ESSENTIAL HYPERTENSION , COMBINATION OF CCB AND ARB,

CHOICE AGENTS

BYDr. BAMBANG SN, Sp. PD

DEPARTMENT OF INTERNAL MEDICINEGENERAL HOSPITAL OF Dr. SOEDARSO

PONTIANAK

Presented on Round Table Discussion of Hypertension

April, 07th 2013, Pontianak, West Kalimantan

I. INTRODUCTIONHypertension is still an important problem in the world time by time, because of highly prevalence and its serious complication esspecially cardio vascular disease (CVD).

More than 95% cases is essential hypertension, the rest is secondary.Associated with modern style, the risk factors such as sedantary life, physical inactivity, hyperlipidemie, obesity, distress, and tobacco smoking have important role on pathogenesis essential hypertension.

Life style modification is a basic way in management of hypertension before or together medication treatment.

Provider must recognize profile of anti-hypertensive agent that will be given to hypertensive patient for safety and better result.

Blood pressure can be controlled by medication besides life style modification to avoid or delay acute or chronic complication esspecially CVD.

II. PATHOGENESIS II. PATHOGENESIS There are many factors contribute to controle blood There are many factors contribute to controle blood

pressure, such as genetic, obesity, stress, sodium pressure, such as genetic, obesity, stress, sodium intake, nephron number and endothelium derived intake, nephron number and endothelium derived factors.factors.

Renin angiotensin aldosteron system is the most Renin angiotensin aldosteron system is the most important system, that regulate blood important system, that regulate blood pressurepressure

When thWhen thisis system does uncontrole, blood pressure will system does uncontrole, blood pressure will go up persistanly and hypertension will accure. go up persistanly and hypertension will accure.

To control and lower blood pressure, we have to stop To control and lower blood pressure, we have to stop production of angiotensinproduction of angiotensin II II or eliminate its effect on or eliminate its effect on the receptor.the receptor.

All conditions as risk factors of All conditions as risk factors of hypertension produce oxidatif stress, that hypertension produce oxidatif stress, that affect endothelial dysfuction and smooth affect endothelial dysfuction and smooth muscle activation.muscle activation.

Treatment of hypertension must be started Treatment of hypertension must be started by lifestyle modification and then followed by lifestyle modification and then followed drug medication.drug medication.

Lifestyle modification incluLifestyle modification includede weight weight reduction, eating plan, sodium reduction reduction, eating plan, sodium reduction intake, phisycal activity and moderation intake, phisycal activity and moderation alcohol consumption and so on.alcohol consumption and so on.

Some of Factors Involved in Controlling Blood Pressure

Excess Reduced Stress Genetic Obesity Excess Reduced Stress Genetic Obesity EndotheliumEndothelium sodium nephron alteration derivedsodium nephron alteration derived intake number factors intake number factors

Renal Decreased Sympathetic Renin Cell Hyper-Renal Decreased Sympathetic Renin Cell Hyper- sodium filtration nervous over angiotensin membrane insulinemiasodium filtration nervous over angiotensin membrane insulinemia retention surface activity excess alteration retention surface activity excess alteration

Fluid VasoFluid Vaso volume constrictionvolume constriction

Preload Contractability Functional Preload Contractability Functional StructuralStructural constriction constriction hypertrophyhypertrophy

BLOOD PRESSURE = CARDIAC OUTPUT X PERIPHERAL RESISTANCEBLOOD PRESSURE = CARDIAC OUTPUT X PERIPHERAL RESISTANCE Hypertension = Increased CO and/or Increased PRHypertension = Increased CO and/or Increased PR

AutoregulationAutoregulation

The Renin-Angiotensin-Aldosteron System.

Adrenal Kidney Intestine CNS Peripheral nervous Vaskular Heart cortex system smooth muscle Adrenergic facilitation Aldosteron Contractility Symphatetic discharge Distal Nephron Sodium and Thirst Vasopressin VasoconstrictionReabsorption water reabsortion salt appetite release

Maintain or increase Total peripheral Cardiac ECFV resistance output

ANGIOTENSINOGEN Renin ANGIOTENSIN I Converting enzyme ANGIOTENSIN II

Angiotensinase A

Macula densa signalRenal arteriolar pressureRenal nerve activity

ANGIOTENSIN III

Angiotensinogen

Angiotensin I

Angiotensin II

AT1 Receptor AT2 Receptor

VasoconstrictionSalt/water retentionRemodelling

AntiproliferativeCell differentiationTissue repair

VasodilationNatriu-/diuresisAnti-remodelling

NO

BK IIReceptor

ChymaseTrypsinPeptidase

Renin

ACE-Kininase II

Bradykinin

InactiveDegradationproducts

ACE-I

ARB

The Role of ACE Inhibitor and ARB in Decreasing Blood Pressure

Renin-Angiotensin Aldosterone System

Angiotensinogen

Non-ACE pathways(eg, chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Renin Angiotensin I

Angiotensin IIACE

Cough,angioedema

Benefits? Bradykinin Inactive

fragments

Vasodilation Antiproliferation

(kinins)

Aldosterone AT2

AT1

III. Classification of Hypertension

• The classification of hypertension is changed time by time according to the improvement and development knowledge and experiences.

• To be called hypertension, if blood pressure the same or more 140/90 mmHg.

Blood Pressure Classification (JNC 7)

Normal <120 and <80

Prehypertension 120–139 or 80–89Stage 1 Hypertension 140–159 or 90–99Stage 2 Hypertension >160 or >100

BP Classification SBP mmHg DBP mmHg

Blood Pressure Classification (ESH)

CategoryCategory SSyystolistolicc (mmHg)(mmHg)

DDiiastoliastolicc (mmHg) (mmHg)

OptimalOptimal <120<120 anandd <80<80Normal Normal 120–129120–129 anandd 80–8480–84High High NormaNormall 130–139130–139 and/and/

oror85–8985–89

HHyypertenpertentiontionGradeGrade 1 ( 1 (mild)mild) 140–159140–159 and/and/

oror90–9990–99

GradeGrade 2 ( 2 (moderatemoderate)) 160–179160–179 and/and/oror

100–109100–109

GradeGrade 3 ( 3 (severesevere)) 180180 and/and/oror

110110Guidelines Committee. J Hypertens 2003;21:101153

Table 2. Awareness hypertension people

• How serious and dangerous of hypertension because it has many complications, acute and chronic esspecially cardiovascular events.

• It is our task and responsibility to socialize and inform about hypertension and its implication to all people, esspecially those at risk.

• Unfortunetelly not all people know about their blood pressure, also hypertension patients do not understand well and not allert to seek medical acces.

IV. Prevalence of Hypertension

• In fact, prevalence of hypertension is increased time by time.

• It is influenced by several condition and risk factors. The older people the higher blood pressure.

Franklin, S.S., J Hypertens 1999; 17 (suppl 5): S29-S36

Hypertension is one of the most frequent clinical discorders.

0

10

20

30

40

50

60

70

18-29 30-39 40-49 50-59 60-69 70-79 80+

SBP > 140 mm Hg DBP > 90 mm Hg

age (yrs)

prev

alen

ce o

f hyp

erte

nsio

n (%

)

4 11

21

44

54

64 65

Prevalence of Hypertension

V. Complication of hypertension

• Clinical trials proved, the high corellation between hypertension and prevalence of stroke.

• People with hypertension have high risk to have chronic renal diseases. The higher blood pressure the hinger the risk decreasing of renal function.

• Systolic blood pressure interact with diabetes mellitus to increase risk of cardiovascular disease.

BP directly correlates with risk of stroke

Adapted from He and Whelton, J Hypertens, 1999.

<112 112- 118- 121- 125- 129- 132- 137- 142- ≥151<71 71- 76- 79- 81- 84- 86- 89- 92- ≥98

Rel

ativ

e ris

k of

str

oke

mm Hg

0

1

2

3

45

6

7

8

9

Systolic BPDBP

Systolic BP

Diastolic BP

MRFIT

Hypertension Linked To Chronic Renal Disease Among 332,544 Men Screened for MRFIT

0

50

100

150

200

250

<8080-84

85-8990-99

100-109110

180 160-179 140-159 130-139 120-129 <120

Systolic BP (mm Hg) Diastolic BP (mm Hg)

Adapted from Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.© Massachusetts Medical Society

250

200

150

100

50

0Age

-Adj

u st e

d R

ate

o f E

S RD

Per

1 00 .

0 00

P er s

o n-Y

e ar s

Elevated systolic BP interacts with diabetes to increase CVD risk

MRFIT: men with diabetes and elevated systolic BP are at greater risk of CVD than those without

diabetes

0

50

100

150

200

250

300

<120 120-139 140-159 160-179 180-199 ≥200

CVD

dea

ths

per 1

0,00

0 pe

rson

-ye

ars

Systolic BP (mm Hg)

Patients with diabetesPatients without diabetes

Stamler et al, Diabetes Care, 1993.

VI. Treatment of Hypertension• Trials and experiences indicate that decreasing blood

pressure decreasing prevalence all complication.• Every lowering systolic blood pressure of 23 mmHg, lower

incidens of stroke, heart failure and myocardial infartion.• Doctors have to initiate treatment as soon as possible for

patients with hypertension, to ovoid and eliminate acute or chronic complication.

• There are 2 ways approachs, the 1st is nonfarmacologic and the 2nd is farmacologic. Don’t wait to treat hypertension, more earlier more better result.

In every 23 mmHg reduction in Systolic Blood In every 23 mmHg reduction in Systolic Blood Pressure, Pressure, lowers incidence of........lowers incidence of........

-42%

-26%-29% -30% -31%

-45%

-30%

-15%

0%

Per

cent

Red

uctio

n

*Fatal and nonfatal heart failure and nonfatal myocardial infarction and sudden death **Fatal and nonfatal heart failure and nonfatal myocardial infarction, sudden death and stroke

* **Stroke All cardiac

end pointsMIHeart

Failure

All fatal/ nonfatal cardiovascular

end points

Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB,

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

http://www.nice.org.uk/download.aspx?o=CG034fullguideline.Accessed June 2006

UK NICE Guidelines: Treatment for Recent Diagnosis of Hypertention

*If ACE inhibitor (ACEI) not tolerated

ACEI (or ARB*) + CCB orACEI (or ARB*) + thiazide diuretic

<55 years

ACEI (or ARB*) + CCB + diuretic

CCB or thiazide-type diureticACEI (or ARB*)

55 years or black at any age

Add further diuretic therapy, α-blocker, or β-blocker.

Consider seeking specialist advice

Step 1

Step 2

Step 3

Step 4

Lifestyle ModificationJNC VII

Drugs RecomendationJNC VII/ WHO

• Diuretic• Beta blocker• ACE inhibitor• Calcium channel blocker• Angiotensin receptor blocker

Diuretic

AT1 receptorblocker

Calcium antagonist

ACE inhibitor

Alpha blocker

Beta blocker

European Society Of Hypertension

2003

Possible combination of different classes of anti hypertension drugs

Most rationalcombination

Proven bene-ficial in trialsJournal. Of Hypertension 2003

Current Guidelines Recommend Initiating Combination Therapy Early in Patients with Stage 2 Hypertension or High Cardiovascular Risk

• JNC 7 guidelines state1:“When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs...”

• ESH/ESC guidelines state2:“A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high.”

1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587

ESH = European Society of HypertensionESC = European Society of CardiologyJNC = Joint National Committee

Angiotensin II Effects

– Vasoconstriction– Aldosteron secretion– Sodium reabsorption– Symphatic activation– Vasopressin release– Hypertrophy and proliferation of

myocardium and vascular cells

ARB

AT Receptors:•Heart•Vascular•Lung•Liver•Kidneys•Adrenal, Prostate•Placenta, Brain

Angiotensin Receptor Blocker

• Angiotensin Receptor– Mostly on heart and vascular– Another organs : lungs, liver, kidneys,

adrenal gland, postate gland, brain, placenta

– AT1 & AT2

– AT1 effects dominantly on cardiovascular organ

counter-regulation synergi

Synergisticlowering BP

Increased cllinical effects

Amlodipin Arteriodilation Peripheral Edema Effective in low renin level Decreased myocardial ischemia

Amlodipin Stimulates RAS Minimal effect on

CHF and kidneys

Rational Concept of CCB-ARB

Valsartan Venodilation Decreased peripheral edema Effective in high renin level No effect on cardiac ischemia

Valsartan Inhibits RAS Usefull on CHF and

kidneys BP

ARB minimizes CCB side effect– peripheral edema

CCB mendilatasi arteri

Diameter vena tidak berubah

ARB mendilatasi arteri dan vena

Single mechanism of CCB

Combination mechanism of CCB+ARB

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:4348

Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131

Illustration modified from www.lotrel.com

Artery Dilation

(CCB andARB)

Vein Dilation(ARB)

Capillary bed

Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol

1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827