Jiří Slíva, MD, PhD.

HypertenzionHypertenzion

Cardiovascular diseases (CVDs)Cardiovascular diseases (CVDs)

• CVDs are the number one cause of death globally: more people die annually from CVDs than from any other cause.

• An estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million were due to coronary heart disease and 6.2 million were due to stroke.

• Low- and middle-income countries are disproportionally affected: over 80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women.

• By 2030, almost 25 million people will die from CVDs, mainly from heart disease and stroke. These are projected to remain the single leading cause of death.

• Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity, raised blood pressure, diabetes and raised lipids.

• 7.5 million deaths each year, or 13% of all deaths can be attributed to raised blood pressure. This includes 51% of deaths due to strokes and 45% of deaths due to coronary heart disease.

WHO, 2012

Prevalence & well-controlled hypertenzion Prevalence & well-controlled hypertenzion in the Czech republic in 2000/01 in the Czech republic in 2000/01

testedtested33253325

normotenzionnormotenzion20842084

hypertenzionhypertenzion1241 (37.3 %)1241 (37.3 %)

undiagnosedundiagnosed414414

diagnoseddiagnosed827 (66.6 %)827 (66.6 %)

untreateduntreated202202

treatedtreated625 (50.4 %)625 (50.4 %)

uncontrolleduncontrolled385385

well-controlledwell-controlled240 (19.3 %)240 (19.3 %)

Definition and classification of BPDefinition and classification of BP

WHO & ISH, 1999

target for DM, espec. in the pasttarget for DM, espec. in the pasttarget for everyonetarget for everyone

Optimal

Normal

High normal

Mild HT

Moderate HT

Serious HT

Isolated systolic HT

Category Systolic pressure Diastolic pressure

Age-standardized prevalence of raised blood pressure in adults aged 25+ years, by WHO Region and

World Bank income group, comparable estimates

WHO, 2008

• the number of people with hypertension rose from 600 million in 1980 to nearly 1 billion in 2008

EMR - Eastern Mediterranean, SEAR - South East Asia, WPR - Western Pacific

0% 5% 10% 15% 20% 25%

astma

alergie

cukrovka

vysoký krevní tlak

srdeční záchvat

mozková mrtvice

artróza/artritida

osteoporóza

žaludeční/dvanáct. vřed

zhoubný nádor

migréna

chronická úzkost a deprese

chronické onem.páteře

chronický zánět moč.měchýře

onem.štítné žlázy

potíže se střevy

chronické onem.kůže

ostatní nemoci

muži

ženy

Prevalence of HT & most common diseases in the Czech republicPrevalence of HT & most common diseases in the Czech republic

June, 2005ÚZIS

Standard. úmrtnost na oběhové nemoci, muži, 0-64

60

75

90

105

120

135

150

165

180

195

210

225

24019

80

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

Roky

na 1

00 0

00 o

byva

tel

Průměr EU 15 před 1.05.2004

Průměr přistupující 10.

ČR

ÚZIS, 2005

Standard. úmrtnost na oběhové nemoci, ženy, 0-64 let

15

25

35

45

55

65

75

85

9519

80

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

Roky

na 1

00 0

00 o

byva

tel

Průměr EU 15 před 1.05.2004

Průměr přistupující 10.

ČR

ÚZIS, 2005

Standard. úmrtnost na oběhové nemoci, muži, 65+

2000

2500

3000

3500

4000

4500

5000

5500

6000

650019

80

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

Roky

na 1

00 0

00 o

byva

tel

Průměr EU 15 před 1.05.2004Průměr přistupující 10.ČR

ÚZIS, 2005

Standard. úmrtnost na oběhové nemoci, ženy, 65+

1000

1500

2000

2500

3000

3500

4000

4500

5000

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

Roky

na 1

00 0

00 o

byva

tel

Průměr EU 15 před 1.05.2004

Průměr přistupující 10.

ČR

ÚZIS, 2005

Meta-analysis of 61 prospective, observational studies (1 million of adult patients; 12.7 million of patient/years)

average decrease of

SBP by 2 mmHg 10% decreased

risk of mortality in patients with stroke

7% decreased risk of mortality in patients with CAD

Lewington et al. Lancet. 2002;360:1903–1913

Small change =Small change = high benefithigh benefit

1999 WHO-ISH HYPERTENSION PRACTICE GUIDELINES FOR PRIMARY CARE PHYSICIANS

Which Factors Influence Prognosis?

I. Used for risk stratification• Levels of systolic and diastolic blood

pressure (Grades 1-3)• Men >55 years• Women >65 years• Smoking• Total cholesterol >6.5 mmol/L (250

mg/dl)• Diabetes• Family history of premature

cardiovascular disease

1999 WHO-ISH HYPERTENSION PRACTICE GUIDELINES FOR PRIMARY CARE PHYSICIANS

Which Factors Influence Prognosis?

II.Other factors adversely influencing prognosis• Reduced HDL cholesterol• Raised LDL cholesterol• Microalbuminuria in diabetes• Impared glucose tolerance• Obesity• Sedentary lifestyle• Raised fibrinogen• High risk socioeconomic group• High risk ethnic group• High risk geographic region

1999 WHO-ISH HYPERTENSION PRACTICE GUIDELINES FOR PRIMARY CARE PHYSICIANS

Stratifying Risk - Quantifying Prognosis

1999 WHO-ISH HYPERTENSION PRACTICE GUIDELINES FOR PRIMARY CARE PHYSICIANS

Effects of Antihypertensive Treatment in Randomised Controlled Trials

- avoidance of NSAIDs, sympathomimetics, CSs, hormonal CC

- weight reduction

- sodium intake reduction to 5-6 g/day

- moderation of alcohol consum. < 30 g/day - M < 20 g/den - F

- increased aerobic physical activity

- smoking cessation

- more fruits, vegetables, omega-3 FA

Non-pharmacological approachesNon-pharmacological approaches

- monotherapy is successful in cca 30 % - inicially combination th. when SBP > 160 and/or DBP > 100

Antihypertensives:ю diureticsю -blockersю ACEIsю CaIsю antagonists of ATIIю centrally acting drugs (-methyldopa, clonidine, moxonidine)ю blockers of periph. -receptors (prazosin, terazosin)ю direct vasodilators (dihydralazine, endralazine, minoxidile)

Pharmacological approachesPharmacological approaches

Sites of action of antihypertensivesSites of action of antihypertensives

Possible combinations of AHsPossible combinations of AHs

2007 ESH/ESC guidelines

Possible combinations of AHsPossible combinations of AHs

NICE/BHS 2006 recommendations

A = ACE inhibitor (consider angiotensin-II receptor antagonist if ACE inhibitor–intolerant); C = calcium channel blocker; D = thiazide or thiazide-type diuretic.

Possible combinations of AHsPossible combinations of AHs

NICE/BHS 2011 recommendations

A = ACE inhibitor (consider angiotensin-II receptor antagonist if ACE inhibitor–intolerant); C = calcium channel blocker; D = thiazide or thiazide-type diuretic.

thiazide diuretics

ACEIor

AT1 blockersbeta-blockers

CaI-dihydropyridines

Non DHP CaIs + BBs = CIACEIs/AT1 blockers + BBs = suitable in chronic HF, CADACEIs + AT1 blockers = suitable in extensive proteinuria

Possible combinations of AHs – CZPossible combinations of AHs – CZ

ACEI/sartans + thiazides:

HT + HF, HT + stroke in history

ACEI/sartans + CaI:

HT + AS, HT + nephropathy, metabolic sy, DM

CaI + thiazides:

HT in elderly

ACEI + BB:

HT + CAD, HT + HF

Alpha-blockers + BB:

pheochromocytoma

ACEI + sartans:

HT + nephropathy

ACEI/sartans + thiazides:

HT + HF, HT + stroke in history

ACEI/sartans + CaI:

HT + AS, HT + nephropathy, metabolic sy, DM

CaI + thiazides:

HT in elderly

ACEI + BB:

HT + CAD, HT + HF

Alpha-blockers + BB:

pheochromocytoma

ACEI + sartans:

HT + nephropathy

Suitable combinationsSuitable combinations

LOX-1

VCAM

ICAM

Jacoby DS, Arch Intern Med. 2003;163:1155-64.

RAAS & atherothrombosis

IL-6

PDGF

NOS

PAI-1

TF

TGF-

thrombosis

inflammation

fibrous tis. prolif.

ED lipids oxidation

leu

adhesionAT1R

hypertenion

angiotensin II

Renin-Angiotensin SystRenin-Angiotensin Systeemm

ACE = Angiotensin-converting enzyme; CAGE = Chymase-angiotensin generating enzyme

Renin

ACE cascade

ACE

BradykininBradykinin

InactiveInactivesubstancesubstancess

Non-ACEcascade

Tissueplasminogen

activatorCathepsin G

ChymChymaseaseCAGECAGE

Angiotensinogen

Angiotensin I

Angiotensin II

Sympaticusactivation

Vasoconstriction Cellproliferation

Sodium & waterretention

AT1-receptor

Hypertension

sartans

ACEIs

aliskiren

Adapted from Hollenberg 1998.

Pharmacodynamic effects of ARBs & ACEIs

decreased PVR (more pronounced in ACEIs) dilation of vas efferens decreased release of aldosteron and ADH => less thirsty, natriuresis, potassium retention decreased release of NE fibrinolysis stimulation antiproliferatory activity

ACE inhibitorsACE inhibitors

• Mech. of eff.: inhibition of the conversion of AT I onto AT II, degradation of bradykine, decrease of PVR and slight venodilatation vasokonstriction ATII, secretion of aldosterone -natriuresis– regression of hypertrophia of left ventricle and vessel’s wall

• heart insufficiency - mortality rate 20‒30 % glom. pressure - proteinuria during DM nephropatia• - cardioprotective, vasoprotective and renoprotective eff.• AE: hypotension after initial dose, renal impairment (acute renal

insufficiency, hyperkalaemia, dry cough, angioedema• short acting: captoprilecaptoprile - three times a day• medium term: enalaprileenalaprile - twice a day• long acting: perindoprile, lisinoprile, ramiprile, spiraprile, perindoprile, lisinoprile, ramiprile, spiraprile,

trandolapriletrandolaprile

ACEIs

Time to onset of action (h)

Duration of action (h)

Dose (mg)Substance

short-term actingshort-term acting

medium-term actingmedium-term acting

long-term actinglong-term acting

- arterial HT with chronic HF - HT with either systolic dysfunction of left ventricle

- HT after MI with systolic dysfunction of left ventricle

- HT in DM

- HT in patients with kidneys disease with proteinuria/renal insufficiency

ACEIs are suitable drugs in HTACEIs are suitable drugs in HT

ACEIs in the treatment of HTACEIs in the treatment of HT

• no negative metabolic effects (saccharides, lipids)

• significantly decrease heart and vessels hypertrophy

• cause regression of collagen fibres in hypertroph. myocardium

• decelerate progression of DM nephropathy

• decrease insulinoresistance

• possess cardioprotective eff. • prevent dilated cardiomyopathy• decrease mortality in chronic HF

• prevent kalium loss during use of diuretics

Antagonists of AT IIAntagonists of AT II

• Antagonists of AT II

– syn. „sartans“, ARB, AT1 receptor antagonists

– 1st line antihypertensives, 2nd line in HF (after failure of ACEIs)

– cardioprotective & nephroprotective eff.

– losartan, valsartan, irbesartan, eprosartan, candesartan, olmesartan,

telmisartan,……

†

CaIcium ion channel blockers

Classification - examples

1st gen. 2nd gen. 3rd gen.

Mechanism of action

-adrenergics-adrenergics• Centrally acting - 2, I1 rec. – decrease tonus of

sympathicus

– methyldopa - 2-rec.

– moxonidin, rilmenidin - imidazoline I1 rec. agonists

– reserpine – indirect sympatholytic agent

• Combined - urapidile - block postsyn. 1-rec.,

activation of 5-HT1Arec. in CNS

• Peripheral -blockers 1 - prazosin, doxazosin, metazosin, terazosin

1+2 - phentolamin

+ - labetalol, carvedilol

Diuretics

CLASSIFICATION OF CLASSIFICATION OF BETA-BLOCKERS (BB)BETA-BLOCKERS (BB)

Non-selective:Non-selective: on on 11 and and 22 metipranol, sotalol, propranolol, timolol, metipranol, sotalol, propranolol, timolol,

Cardioselective: Cardioselective: mostly onmostly on 11

bisoprolol, metoprolol, atenolol, betaxololbisoprolol, metoprolol, atenolol, betaxolol

Non-selective with ISA: Non-selective with ISA: partialpartial --agonistic activityagonistic activity

pindolol, bopindolol, oxprenolol,levobunololpindolol, bopindolol, oxprenolol,levobunolol

Cardioselective with ISA: Cardioselective with ISA: acebutolacebutol (ACECOR),(ACECOR), celiprololceliprolol

BB with vasodilatory eff.: BB with vasodilatory eff.:

blockage blockage 11 + + 22++ 1 1 carvedilol, labetalolcarvedilol, labetalol

blockage blockage 11 + + 11++ 2 2 + ISA + ISA celiprolol - TENOLOCceliprolol - TENOLOC

blockage blockage 11 + + 2 2 + ISA + ISA bopindolol - SANDONORMbopindolol - SANDONORM

HYDROPHILICITY x LIPOPHILICITYHYDROPHILICITY x LIPOPHILICITY

a) lipophilic moleculesa) lipophilic molecules - - cross to CNScross to CNS (insomnia, depression) (insomnia, depression) - - metabolized in the livermetabolized in the liver ( ( bioavailability) bioavailability) - - variable levelvariable level (CYP polymorphism) (CYP polymorphism) -- metoprolol,... metoprolol,...

b) hydrophilic moleculesb) hydrophilic molecules - - less ADRsless ADRs (those of CNS origin) (those of CNS origin) - - eliminated via kidneyseliminated via kidneys (longer eff., (longer eff., bioavailability) bioavailability) -- atenolol, bisoprolol... atenolol, bisoprolol...

NO DIFFERENCE IN CLINICAL EFF. WAS DEMONSTRATEDNO DIFFERENCE IN CLINICAL EFF. WAS DEMONSTRATED

• no salt restrictions

• weight reduction not recommended

• drug of choice is methyldopa

HT in pregnancyHT in pregnancy

BP reductions achieved in recent RCTsBP reductions achieved in recent RCTs

Mancia et al. J Hypertens. 2002;20:1461-1464.

Adherence & persistence Adherence & persistence (st.p. AIM, n = 30 028)(st.p. AIM, n = 30 028)

Mangiapane S, Busse R: Prescription prevalence and continuing medication use for secondary prevention after myocardial infarction: the reality of care revealed by claims data analysis. Dtsch Arztebl Int 2011; 108: 856-862