1

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

•

•

•

•

•

•

•

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 )

21

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

22

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.

23

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.

24

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

25

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.

26

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

27

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

28

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

29

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

30

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.

31

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.

32

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

33

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

34

• 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.

35

• 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.

36

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

37

• 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.

38

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

39

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

40

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

41

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

42

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

43

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

44

Development of Atherosclerotic

Plaques

NormalFatty streak

Foam cells

Lipid-rich plaque

Lipid core

Fibrous cap

Thrombus

Angina

45

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.

47

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.

48

- 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.

49

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.

52

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.

53

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

54

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.

56

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

63

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

67

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.

68

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)

69

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.