ESSENTIAL HYPERTENSION , COMBINATION OF CCB AND ARB, CHOICE AGENTS

BY Dr. BAMBANG SN, Sp. PD DEPARTMENT OF INTERNAL MEDICINE GENERAL HOSPITAL OF Dr. SOEDARSO PONTIANAK

Presented on Round Table Discussion of Hypertension April, 07th 2013, Pontianak, West Kalimantan

I. INTRODUCTION
Hypertension 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 antihypertensive 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

There are many factors contribute to controle blood pressure, such as genetic, obesity, stress, sodium intake, nephron number and endothelium derived factors. Renin angiotensin aldosteron system is the most important system, that regulate blood pressure When this system does uncontrole, blood pressure will go up persistanly and hypertension will accure. To control and lower blood pressure, we have to stop production of angiotensin II or eliminate its effect on the receptor.

All conditions as risk factors of hypertension produce oxidatif stress, that affect endothelial dysfuction and smooth muscle activation. Treatment of hypertension must be started by lifestyle modification and then followed drug medication. Lifestyle modification include weight reduction, eating plan, sodium reduction intake, phisycal activity and moderation alcohol consumption and so on.

Some of Factors Involved in Controlling Blood Pressure

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

Renal sodium retention

Decreased filtration surface

Sympathetic nervous over activity

Renin angiotensin excess

Cell membrane alteration

Hyperinsulinemia

Fluid volume

Vaso constriction

Preload

Contractability

Functional constriction

Structural hypertrophy

BLOOD PRESSURE = CARDIAC OUTPUT Hypertension = Increased CO

X and/or Autoregulation

PERIPHERAL RESISTANCE Increased PR

The Renin-Angiotensin-Aldosteron System.

ANGIOTENSINOGEN Renin

ANGIOTENSIN I Converting enzyme

ANGIOTENSIN II Angiotensinase A

Macula densa signal Renal arteriolar pressure Renal nerve activity ANGIOTENSIN III

Adrenal cortex

Kidney

Intestine

CNS

Peripheral nervous system Adrenergic facilitation

Vaskular smooth muscle

Heart

Aldosteron Symphatetic discharge Distal Nephron Reabsorption Sodium and water reabsortion Maintain or increase ECFV Thirst salt appetite Vasopressin release Total peripheral resistance Vasoconstriction

Contractility

Cardiac output

The Role of ACE Inhibitor and ARB in Decreasing Blood Pressure

Angiotensinogen

Renin
ACE-I

Chymase Trypsin Peptidase

ARB

Angiotensin I ACEKininase II Angiotensin II

Bradykinin

AT1 Receptor Vasoconstriction Salt/water retention Remodelling

AT2 Receptor

Inactive Degradation products

BK II Receptor

NO
Vasodilation Natriu-/diuresis Anti-remodelling

Antiproliferative Cell differentiation Tissue repair

Renin-Angiotensin Aldosterone System

Non-ACE pathways
(eg, chymase)
Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Angiotensinogen Renin

Angiotensin I
ACE Angiotensin II Aldosterone

AT1

AT2

Cough, angioedema Benefits?

Bradykinin

Inactive fragments

Vasodilation Antiproliferation (kinins)

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)

BP Classification SBP mmHg

Normal Prehypertension
Stage 1 Hypertension

DBP mmHg

<120 120139 140159

and or or

<80 8089 9099

Stage 2 Hypertension

>160

or

>100

Blood Pressure Classification (ESH)

Category Optimal Systolic (mmHg) <120 and Diastolic (mmHg) <80

Normal
High Normal Hypertention

120129
130139

and
and/or

8084
8589

Grade 1 (mild)
Grade 2 (moderate) Grade 3 (severe)

140159
160179 180

and/or
and/or and/or

9099
100109 110

Guidelines Committee. J Hypertens 2003;21:101153

Table 2. Awareness How serious and dangerous of hypertension hypertension people acute because it has many complications,

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.

Prevalence of Hypertension
Hypertension is one of the most frequent clinical discorders.
prevalence of hypertension (%)

70

60
50

SBP > 140 mm Hg DBP > 90 mm Hg

54 44

64

65

40
30

20
10 0
age (yrs) 4 11

21

18-29

30-39

40-49

50-59

60-69

70-79

80+

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

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

MRFIT
9

Relative risk of stroke

8 7 6 5 4 3 2 1 0

Systolic BP Diastolic BP

Systolic BP DBP

<112 <71

11271-

11876-

12179-

12581-

12984-

13286-

13789-

14292-

151 98

mm Hg Adapted from He and Whelton, J Hypertens, 1999.

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

250 250 200 200 150 150

100 100 5050 00

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

<80

110 100-109 90-99 85-89 80-84

Systolic BP (mm Hg)

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

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 300
CVD deaths per 10,000 personyears Patients with diabetes
250

Patients without diabetes

200

150

100

50

0
<120 120-139 140-159 160-179 180-199 200

Systolic BP (mm Hg)

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. Dont wait to treat hypertension, more earlier more better result.

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

Stroke All cardiac Heart end points * Failure MI
All fatal/ nonfatal cardiovascular end points **

0%

Percent Reduction

-15%

-30%

-26%

-29%

-30%

-31%

-45%

-42%

*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

Algorithm for Treatment of Hypertension

Lifestyle Modifications

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

Initial Drug Choices

Without Compelling Indications

With Compelling Indications

Stage 1 Hypertension
(SBP 140159 or DBP 9099 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

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)

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

UK NICE Guidelines: Treatment for Recent Diagnosis of Hypertention

<55 years Step 1 ACEI (or ARB*) 55 years or black at any age CCB or thiazidetype diuretic

Step 2

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

Step 3

ACEI (or ARB*) + CCB + diuretic Add further diuretic therapy, -blocker, or blocker. Consider seeking specialist advice
http://www.nice.org.uk/download.aspx?o=CG034fullguideline. Accessed June 2006

Step 4

*If ACE inhibitor (ACEI) not tolerated

Lifestyle Modification JNC VII

Drugs Recomendation JNC VII/ WHO

Diuretic Beta blocker ACE inhibitor Calcium channel blocker Angiotensin receptor blocker

Possible combination of different classes of anti hypertension drugs

European Society Of Hypertension 2003

Beta blocker

Diuretic AT1 receptor blocker

Alpha blocker

Calcium antagonist
Most rational combination

Journal. Of Hypertension 2003

ACE inhibitor

Proven beneficial in trials

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.
ESH = European Society of Hypertension ESC = European Society of Cardiology JNC = Joint National Committee
1Chobanian 2Mancia

et al. Hypertension 2003;42:120652 et al. J Hypertens 2007:25:110587

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

Rational Concept of CCB-ARB

counter-regulation synergi
Amlodipin Arteriodilation Peripheral Edema Effective in low renin level Decreased myocardial ischemia
Valsartan Inhibits RAS Usefull on CHF and kidneys

BP

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

Synergistic lowering BP Increased cllinical effects

Amlodipin Stimulates RAS Minimal effect on CHF and kidneys

ARB minimizes CCB side effect peripheral edema

CCB mendilatasi arteri Diameter vena tidak berubah ARB mendilatasi arteri dan vena

Single mechanism of CCB

Illustration modified from www.lotrel.com

Combination mechanism of CCB+ARB

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White et al. Clin Pharmacol Ther 1986;39:4348 Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131

Artery Dilation (CCB and ARB)

Vein Dilation (ARB)

Capillary bed
Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White 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