiography
High Risk Features
Early recurrent ischemic discomfort
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
Initiate clopidogrel (Class I, LOE: A)
Consider adding IV eptifibatide or tirofiban (Class IIb,
LOE: B)
Conservative Strategy
Initiate A/C Rx (Class I, LOE: A):
Acceptable options: enoxaparin or UFH (Class I, LOE: A) or
fondaparinux (Class I, LOE: B), but enoxaparin or
fondaparinux are preferable (Class IIA, LOE: B)
Select Management Strategy
ASA (Class I, LOE: A)
Clopidogrel if ASA intolerant (Class I, LOE: A)
Diagnosis of UA/NSTEMI is Likely or
Definite
Algorithm for Patients with UA/NSTEMI Managed by an
Initial Conservative Strategy
Proceed with
Invasive Strategy
(Continued) Anderson JL. J Am Coll Cardiol. 2007. In press. Figure 8
C2
C1
A
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
• Cont ASA (Class I, LOE: A)
• DC clopidogrel 5 to 7 d prior to
elective CABG (Class I, LOE: B)
• DC IV GP IIb/IIIa 4 h prior to CABG
(Class I, LOE: B)
• Cont UFH (Class I, LOE: B); DC
enoxaparin 12 to 24 h prior to CABG;
DC fondaparinux 24 h prior to CABG;
DC bivalirudin 3 h prior to CABG.
Dose with UFH per institutional
practice (Class I, LOE: B)
• Cont ASA (Class I, LOE A)
• LD of clopidogrel if not given pre
angio (Class I, LOE: A)
&
• IV GP IIb/IIIa if not started pre
angio (Class I, LOE: A)
• DC A/C Rx after PCI for
uncomplicated cases
(Class I, LOE: B)
• Cont ASA (Class I, LOE: A)
• LD of clopidogrel if not
given pre angio (Class I, LOE A)*
• DC IV GP IIb/IIIa after
at least 12 h if started pre angio (Class I,
LOE: B)
• Cont IV UFH for at least 48 h (Class I,
LOE: A) or enoxaparin or fondaparinux
for dur of hosp (LOE: A); either DC
bivalirudin or cont at a dose of 0.25
mg/kg/hr for up to h at physician‘s
discretion (Class I, LOE: B)
Antiplatelet
and A/C Rx at
physician’s
discretion
(Class I, LOE:
C)
No significant
obstructive
CAD on
angiography
CAD on angiography
Medical therapyPCICABG
Select Post Angiography Management Strategy
Dx Angiography
Management after Diagnostic Angiography in Patients with
UA/NSTEMI
Anderson JL. J Am Coll Cardiol. 2007. In press. Figure 9
F
Anderson JL. J Am Coll Cardiol 2007;50:e1-157
99
100
1st
24 h
During
Hosp
Hosp DC +
Long Term
Aspirin 162-325 mg
chewed
75-162
mg/d p.o.
75-162 mg/d
p.o.
Fibrinolytic tPA,TNK,
rPA, SK
UFH
60U/kg (4000)
12 U/kg/h (1000)
aPTT 1.5 - 2 x C
aPTT
1.5 - 2 x C
Beta-blocker Oral daily Oral daily Oral daily
Summary of Pharmacologic Rx: Ischemia
JACC 2004;44: 671
Circulation 2004;110: 588
1st
24 h
During Hosp Hosp DC +
Long Term
ACEI Anterior MI,
Pulm Cong., EF < 40 Oral
Daily
Oral
Daily
IndefinitelyARB ACEI intol.,
HF, EF < 40
Aldo
Blocker
No renal dysf,
K+ < 5.0 mEq/L
On ACEI,
HF or DM
Same as
during Hosp.
Statin Start w/o lipid
profile
Indefinitely,
LDL << 100
Summary of Pharmacologic Rx: LVD, Sec. Prev.,
JACC 2004;44:671
Circ 2004;110:588
ER Patient Care
Initial assessment (< 10 min)
Measure vital signs
Measure SpO2
Obtain IV access
Obtain 12-lead ECG
Perform brief, targeted
history and PE)
Obtain initial cardiac
marker levels
Evaluate initial
electrolyte and
coagulation studies
Request, review
portable chest x-ray
(<30 min
101
ER patient care
Initial general treatment (memory aid: “MONA”
greets all patients
Morphine, 2-4 mg repeated q 5-10 min
Oxygen, 4 L/min; continue if SaO2 < 90%
NTG, SL or spray, followed by IV for persistent
or recurrent discomfort
Aspirin, 160 to 325 mg (chew and swallow)
MI خجش ی وذ فشد اص ثشص آ االػی ذاسد. ؤثشسشی داسی وه وذ دس ح لعMI آػذشی ،low
dose اػز. آػذشی ػ دص داسد، هذ دالوشی، هذ دسدی هذ اشبثی. آػذشی ثبیذ خیذ ؿد سب ػشیغ خزة
( سفی، اوؼیظ، یششار آػذشی دس كح ی دبساوییه MONAسا ثیشد. ) coronary eventؿد خی
ثیبسای و یه دفؼ اص دسد ث خد ی دیچذ ثبیذ دس ظش شفش ؿد.
What is the right dose of ASA?
Campbell, JAMA 2007
Suggested
Loading dose: 160-325 mg
Daily dose: 75-81 mg
102
ACC/AHA Guidelines for Aspirin Therapy
Aspirin should be given in a dose of 75-325
mg/day to all patients with ACS unless there
is a contraindication (in which case,
clopidogrel should be given)
ST elevation or new LBBB, time < 12 hr
Reperfusion strategy based on local resources
Thrombolytics (< 30 min)
TPA 15 mg bolus + 0.75 mg/Kg over 30
min + 0.5 mg/Kg over 60 min
or
SK 1.5 million IU over 1 h
Primary percutaneous coronary intervention
(PCI, angioplasty ± stent) (90 30 min)
Cardiothoracic surgery backup
Fibrinolysis
Plasminogen
Plasmin
Fibrin, fibrinogen
ActivationExtrinsic: t-PA, urokinase
Intrinsic: factor XIIa, kallikrein
Exogenous: streptokinase
Fibrin, fibrinogendegradation products
103
Fibrinolysis
Comparison of Approved Fibrinolytic Agents
Streptokinase Anistreplase Alteplase Reteplase
Dose 1.5 MU 30 mg 100 mg 10U x 2
in 30-60 min in 5 min in 90 min over 30 min
Bolus administration NO Yes No Yes
Antigenic Yes Yes No No
Allergic reactions Yes Yes No No
(mostly hypotension)
Systemic fibrinogen Marked Marked Mild Moderate
depletion
90-min patency rate ~50% ~65% ~75% ~75%
TIMI-3 flow 32% 43% 54% 60%
Mortality rate 7.3% 10.5% 7.2% 7.5%
Cost /dose (US) $294 $2116 $2196 $2196
ؿذ ثبیذ سشجیشیه ؿشع ؿد. ثؼذ اص ای و سؼز سشدی حشم CCUثؼذ اص ای و شین اسد اسطاغ یب
اثش ی زاسذ. ثؼوی ب ثب یه ؼ داسد ثؼوی ب ؼشمیب سی فیجشی 4ؿذ، فیجشییشیه داد ی ؿد، و
plasmin activatorؿذ ای وذىغ سا ایدبد وذ سب یض خش سا ادب دذ، ای ب سشویجبر jointاػ ثبیذ
ؿذ وذىغ اػز. دس حبیى ثب صد joint. ای صب ؿددلیم افصی 45 ثبیذ ػشم اػششدشویبصؼشذ.
reteplase tenecteplase ػشیؼب شین ساحز ی ؿد دسدؽ سؼىی ی یبثذ. ش وذا اص ای بrate
%، ؼ 40-50% اػز، ؼ د 30ؼ ا TIMI flow( سا ی دذ. یضا TIMI flowخبكی اص ثبص ؿذ ػشق )
وشد سا داسذ ؼال ثبص لذسر % investigation 90-80ثبص وذ. داسبی سي سا % ی ساذ75ػ چبس
اػز و سي ثبص ؿذ اػز. post injectionـب دذ ای فمیز دس ثبص ؿذ ػشق آسیشی بی
104
ContraindicatIons and Cautions for
Fibrinolytic Used in Myocardial Infarction
Absolute Contraindications:
Previous hemorrhagic stroke at any time: other
strokes or cerebrovascular events within one year
Known intracranial neoplasm
Active internal bleeding (does not include menses)
Suspect aortic dissection
کترااذیکاسیى ای سبی هطلق
یجشییشیه ب سا دس آسیؼ آئسر، افضایؾ فـبس خ وبسػیببی خشف ثبیذ شالت ثد و ی سا ف
free dose .سدیض وشد
Artery
Invasive Treatments (PTCA & CABG)
Coronary Artery
Bypass Surgery
(CABG)
Stent and/or
Balloon Angioplasty
105
Evolution of PCI for STEMI
Antman. Circulation 2001;103:2310.
Balloon Antiplatelet
Rx
Stent DES
GP IIb/IIIa inhibitor
AngioJet
Thrombus
Removal and
Distal
Embolization
Protection
Devices
Embolization
Protection Device
Platelet
Rotational Atherectomy
Baloon Angioplasty
Stent
106
شی و سذبی ىبیىی ؿییبیی ی ساذ ثبص وذ ی سي ثبؿذ.دغ دچبس یه سشجص ؼ
ادب ی ؿذ ثؼذ ثب صد ی ؿذ ثب ا سي ثبص ی ؿذ ثؼذ Atherectomyثب سذبی خشف، دس زؿش
stent سی ػذغ ذ.شفش ی ثبص ؿذ سد اػشفبد لشاس بیی و ث كسر فشبstent داسیی ساelut .وشدذ
یؼی د فش ی ا اثش زاسذ، داس سا آصاد ی وذ، ؼال acute phaseای سشویجبر سشویجبسی ؼشذ و دس
بی ییبسسی ثب خلز بی آشی یشسیه ؼشذ. اثشذائب وسس ثدذ. ؼ ا وسسیىاػششئیذب، ثؼذ
ی ؿد هشیت interventionاب ثؼذا دیذ ؿذ خبیی و دبویشبوؼ. سشویجبر آشی یشسیه ث سادببیؼی
ی ؿد. restenosisسؿذ ػی دس آدب ؼجز ث م ی دبس ثبال ی سد دغ ای سؿذ ػی صیبد ثبػث
ب ػاس stentثبیذ ث دجب سذی ثد و خی سؿذ ػی سا ثیشد. اآل وب آشی ثبدی ب سا سی
سا ی یشد. دس وبس restenosisوشدذ. سشویجبر ط ؼ چبس اػز و آة ی ؿد ثذ یچ اثشی خی
ثد؛ دس دع rethrombosisی زاؿز ثحث bare stentسا دس ثشاثش drug-Eluting stentای ب سذی و
107
اػشفبد ؿد اجش ضی ثبالیی داسد. دس وبس اػشفبد اص drug-Eluting stentث ای شید ی سػی و ثبیذ اص
stent .ثبیذ داسی آشی سشجسیه لشف وشد سب خ ػیال ثششی داؿش ثبؿذ خی سدغ دالوشی شفش ؿد
بسا ثشای ای ثی low doseاػشفبد ی ؿد و لذیی سشی آ آػذشی اػز. آػذشی anti-plateletاص سشویجبر
یی ش ؿشع ی 300سب لشف یؼی ثب 4سا loading 75mgاػشفبد ی ؿد سشویجبر ث ودیذش و
یی ش اػشفبد ؿد و یضا خشیضی آ وشش اػز. داسی 600ؿد. اجش اآل سكی ی ؿد اص سطی
یی ش دس سص 10ی ؿد loadیی ش 60 اػز خلكب ثشای دیبثشی ب ثب Prasugrelخذیذ سشویت
دیذیشیذا fix dose combinationداسذ اص سشویت TIA CVAسد اػشفبد لشاس ی یشد. وؼبی و سیؼه
خد داسذ. اشص دس 2b3aاػشفبد ی وذ. دس وبس ای ب سشویجبر اشخبثی سشی ث الیىدشسئی آػذشی
اص فش ی د خبسج وشد اسد ثخؾ ی ؿد. CCU. حبال شین سا اص بد ی ؿداػشف Eptifibatide اصشا ای
فش ی ؿد. د سشویت ؼشذ و لت سا خغ ی remodelingلت سجی ی وذ و اكالحب ث آ MIثؼذ اص
. ثشب ثالوش ACEIوذ، سشویت
Stent Differentiation
108
Drug Eluting Stents
109
Drug-Eluting Stents
> $5 Billion Market (~4.5M DES deployed)
DES 10x price of bare stent system in Europe
Cypher (Cordis) & Taxus (Boston Scientific) only currently approved
devices in US
2nd Gen in Europe - Cypher-Select (Cordis)
Taxus Liberte (Boston Scientific)
Host of others (“-limus family”)
Issues for current DES (especially in certain subsets)
- Remaining Restenosis
- Stent Thrombosis
- Unapproved Indications
Combined Cypher Studies
At 36 months
Cypher
6.4%
Bare
23.2%
Combined Taxus Studies
At 36 months
Taxus
9.4%
Bare
19.9%
“Evidence-based medicine guidelines for drug-eluting stent use”, Greg Stone, Cardiovascular Research Foundation
Stent Thrombosis
Milan/Siegburg Experience (Lakovou et al, JAMA 2005;293:2126-2130)
110
Sirolimus
Everolimus
ABT-578
Cell-cycle regulating: Cytostatic VS cytotoxic
Antiproliferative
Antimigratory
Immunomodulatory
Mechanisms of action to prevent in-stent restenosis
Differences
Systemic bioavailability
Local retention (lipophilicity, transport, etc)
Macrolide Antibiotics used in DES
Rapamycin Analogs
Chemical
Formula
C53H83NO14
Molecular Wt: 958.25
C51H79NO13
Molecular Wt: 914.2
C52H79NO12
Molecular Wt: 966.23
Intended
Pharma
Indications
Chronic & Acute
Rejection – Heart,
Kidney, Lung
Acute Rejection –
Kidney, Liver and
Heart
None
N O
O
O O
O
O
H O
O
O H
O
O
O
H 3 C
C H 3
C H 3
H 3 C
C H 3
H 3 C
H 3 C
C H 3
H H
H
H
C H 3
H 3 C
EVEROLIMUS
SIROLIMUS
Cypher ® StentsABT-578
N
NN
N
N O
O
O O
O
O
H O
O
O H
O
O
O
H 3 C
O H
C H 3
C H 3
H 3 C
C H 3
H 3 C
H 3 C
C H 3
H H
H
H
C H 3
H 3 C
Chiral
N
OO
O
CH3
O
O
O
H3C
O
HO
CH3
CH3
CH3
HOH3C
H
O
OH
H3C
H
CH3
H
OOH
OH3C H3C
ChiralN
NN
N NN
Paclitaxel (Taxus ® Stents)
Isolated from bark and needles of Pacific yew tree
Chemotherapeutic agent, administered with
solubilizing agent Cremophor®
Antitumor activity:
(ovarian, NSC lung, breast)
Doses used systemically approximately 1000-fold
higher than stent-based doses
Sirolimus Paclitaxel
111
Stenting vs. PTCA
Prevents acute closure
Tacks back intimal flaps
Less restenosis:
30–50 % restenosis with PTCA (coronary
arteries).
Coronary stents are associated with
fewer repeat revascularisation
procedures
Rates of death and MI are low and are
not significantly different between
stents and PTA.
Stent Failure
Restenosis20-30 %
112
ST depression or dynamic T-wave inversion
Thrombolytics contraindicated
Adjunctive therapy:
Heparin (UFH/LMWH)
Aspirin 160-325 mg qd
Glycoprotein IIb/IIIa receptor inhibitors
NTG IV
-blockers
Cardiac catheterization for high-risk patients or monitoring for clinically stable patients
CABG
113
Beta Blockers in Acute MI
Recommendations
• IV to oral beta blocker therapy in patients without
contraindications in first 24 hours
• Avoid early therapy in patients with bradycardia,
hypotension, inferior MI, CHF, impaired LV
function, AV block, asthma
• Continue treatment for at least 2-3 years
Effects of Beta Blockers Post MI
Immediate: reduces cardiac index, heart rate and
blood pressure. Net effect is to reduce myocardial
oxygen consumption/minute/beat. (Reduces Chest
Pain)
Reduces infarct Size in Acute MI
Diminishes circulating levels of free fatty acids by
antagonizing lipolytic effects of catecholamines.
(FFA augment O2 consumption and increases
incidence of arryhthmias.
114
115
Subtitle
-Adrenoceptor Antagonists
NonselectiveCardioselective a & antagonist activity
Acebutalol*
Atenolol
Betaxolol
Bevantolol
Bisprolol
Celiprolol
Esmolol
Metoprolol
Practolol*
Alprenolol*
Carteolol*
Nadolol
Oxprenolol*
Penbutolol*
Pindolol*
Propranolol
Sotalol
Timolol
Bucindolol
Carvedilol
Labetolol
Pharmacokinetics
Variable, depends on preparation, hepatic
metabolism and renal elimination and lipid
solubility.
Generally beta-blockers have a short half-life
(<4hrs) but long acting preparations are
available.
116
Beta Blockers in Acute MI
Recommendations
• IV to oral beta blocker therapy in patients without
contraindications in first 24 hours
• Avoid early therapy in patients with bradycardia,
hypotension, inferior MI, CHF, impaired LV
function, AV block, asthma
• Continue treatment for at least 2-3 years
Effects of Beta Blockers Post MI
Immediate: reduces cardiac index, heart rate and
blood pressure. Net effect is to reduce myocardial
oxygen consumption/minute/beat. (Reduces Chest
Pain)
Reduces infarct Size in Acute MI
Diminishes circulating levels of free fatty acids by
antagonizing lipolytic effects of catecholamines.
(FFA augment O2 consumption and increases
incidence of arryhthmias.
117
Adverse effects
Result of beta-blockade:
Tiredness, weakness
Bradycardia and heart block
Bronchospasm
Congestive cardiac failure – negatively
ionotropic
Cold hands, worsening claudication
Impotence in males – mechanism not known
Beta-Blockers
Contraindication:
2nd-3rd degree heart block
Precautions:
Asthma / COPD
Type 1 diabetes
Congestive heart failure
Monitor :
Blood pressure, heart rate, compliance, other adverse
effects (i.e. fatigue)
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— BETA BLOCKERS —
Beta Blockers – Problem Solving
Worsening symptoms/signs (e.g. increasing dyspnoea,
fatigue, oedema, weight gain):
• If increasing congestion, double the dose of diuretic and/or halve the dose of beta-blocker
(if increasing diuretic does not work)
• If marked fatigue (and/or bradycardia – see below), halve the dose of beta-blocker (rarely
necessary)
• Review patient in 1–2 weeks; if not improved, seek specialist advice
• If serious deterioration, halve the dose of beta-blocker or stop this treatment (rarely
necessary); seek specialist advice
118
Renin-Angiotensin System (RAS)
Angiotensinogen
Angiotensin I
AT1 receptor
ARBs AT2 receptor
ACE inhibitors
ACE
Renin
• CAGE
• Cathepsin G
• Chymase
• tPA
• Cathepsin G
• Tonin
Angiotensin II
ACE inhibitors
Bradykinin
(active)
Bradykinin1-7
(inactive)
CAGE = chymostatin-sensitive angiotensin-generating enzyme; tPA = tissue plasminogen activator.
Figure adapted with permission from Dzau VJ, et al. J Hypertens. 1993;11(suppl 3):S13-S18.
ACE Inhibitor: Mechanism of Action
Angiotensin II
Kininase II
Angiotensin I
Angiotensinogen
InhibitorACE
ReninBradykinin
Inactive Fragments
Sympathetic
Vasopressin
Aldosterone
Vasoconstriction
ACE=Angiotensin converting enzyme
Kininogen
Kallikrein
Vasodilation
Prostaglandins
tPA
119
Effects of ACE I on AT II & Bradykinin
ACE I
Angiotensinogen
Renin
Angiotensin I
Converting Enzyme
Angiotensin II
AT1 and AT2
Vasoconstriction
Converting Enzyme
Inactive
Bradykinin
Bradykinin
NO
Vasodilitation
•Cough
•Angioedema
•Renal Dysfunction
•Hypotension
•Antigrowth
•Antiproliferation
ACE inhibitors
Benzapril (Lotensin)
Captopril (Capoten)
Enalpril (Vasotec)
Fosinopril (Monopril)
Lisinopril (Prinivil, Zestril)
Moexipril (Univasc)
Perindopril (Aceon)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)
120
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – Why?
• CONSENSUS I, the SOLVD-treatment study and a meta-analysis of smaller trials
showed conclusively that ACE inhibitors increase survival, reduce hospital admissions
and improve NYHA class and quality of life in patients with all grades of symptomatic
heart failure
• ATLAS showed clinically important advantages with higher doses of ACE inhibitors in
heart failure
• SAVE, AIRE and TRACE showed that ACE inhibitors increase survival in patients
with systolic dysfunction after acute myocardial infarction
• SOLVD-prevention study showed that ACE inhibitors delay or prevent the
development of symptomatic heart failure in patients with asymptomatic LVSD
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – In Whom and When?
Indications:
Potentially all patients with heart failure
First-line treatment (along with beta-blockers) in NYHA class I–IV heart failure
Contra-indications:
History of angioneurotic oedema
Cautions/seek specialist advice:
Significant renal dysfunction (creatinine >2.5 mg/dL or 221 µmol/L) or hyperkalaemia (K+
>5.0 mmol/L)
Symptomatic or severe asymptomatic hypotension (SBP <90 mmHg)
Drug interactions to look out for:
K+ supplements/ K+ sparing diuretics (including spironolactone)
NSAIDs*
AT1-receptor blockers *avoid unless essential
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – How to Use
• Start with a low dose
• Double dose at not less than two weekly intervals
• Aim for target dose or, failing that, the highest tolerated dose
• Remember some ACE inhibitor is better than no ACE inhibitor
• Monitor blood chemistry (urea, creatinine, K+) and blood pressure
• When to stop up-titration/down-titration – see PROBLEM SOLVING
121
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – How to Use
• Start with a low dose
• Double dose at not less than two weekly intervals
• Aim for target dose or, failing that, the highest tolerated dose
• Remember some ACE inhibitor is better than no ACE inhibitor
• Monitor blood chemistry (urea, creatinine, K+) and blood pressure
• When to stop up-titration/down-titration – see PROBLEM SOLVING
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – Advice to Patient
• Explain expected benefits (see WHY?)
• Treatment is given to improve symptoms, to prevent worsening of heart failure and to
increase survival
• Symptoms improve within a few weeks to a few months
• Advise patients to report principal adverse effects
(i.e. dizziness/symptomatic hypotension, cough)
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – Problem Solving
Asymptomatic low blood pressure:
• Does not usually require any change in therapy
Symptomatic hypotension:
• If dizziness, light-headedness and/or confusion and low blood pressure occur, reconsider
need for nitrates, calcium channel blockers* and other vasodilators
• If no signs/symptoms of congestion, consider reducing diuretic dose
• If these measures do not solve the problem, seek specialist advice
*calcium channel blockers should be discontinued unless absolutely essential
(e.g. for angina or hypertension)
122
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – Problem Solving (continued)
Worsening renal function:
• Some increase in urea (blood urea nitrogen), creatinine and K+ is to be expected after initiation; if the increase is small and asymptomatic no action is necessary
• An increase in creatinine of up to 50% above baseline, or 3 mg/dL (266 µmol/L), whichever is the smaller, is acceptable
• An increase in K+ 6.0 mmol/L is acceptable
• If urea, creatinine or K+ rise excessively, consider stopping concomitant nephrotoxicdrugs (e.g. NSAIDs), other K+ supplements/ K+ retaining agents (triamterene, amiloride) and, if no signs of congestion, reducing the dose of diuretic
• If greater rises in creatinine or K+ than those outlined above persist, despite adjustment of concomitant medications, halve the dose of ACE inhibitor and recheck blood chemistry; if there is still an unsatisfactory response, specialist advice should be sought
Practical Recommendations for Heart Failure Treatment:
Putting Guidelines into Practice
— ACE INHIBITORS —
ACE Inhibitors – Problem Solving (continued)
Worsening renal function (cont.):
• If K+ rises to >6.0 mmol/L, or creatinine increases by >100% or to above 4 mg/dL (354
µmol/L), the dose of ACE inhibitor should be stopped and specialist advice sought
• Blood chemistry should be monitored serially until K+ and creatinine have plateaued
NOTE: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if
treatment is withdrawn; ideally, specialist advice should be sought before treatment
discontinuation
ACE-Inhibitors
“A limited increase in serum creatinine of as much as 35% above baseline with ACE inhibitors or ARBs is acceptable and not a reason to withhold treatment
unless hyperkalemia develops.”
“an increase in SCr level, if it occurs, will happen within the first 2 weeks of therapy initiation.”
JNC-7
123
ACEI Started & SCR > 30 %
BP at Goal
Recheck SCr in 2-3 weeks
if > 30% increase:
Reduce dose by 50% then add other agents
Recheck SCr in 4 wk
if stable, continue
if > 30%, stop ACEI
BP not at goal
Recheck SCr in 2-3 wk
If < 30%, continue ACEI &
monitor
If > 30%, reduce dose by 50% &
add other agents
Additional Considerations
• ACE-I
• Compelling indications: DM, HF, post-MI, high risk CAD, chronic kidney disease, recurrent stroke
prevention (6 of 7)
• May have unfavorable effects on: hyperkalemia
• Contraindicated in pregnancy
Angiotensin II antagonists
Candesartan (Atacand)
Eprosartan (Tevetan)
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)
124
Receptors
Angiotensin Receptor Blocker: Mechanism of Action
AT II
Receptor
Blocker
Antiproliferative
Action
VasodilationProliferative
Action
Vasoconstriction
ATIIATI
Angiotensinogen
Other Pathways
Renin
AT I
Receptor
Blocker
Angiotensin I
Angiotensin IIACE
Effects of ARB on AT II & Bradykinin
ARB
Angiotensinogen
Renin
Angiotensin I
Converting Enzyme
Angiotensin II
AT1 and AT2
Vasoconstriction
Converting Enzyme
Inactive
Bradykinin
Bradykinin
NO
Vasodilitation
• No Cough
• No Angioedema
No growth
125
Differential Effects of ACE-I and ARBs
ACE Inhibitor ARB
Ang II
AT1 Stimulation
AT2 Stimulation
Renin
Aldosterone
Bradykinin
NO production
Deleterious Effects of Angiotensin II
Ang IIAbnormal
vasoconstriction
Activate SNS
Aldosterone
Vasopressin
Endothelin
Myocyte
Growth
Vascular
smooth
muscle
growth
Collagen
Remodeling
Superoxide
Production
Platelet
Aggregation
126
Additional Considerations
• ARB’s
• Compelling indications: DM, HF, chronic
kidney disease
• Contraindicated in pregnancy
Renin Angiotensin Aldosterone
Drug Initial Dose Max Single Dose
ACE- inhibitors
Captopril 1.0 mg 4 to 8 mg
Enalapril 40 mg 160 to 200 mg
Fosinopril 10 mg 100 to 200 mg
Lisinopril 2.5 to 5 mg 20 to 40 mg once
Perindopril 2 mg once 8 to 16 mg once
Quinapril 5 mg twice 20 mg twice
Ramipril 1.25 – 2.5 once 10 mg once
Trandolapril 1 mg once 4 mg once
Angiotensin Receptor Blocker
Candesartan 4 to 8 mg once 32 mg once
Losartan 25 to 50 mg once 50 to 100 mg once
Candesartan 4 to 8 mg 160 mg twice
Aldosterone Antagonists
Spironolactone 12.5 to 25 mg 25 mg once or twice
Eplerenone 25 mg once 50 mg once
127
Coronary Remodeling
Normal
vessel
Minimal
CAD
Progression
Compensatory expansion
maintains constant lumen
Expansion overcome:
lumen narrows
Severe
CAD
Moderate
CAD
128
Sinus Brady Treat if hemodynamic compromise;
atropine / pacing
Junctional Treat if hemodynamic compromise;
atropine / pacing
Arrhythmias During Acute Phase of STEMI:
Bradyarrhythmias
Arrhythmia Treatment
ICD Implantation After STEMIOne Month After STEMI;
No Spontaneous VT or VF 48 hours post-STEMI
EF < 0.30
EPS
Yes
+
NEJM 349:
1836,2003
EF 0.31 - 0.40
No
No ICD.
Medical Rx
EF > 0.40
-
Additional Marker of
Electrical Instability?
Secondary Prevention and Long Term Management
If blood pressure is 120/80 mm Hg or greater:
• Initiate lifestyle modification (weight control, physical activity,
alcohol moderation, moderate sodium restriction, and emphasis on
fruits, vegetables, and low-fat dairy products) in all patients.
If blood pressure is 140/90 mm Hg or greater or 130/80 mm Hg or
greater for individuals with chronic kidney disease or diabetes:
• Add blood pressure-reducing medications, emphasizing the use of
beta-blockers and inhibitors of the renin-angiotensin-aldosterone
system.
Blood pressure
control:
Goal: < 140/90 mm
Hg or <130/80 mm
Hg if chronic kidney
disease or diabetes
Goals Recommendations
129
Secondary Prevention and Long Term Management
• Assess risk, preferably with exercise test, to guide prescription.
• Encourage minimum of 30 to 60 minutes of activity, preferably
daily but at least 3 or 4 times weekly (walking, jogging, cycling, or
other aerobic activity) supplemented by an increase in daily lifestyle
activities (e.g., walking breaks at work, gardening, household work).
• Cardiac rehabilitation programs are recommended for patients
with STEMI.
Physical activity:
Minimum goal:
30 minutes 3 to 4
days per week;
Optimal daily
Goals Recommendations
Secondary Prevention and Long Term Management
• Start dietary therapy in all patients (< 7% of total calories as
saturated fat and < 200 mg/d cholesterol). Promote physical activity
and weight management. Encourage increased consumption of
omega-3 fatty acids.
• Assess fasting lipid profile in all patients, preferably within 24 hours
of STEMI. Add drug therapy according to the following guide:
Lipid
management:
(TG less than 200
mg/dL)
Primary goal:
LDL-C << than 100
mg/dL
Goals Recommendations
LDL-C < 100 mg/dL (baseline or on treatment):
Statins should be used to lower LDL-C.
LDL-C ≥ 100 mg/dL (baseline or on
treatment):
Intensify LDL-C–lowering therapy with drug treatment, giving
preference to statins.
Secondary Prevention and Long Term Management
If TGs are ≥ 150 mg/dL or HDL-C is < 40 mg/dL:
Emphasize weight management and physical activity.
Advise smoking cessation.
If TG is 200 to 499 mg/dL:
After LDL-C–lowering therapy, consider adding fibrate or
niacin.
If TG is ≥ 500 mg/dL:
Consider fibrate or niacin before LDL-C–lowering therapy.
Consider omega-3 fatty acids as adjunct for high TG.
Lipid
management:
(TG 200 mg/dL or
greater)
Primary goal:
Non–HDL-C <<
130 mg/dL
Goals Recommendations
130
Secondary Prevention and Long Term Management
Goals Recommendations
Appropriate hypoglycemic therapy to achieve
near-normal fasting plasma glucose, as
indicated by HbA1c.
Treatment of other risk factors (e.g., physical
activity, weight management, blood pressure,
and cholesterol management).
Diabetes
management:
Goal:
HbA1c < 7%
Secondary Prevention and Long Term Management
Goals Recommendations
• In the absence of contraindications, start aspirin 75 to
162 mg/d and continue indefinitely.
• If aspirin is contraindicated, consider clopidogrel 75
mg/day or warfarin.
• Manage warfarin to INR 2.5 to 3.5 in post-STEMI
patients when clinically indicated or for those not able to
take aspirin or clopidogrel.
Antiplatelet
agents/
anticoagulants
Secondary Prevention and Long Term Management
Goals Recommendations
ACE inhibitors in all patients indefinitely; start early in stable,
high-risk patients (ant. MI, previous MI, Killip class ≥ 2 [S3
gallop, rales, radiographic CHF], LVEF < 0.40).
Angiotensin receptor blockers in patients who are intolerant of
ACE inhibitors and with either clinical or radiological signs of
heart failure or LVEF < 0.40.
Aldosterone blockade in patients without significant renal
dysfunction or hyperkalemia who are already receiving
therapeutic doses of an ACE inhibitor, have LVEF ≤ 0.40, and
have either diabetes or heart failure.
Renin-
Angiotensin-
Aldosterone
System
Blockers
131
Secondary Prevention and Long Term Management
Goals Recommendations
Start in all patients. Continue indefinitely.
Observe usual contraindications.
Beta-
Blockers
132
ارسایی قلبی
هذرس:دکتر ابراین صالحی فر
By: E. Salehifar (PharmD, BCPS)
Epidemiology 1.5% to 2% of the population (6% to 10% for > 65 y.o.)
↑ Prevalence (esp. diastolic HF)
similar prevalence in men and women
More Diastolic heart failure in women
Systolic dysfunction in the majority of men
the most common cause of hospitalizations in the elderly (in
the US)
ػذ یؼی ؿذ فش حثبج اػز آ اص ای دػ صیش احشمبی بسػبیی و heart failure ثحث ػ سشی
و اػز ثیبسی سب. ثبؿذ ی ـى ای ث جشال خؼیز % 2سب 1 .ثبؿذ ی MI آظی خ، فـبس افضایؾ وشش
. ثبؿذ ی یىؼب آلبیب ب خب اثشالی سیؼه. اػز یبفش افضایؾ آ incidence prevalence آشیىب دس
.ؿد ی ثشاثش 2 آ ثشص احشب ػش افضایؾ ػب 10 ش اصای ث ثؼذ ث ػبی 50 اص
133
Heart Failure MI: the most important relative risk for symptomatic
HF (hazard ratios 6.34 for men and 6.01 for women)
Quality of life ↓
High mortality rate
HF: Low-Output vs. High-Output Failure
A clinical syndrome that heart fails to pump sufficient
blood to meet the body's metabolic needs
Low-Output Failure
>90% cases, ↓ CO
Coronary ischemia, MI, Hypertension, Valvular disorders,…
High-Output Failure
↑ metabolic needs
normal size heart, normal or ↑ EF & SV; ↑ CO
anemia, hyperthyroidism
Low-Output Failure
Systolic vs. Diastolic Dysfunction
Systolic Dysfunction (60-70%)
↓ contractility, EF< 40%, ↓ SV, ↓ CO, S3, ↑ SVR , cardiomegaly
1- ↓ Contractility:
Coronary ischemia & MI (2/3 of systolic dysfunction)
mitral valve stenosis or regurgitation, alcoholism, Viral, Drugs, …
2- ↑ SVR:
HTN
aortic stenosis
Diastolic Dysfunction (30-40%)
134
Systolic Dysfunction (60-70%)
Diastolic Dysfunction (30-40%) Normal LV contractility, EF & size of heart
Stiff left ventricle, impaired left ventricular relaxation, impaired left ventricular filling, ↓ LVEDV, ↓ SV; ↓ CO; S4 sound 1- LVH (hypertrophic cardiomyopathy):
Coronary ischemia. MI, hypertension. aortic stenosis and regurgitation. pericarditis
2- Stiff left ventricle (restrictive cardiomyopathy) Amyloidosis, sarcoidosis
3- ↑ Preload
Sodium and water retention
Low-Output Failure
Systolic vs. Diastolic Dysfunction
Clinical signs and symptoms do not differentiate between systolic and
diastolic HF
Echocardiography
135
Low output failure: Left Ventricular Dysfunction (Systolic or Diastolic)
the most common form
Right Ventricular Dysfunction
primary or secondary pulmonary arterial hypertension
Biventricular failure
Injury to both ventricles (e.g., MI)
Cardiac Workload Preload (LVEDP)
↑ : Fluids, Aortic stenosis, Mitral regorgitation, Systolic
failure, Diastolic failure (stiffened left ventricle)
↓ : Venodilation (ACEIs, Nitrates) and diuretics
Afterload
↑ : HTN, atherosclerosis, aortic valve stenosis
↓ : ACEIs, Prazosin, …
Contractility
↓ in systolic HF (MI, cardiomyopathy, CAD, valvular)
↑ : Dig, Dobutamin, Milrinone
Heart rate (↑ sympathetic activity)
Low Output
↑Preload ↑ Afterload Norepinephrine ↑
Increased Salt Vasoconstriction Renal Blood
Flow
Renin
Angiotension I
Angiotension II
Aldosterone
136
دارساز چ تصی ایی برای بیواراى هی تاى داضت؟ ب عاى
ایچ آة ثشای آة دی ث صی لشاس داسد، سی چب 5ىشبسی سا دس ظش ثیشیذ، چبی ثب 5ثب: صی وـبسصی
ؿذ. ػای و ى دسػز وبس ادب ـد:دذی سؼجی ؿذ اػز. خض سأی آة ای چب سدخب ای ی ثباػز، بی و لت شاذ خة contractilityى اػز سس آة سی چب خة وبس ىذ. دغ یىی اص ثحث ب
دبیی ی آیذ جیؼشب دشفیط ثبفز ب خش cardiac outputو ی ؿد ثؼذ stroke volumeمجن ؿد،
ی یىی اص دسب ب ی ساذ داسبی ایسشح ثبؿذ. ی شدد. ثبثشا
ـى دیشی و اىب داسد، غیب سدخب ی سأی وذ ی آة چب اػز و ی ساذ ثیـشش اص ظشفیز آ آة
) فـبسی و دس دبیب دیبػش ثش دیاس بی لت اسد ی ؿد( ی preloadاسدؽ وذ. ای ـب دذ ی
دس ای حبز ثبیذ داسی دیسسیه داد ؿد سب احشجبع آة ه ادی و دس ای ثیبسا خد داسد سا ثبؿذ.
ثششف وذ.
ایچ. ؼب ث سس 3ـى دیش ای اػز و ای و ث سس ك ؿذ اػز وشش اص ظشفیز آ اػز ثال
)مبشی و after loadس خبسج وذ. ای هع ـب دذ ی ایچ آة سا اص س 5فـبس ی آیذ ی ساذ
ث ثبیذ ثش آ غج وذ سب ثشاذ دشفیط بػت سا حفظ وذ( ی ثبؿذ. سشی ػبی و دس ایدب ؤثش اػز
فـبس خ ثبالی ثیبس ی ثبؿذ.
وبؾ -contractility 3افضایؾ -preload 2وبؾ -1ػ وبس اػز: heart failureدغ اك دسبی دس
after load
دبیی ثبؿذ سحشیه ػیؼش cardiac output اسفبق ی افشذ، دس كسسی و ای ىبیؼ خجشای و دس ثذ
افضایؾ ی یبثذ. اجش ای اش دس خز حبیز اص after loadػذبسیه اػز. ثب ای وبس ػشق مجن ی ؿذ
و دس Vasoconstriction vasoconstrictionثیبس دشفیط اػز ی دسبیز ث هشس لت سب ی ؿد.
اثشذا خة اػز ی اش ثشای الی ذر ادا دیذا وذ ث هشس ثیبس اػز. دغ یىی اص دسب ب و وشد فؼبیز
ثشب ثالوشبػز. ثشبثالوشبیی و ی ساذ سدیض ؿد شدش ػوؼیبر آؼش داد بذ ػیؼش ػذبسیه
ثشب ثالوش( اػز. دس زؿش فش ی ؿذ -ؿش ثبؿذ( وبسدی )آفبسؾ )ح سبسسشار ى اػز ای لبثیز سا ذا
II IIIداسد ثشب ثالوش داد ـد ی اآل فش ی ؿد حشی ثشای ثیبسای و دس والع heart failureث وؼی و
خبیب ثؼیبس heart failure systolicؼشذ هؼیز دبیذاس داسد اػشفبد ؿد. اشص ثشب ثالوشب دس دسب
ب شي یش ACEIب و دس زؿش شح ثدذ فمي ACEIی داسذ. اص یب داسبی دیسسیه، دیوؼی
ثیبسا سا وبؾ ی دادذ ی اآل ثشبثالوشب ای یظی سا داسذ.
ACEI.ب خي ا دسب ی ثبؿذ
ejectionز ی سا ث ػبدی اص آ ب زؿز. ثیبسی و دیوؼی یظی بیی داسد و ثؼیبس خة اػ
fraction دبیی داؿش ثبؿذ، ػالز داس ثبؿذ شاذ فؼبیز سصش ی خد سا ادب دذ یبص ث دیوؼی داسد
ی اؿىب ایدبػز و دیوؼی فمي ثبػث ی ؿد و شین ساحز سش ثبؿذ وشش ثؼششی ؿد ی
137
mortality سا دبیی ی آسد. دغ خبیب دیوؼی، دسب یثیبس systolic heart failure اػز. دسdiastolic
heart failure ـى ثیبس دس فبص دیبػش اػز و ث دچبس یهstiffness اػز یب دچبسremodeling ؿذ
یض یؼز.اػز، دس ای خب چ لذسر امجبهی لت خش ـذ، دیوؼی لبث سد
ACEIبسػبییب داسبی ثؼیبس خثی ؼشذ و دس systolic بسػبیی دس diastolic وبسثشد داسذ
138
Heart Failure ↓ CO → Sympathic activation HR↑, ↑ venous return, ↑
arterial constriction → LVH, Cardiomegaly & Heart
Failure
↓ CO → Renin-Ag-Ald. Activation → Na/water Retention
→ ↑ venous return → LVH, Cardiomegaly & Heart
Failure
Symptoms: dyspnea, congestion (peripheral, pulmonary,
cardiac), JVD, fatigue
Table :
139
Edema Na restricted diet (2-4 g NaCl)
Elastic hosiery
During Exacerbation:
bed rest [↑renal perfusion (nacturia), ↓ gravitational forces)
restricted physical activity ↓ demand
Other Hormonal Mediators Endothelin-1 (ETA, ETB)
Natriuretic Peptides (ANP, BNP, CNP)
Arginine vasopressin (ADH)
IL-1, IL-6, TNF-α, PGI2, NO
140
NYHA Functional Class 1. Asymptomatic or no limitations on normal physical
activity, but symptoms with strenuous exercise
II. Symptoms with normal activity or with moderate
exertion
III. Symptomatic with minimal exertion; marked
limitations in physical activity including activities of daily
life (e.g . bathing, dressing) (or IIIB) Symptoms of heart
failure at rest.
IV (or IVB). Symptoms of heart failure at rest and
requiring hospitalization or intravenous inotropic support
American College of Cardiology-American Heart
Association (ACC/ AHA) Staging
A. At high risk for heart failure, but without structural
heart disease (HTN, CAD, DM, alcoholism, strong family
history)
B. Structural heart disease present (LVH. dilation,
fibrosis, old MI) but without symptoms of HF
C. Structural heart disease with prior or current symptoms
of HF
D. Refractory HF requiring specialized interventions
Objectives of therapy Abolishing symptoms
Avoiding complications such as arrhythmias
Improving the quality of the life
The ultimate goal: Survival ↑
Evaluation
↑ walking distance during a 6-minute treadmill test
transition to a lower NYHA symptom class
Except heart transplant, none of the treatment measures
are curative
141
Treatment: Stage A
(high risk for HF without structural heart disease/symptoms)
Therapy of HTN, HLP, smoking cessation, regular
exercise, discourage alcohol intake/illicit drugs
Drugs:
ACEI or ARB in appropriate patients (HTN, DM)
Treatment: Stage B (Structural heart disease without symptoms)
Patients with
Previous MI
LV remodeling including
LVH and low EF
Asymptomatic valvular
disease
Drugs:
ACEI or ARB in
appropriate patients
β- blockers in appropriate
patients
Treatment: Stage C (Structural heart disease with symptoms)
Symptoms: Shortness of breath, fatigue, reduced exercise
tolerance
Treatment
Dietary salt restriction
Drugs:
Diuretics, ACEI, β-blockers
Selected patients: Aldosterone antagonist, ARBs, Dig,
Hydralazine/nitrates
Devices: pacing, defibrillators
142
Treatment: Stage D(Refractory symptoms at rest)
Heart transplant
Chronic inotropes
Permanent mechanical support
Compassionate end-of-life care
Drugs Systolic Failure: (Combination of the following classes and drugs)
Diuretics
ACE inhibitor (↓mortality)
β-adrenergic blocker (Carvedilol, metoprolol)
(↓mortality)
(usually) digitalis
DrugsSpironolactoe/Eplerenone: advanced HF or following
MI with LV dysfuction (↓mortality)
Amiodarone: symptomatic VT and AF associated with
HF
Amlodipine and Felodipine ↓ afterload; safe in
nonischemic dilated Cardiomyopathy)
Diastolic failure:
Dig (relatively contraindicated)
Propranolol or verapamil to slow HR
143
144
IV Diuretic Regimens for Treating
Decompensated Heart Failure
Maximal
Single Dose
Initial Dose
200 mg40 mgFurosemide
4â€―8 mg1 mgBumetanide
100â€―200 mg10 mgTorsemideInfusion of Furosemide:
40 mg IV loading dose; then 5-40 mg/h
Maximal DoseInitial DoseACEIs (in HF)
50 mg t.i.d.6.25 mg t.i.d.Captopril
20 mg b.i.d.2.5 mg b.i.d.Enalapril
40 mg q.d.2.5 mg q.d.Lisinopril
40 mg q.d.5 mg q.d.Fosinopril
10 mg q.d.1.25 mg q.d.Ramipril
20 mg b.i.d.5 mg b.i.d.Quinapril
4 mg q.d.1 mg q.d.Trandolapril
Angiotensin receptor blockers
Maximal
Dose
Initial Dose ARBs (in HF)
100 mg q.d.25 mg q.d.Losartan
160 mg b.i.d.20 mg b.i.d.Valsartan
32 mg q.d.4 mg q.d.Candesartan
145
Aldosterone Antagonists
Maximal DoseInitial Dose
25 mg q.o.d.12.5 mg q.o.d.Spironolactone
50 mg q.d.25 mg q.d.Eplerenone
Beta-adrenergic blockers (Stable HF)
Maximal DoseInitial Dose
200 mg q.d.12.5 mg q.d.Metoprolol XL/CR
(succinate)
50 mg b.i.d.3.125 mg b.i.d.Carvedilol
10 mg q.d.1.25 mg q.d.Bisoprolol
low-dose ARB plus standard doses of
ACEI & beta-blocker in advances HF
Significant morbidity benefit with
reduction in recurrent hospitalizations but
no mortality benefit
146
Newer/Investigational Agents Natriuretic peptides [Nesiritide]
Endothelin inhibitors [Bosentan (Tracleer®) , Tazocentan]
Vasopressin receptor antagonists [Tolvaptan]
Calcium sensitizers [Levosimendan]
TNF-α inhibitors [Etanercept (Enbrel®)]: disappointing
results
Amrinone/Milrinone: arrhythmias and ↑mortality
Therapeutic Intervention ↓ Preload: Diuretics, ACEIs, ARAs, Nitrates
↓ Afterload: ACEIs, ARAs, Prazocin, Hydralazin,
Nitroproside, Phentolamine
Inotropes: Digoxin, Sympathomimetics,
Phosphodiesterase Inhibitors
β-Blockers (Metoprolol succinate, Carvedilol (αβ-
Blocker)
CCBs (Amlodipine)
Sympathomimetics:
Dopamine: 200 mg/5ml
Dobutamine (Dobutrex®:
250 mg/20 ml)
Epinephrine: 1 mg/ml
(1/1000)
Isoproterenol: 2 mg/2ml
Norepinephrine: 1 mg/ml
Phentolamine: 10 mg/ml
Phosphodiesterase
Inhibitors
Amrinone: inj 100 mg/20
ml
Milrinone: 10 mg/10 ml,
20 mg/20 ml
147
Digoxin (Lanoxin®) Tab: 0.25 mg
Elixir: 0.25 mg/5ml
Inj: 0.5 mg/2ml
Drop: 0.5 mg/ml
In CHF: inhibition of Na/K Pump→↑ intracellular Na→
exchange with Ca
In AF: ↑ Refractory period in AV node
Therapeutic doses: beats slowly & strongly
In toxic doses: Sympathomimetic activity
Digoxin: Mechanism of
Action
Digoxin: Pharmacokinetics Bioavailability: Tab: 75%, Elex: 85%, Cap: 95%
t ½ : 36 hr → steady state: 1 week later
Elimination: 70% renal → Dosage adjustment in Renal
failure
148
Digoxin: dose Usual: 0.125-0.25 mg/day (Drug holiday?)
Digitalization: 0.5-0.75 mg
Digoxin: Contraindication VF
Heart Block
AF with accessory Av pathway
Digoxin: ADRs Arrhythmia
PVC (most common), Heart Blocks, VT
Treatment: Lidocaine, Phenytoin
Visual Disturbances (25%)
GI: abdominal pain, anorexia, N, V
overdose in adult: GI + Bradycardia
CNS: fatigue, disorientation, agitation, headache
149
Digoxin: Interactions Βeta-blockers, CCB → inotrope - , HR↓
Diuretics, Amphotericin B Hypokalemia → ↑ Dig
toxicity
ACEIs, Quinidine, Verapamil, Diltiazem, Amiodarone →
↑ Dig level
Antacids, Sulfasalazine, Neomaycine: ↑ Dig absorbtion
Digoxin: Precaution ↓ K, ↓ Mg, ↑Ca → ↑ Dig toxicity
Consider different bioavailability (0.1 inj = 0.125 PO)
IM: Painful & unpredictable absorbtion
Digoxin: TDM Therapeutic Cp: 0.5-2 ng/ml
TDM for:
Probable Toxicity (Dig Fab: Digibind® for sever toxicity)
Ineffective treatment
Compliance evaluation
150
Digoxin: Patient Education Take regularly
If needed to divide, do it carefully
Dig toxicity symptoms (bradycardia, GI)
Missed dose (take if < 12 hr, not double next dose, > 2
missed dose: inform the physician)
Digoxin: Pregnancy &
Lactation Pregnancy: C ↑ need in last weeks of pregnancy
Lactation: safe
ACEIs Captopril (Capoten): tab: 25 mg, 50 mg
Enalapril (Vasotec): 5 mg, 20 mg
Lisinopril: 5 mg, 10 mg, 20 mg
151
ACEIs: Indications HTN ↓ LVH, No adverse effect on lipid & glu,
Renoprotective )
CHF ↓ LVH, ↓ mortality
Post MI ↓ LVH
ACEIs: dose
Captopril: 25 mg BD-TDS 50 mg TDS (Max:
150 mg TDS)
Enalapril: 5 mg QD→ 10-40 mg/day (QD or BD)
Lisinopril: 10 – 40 mg/day
Lower doses in: aged, low Na diet, RF
2-3 Weeks later
→
152
ACEIs: Pharmacokinetics All are Prodrug except Captopril (Enalaprilate: active
metabolite of enalapril)
Interval: Captopril BD or TDS, Enalapril: QD or BD,
Lisinopril: QD
Absorbtion: Captopril : 60-75% (1 hr before meal),
Enalapril: 60% , Lisinopril: 25%
ACEIs: ADRs Cough (up to 20%) : more in felames & non-smokers→ change
to ARAs
Bad taste (2-7%) esp. with captopril
Rash (1-7%)
Angioedema
Hypotension
↑ K (esp. in DM & RF)
Proteinuria
Nutropenia (With higher doses)
Malformation (D in pregnancy)
Monitoring: WBC (Q 2 w up to 3 M), K, Bun, Cr
ACEIs: Interactions K-sparing diuretics, Kcl, Renal failure→↑ K
Loop diuretics, alpha-blockers → Orthostatic hypotension
NSAIDs→↓ ACEIs effects
↑ levels of Dig, Li & glibenclamide
153
ACEIs: Patient Education Lifestyle modification
Cough
Taste disturbances resolve after 8-12 W
Not double the dose if you miss the dose
Orthostatic hypotension (esp with diuretics & alpha
blockers)
Angioedema & agranulocytosis symptoms
Milrinon Inj: 10 mg/10 ml, 20 mg/20 ml
Phosphodiesterase inhibitor → ↑ cAMP → ↑ intracellular Ca → ↑ contractility
for acute LV dysfunction (CHF deterioration, Pre & Post heart operation)
Dose: LD: 50 mcg/kg/10min, then 0.375-0.5 mcg/kg/min (up to 0.75 mcg/kg/min)
Dosage adjustment in RF
ADRs: headache, hypotension, ↓ plt 0.4%), arrhythmia
Interaction: Furosemide (Precipitation)
:وشد سا ی داسػبص یه ػا ث و بیی سكی
دس ثؼیبسی اص وشبة ب سكی ی ؿد. ثبیذ "سصی یه ػذد ث خض ددـج خؼ"یوؼی ثب دػشس لشف د
دس ثیبسا ؼ ػالز داس ث خلف ثب بسػبیی وی )دیوؼی اص وی دفغ ی ؿد ثبیذ سؼذی دص ؿد(
ادب ـد شین دائ داس Drug holidayسصی لف لشف شا ثب چه وشد غظز سدیض ؿد. ثشش اػز
دس غظز دیوؼی اسفبق یفشذ. fluctuationسا لشف وذ سب
، یب دبی ا دچبس س ؿذ یؼی اد ؿذیذ اش ثیبس ؿت ی ساذ ثخاثذ ثبیذ ػ سب ثبـز صیش ػشؽ ثزاسد
حیی داسد. ث ای ثیبس ثبیذ دیسسیه داد ؿد. ثششی دیسسیه فسصبیذ ی ثبؿذ. اش بیذوبی دس شید ی
154
سذاخ دیوؼی فشصبیذ اسفبق ثیفشذ ـى ػبص اػز سیؼه ػاسم دیوؼی سا ثبال ی ثشد، ی ی سا
بیشس وشد. آصؽ داد و اش دچبس هؼف وشاخ ػوالی ؿذ ثبیذ شاخؼ وذ غزایی و حبی مذاس ثیبس سا
ثبؿذ ث volume over loadثیـششی دشبػی اػز اػشفبد بیذ. دغ خبیب دیسسیه ب دس ثیبسای اػز و
خلف وؼبی و جشال ث اد سی ؿذ اذ )یه اسطاغ دضؿىی(
12 اص ثیؾ اش وذ، اػشفبد سا داس ثبیذ آسد یبد ث ثؼذ ػبػز 12 سب اش وذ فشاؽ سا داس لشف ثیبس اش
سا داس اص دص د اش. ىذ ثشاثش د یض سا ثؼذی دص ىذ اػشفبد سا دص آ اػز ثبؿذثشش زؿش ػبػز
افشاد اػز ثبسیه داس ای دسبی ی ددش. ثبؿذ داؿش ـسر داسػبص یب دضؿه ثب ثبیذ ثیبس ؿذ فشاؽ
داس مذاس ؿد ادب دسػز لشف وشد لف سب ثد شالت ثبیذ دغ ؼشذ، آ وذب لشف ثیـششی ؼ
صب كسر ث( شسا خلف ث) ثشبثالوش دیوؼی و داس ػالز ثیبس دس. ثبؿذ ثشاثش ثب ی ش دس
هشث 50 اص وشش ا لت هشثب اش و دی آصؽ ثیبس ث ثبؿی وبسدی ثشادی شالت ثبیذ ؿد، ی لشف
ابالدشی وبدشدشی خبیب ثؼیبس اسصؿذی داسذ، ث ظش .شدد سؼذی داسیؾ سب وذ شاخؼ حشب ؿذ دلیم دس
ب ث صاسسب اضاسسب وبسایی داسذ ی ثشش اػز دس لذ ا angiotansine receptor blockerی سػذ
اسب سغییش دذ.غیشلبث سح ثد سطی سا ث ای د ACEIدسب ثب آ ب ؿشع ـد اش ػاسم
ؿشع 5mg TDSیچ ب ثب heart failureدس ثؼوی اص ش بی خبف ثبیذ اص اػشفبد دص ؼ سشػیذ. دس
ARBب ACEIدس ػشق اثشا اػز ثب داد IIی وی چ دشفیط وی ث ؿذر اثؼش ث اثش آظیسبؼی
acute renalشفیص ؿذ وی خبسج ی ؿد ثیبس دس ؼشم ػشق اثشا ـبد ی ؿد خ ثذ د
failure ػب، وؼبی و و لشف وشد ه سا ثؼیبس سػبیز ی وذ )ػیؼش 60لشاس ی یشد. دس ػ ثبالی
ی IIآذػشش ثبال ی سد ػال دشفیط وی ثؼیبس اثؼش ث اثشار آظیسبؼی –آظیسبؼی -سی
ب سا ثب دصبی وشش ACEIؿد(، لشف وذب دیسسیه یب افشادی و ػبثم ی ـىالر ویی داسد ثبیذ
ؿشع وشد.
ػبػز ثؼذ اص غزا لشف ؿد ی خزة ابالدشی ثب غزا فشلی ی وذ. 2ػبػز لج اص غزا یب 2ثشش اػز وبدشدشی
ب 3سب 2بدشدشی ـبذ ؿد سغییش ؼ چـبیی اػز و ظشف ـى دیشی و ػال ثش ػشف ى اػز ثب و
ثششف ی ؿد ثیبس ثبیذ سح وذ.
خد high output failureثد. اكالح دیشی ث ب low output failureسب بت فش ؿذ دس اسد
ثبالسش اص حذ شب داسد لجؾ cardiac out putداسد. دس وؼی و آیه ثبؿذ یب دشوبسی سیشئیذ داؿش ثبؿذ
ػب اػز ی اش ثیبسی صی ای فشد دسب ـد دس بیز ی ساذ دش ث بسػبیی لت ؿد.