HYPERTENSI

Classification and management of blood pressure for adult*

BP Clasification Normal Prihypertension Stage 1 Hypertension SBP* mmHg < 120 120-139 140-159 DBP* mmHg And < 80 Or 80-90 Or 90-99 Lifestyle Modification Encourage yes yes Initial Drug Therapy Without Compelling With Compelling Indication Indications Drug (s) for No antihypertensive compelling drug indicate indication*** Thiazide-type diuretics for most. Drug(s) for the May consider ACE I combination or ARB, BB, CCB or indication*** other combination antihypertensive Two drug combination drugs (diuretics, for most** (usually ACEI, ARB, BB, thiazide-type diuretic CCB) as needed. and ACEI or ARB or BB or CCB).

Stage 2 Hypertension

> 160

Or > 100

Yes

DBP, diastolic blood pressure; SBP, sysolic blood pressure; Drug abbreviations : ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CCB, calsium channel blocker.

* Treatment determined by highest BP category. ** Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension, *** Treat patients with chronic kidney disease or diabetes to BP goal of < 130/80 mmHg

Clinical trial and guideline basis for compelling indications for individual drug classes
Recommended Drugs **

DIURETIC

Compelling Indication*

ALDO ANT

ACEI

ARB

CCB

BB

Clinical Trials Basis*** ACC/AHA heart failure guideline, MERITHF COPERNICUS, CIBIS, SOLVD, AIRE, ValHEFT, RALES ACC/AHA Post-MI guidelines, BHAT, SAVE, Capricorn , EPHESUS ALLHAT, HOPE, ANBP2, LIFE, CONVINCE NKF-ADA Guidelines, UKPDS, ALLHAT NKF Guidelines, Captopril trial, RENAAL, IDNT, REIN, AASK PROGRESS

Heart Failure Post myocardial infarction High coronary disease risk Diabets Chronic kidney disease Recurrent stroke prevention

Compelling

indications for anthihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP, ** Drug abbreviations : ACEI, angiiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ALDO ANT, aldosterone antagonis; BB, beta-blocker; CCB , calsium channel blocker. *** Condition for which clinical trials demonstrate benefit of specific classes of anti hypertensive drugs

Classification of hypertension according to aetiology

Primary (essential) hypertension Secondary hypertension
Renal hypertension Renoparenchymal hypertension; renovascular hypertension; post-kidney transplant hypertension Pheochromocytoma; primary hyperaldosteronism (Conns syndrome); deoxycorticosterone-producing tumours; adrenogenital syndrome; Cushing's syndrome; primary hyperrenism; acromegaly; hyperparathyroidism; endothelinproducing tumours; hypo- and hyperthyroidism (Pre-) eclampsia; transient hypertension Coarctation of the aorta; hyperkinetic heart syndrome; aortic valve insufficiency; sclerosis of the aorta; severe bradycardia; arteriovenous fistulae Oral contraceptives; high-dose mineralcorticoids or glucocorticoids; erythropoietin; cyclosporine; alcohol licorice Sleep apnoea syndrome; neurological disorders Stimpel. Arterial Hypertension, 1996; Walter de Gruyter Berlin, New York.

Endocrine hypertension

Pregnancy-specific hypertension Cardiovascular hypertension

Drug-/alimentation-induced hypertension Neurogenic hypertension

TABLE 6. Cardiovascular Risk Factors Major risk factors

Hypertension* Age (older than 55 for men, 65 for women) Diabetes mellitus* Elevated LDL (or total) cholesterol or low HDL cholesterol* Estimated GFR 60 mL/min Family history of premature cardiovascular disease (men aged 55 or women aged 65) Microalbuminuria Obesity* (body mass index 30 kg/m2) Physical inactivity Tobacco usage, particularly cigarettes

Target organ damage

Heart Left ventricular hypertrophy Angina/prior myocardial infarction Prior coronary revascularization Heart failure

Brain
Stroke or transient ischemic attack Dementia Chronic kidney disease Peripheral arterial disease Retinopathy
GFR indicates glomerular filtration rate.*Components of the metabolic syndrome. Reduced HDL and elevated triglycerides are components of the metabolic syndrome. Abdominal obesity is also a component of metabolic syndrome. Increased risk begins at approximately 55 and 65 for men and women, respectively. Adult Treatment Panel III used earlier age cutpoints to suggest the need for earlier action.

TABLE 7. Identifiable Causes of Hypertension

Chronic kidney disease Coarctation of the aorta Cushing syndrome and other glucocorticoid excess states including chronic steroid therapy Drug-induced or drug-related (see Table 18) Obstructive uropathy Pheochromocytoma Primary aldosteronism and other mineralocorticoid excess states Renovascular hypertension Sleep apnea Thyroid or parathyroid disease

Epidemiology of Hypertension

Factors affecting blood pressure

Temporary factors Posture Respiration Emotion (eg, defence reaction white coat hypertension) Exercise Meals Various drugs, lifestyle (tobacco, alcohol, etc.)

Temperature Bladder distension Pain

Other factors Age Race Circadian variability

Risk factors for the development of hypertension

Genetic predisposition Black race Diabetes mellitus

Hyperlipidaemia

Lack of exercise

Obesity
Distress (?)

Alcohol

Blood Pressure in a Resting Subject

Mechanisms Responsible for Blood Pressure Variability

Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT

CAD Death Rate per 10,000 Person-Years
80.6

48.3 37.4 31.0 23.8 20.6 25.8 16.9 24.6 13.9 34.7

43.8

38.1 25.2 24.9

25.3

100+

160+ 12.6 12.8 11.8 14010.3 11.8 8.8 8.5 9.2 159 120Systolic <120 139 BP (mm 90-99 80-89 75-79 70-74 <70 Hg) Diastolic BP (mm Hg)

Adapted with permission from Neaton et al. Arch Intern Med. 1992;152:56-64.

Organ Demage caused by Hypertension

Ten-year risk for CHD by SBP and presence of other risk factors. Source: Derived from K.M. Anderson, P.W.F. Wilson, P.M. Odell, W.B. Kannel. An updated coronary risk profile. A statement for health professionals. Circulation 1991;83:356362.

Hypertension and the risk of further disease

Disease Coronary artery disease Stroke Heart failure Peripheral vascular disease Relative risk
(hypertensives versus normotensives)

2- to 3-fold 7-fold 2- to 3-fold 2- to 3-fold

Glagovs Coronary Remodeling Hypothesis

Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows

Normal vessel

Minimal CAD

Moderate CAD Regression

Severe CAD

Adapted from Glagov et al. N Engl J Med. 1987;316:1371-1375.

Diffuse Disease: Effect on Angiographic Measurements

Arterial wall Lumen .5 mm

3 mm 4 mm
1 mm 2 mm

.5 mm

2.5 mm

3 mm
.5 mm

Plaque

2 mm

Measurements % Diameter stenosi Mean width segment (mm) MLD (mm) Plaque area (mm) 25 3.75 3.0 2.0 17 2.9 2.5 1.0

de Feyter et al. Circulation. 1991;84:412-423.

The Tight Stenosis Is Not the Active Lesion

A B

B A A
Atheroma Lumen

Rupture Site

Lipid Core

Images supplied by Steven E. Nissen, MD, Cleveland Clinic.

Pathophysiology of ACS: Disrupted Plaque

Thin cap Plaque rupture High macrophage content Large lipid core

Complete Incomplete coronary coronary occlusion occlusion Spontaneous lysis, repair, and wall remodeling
Temporary resolution Unstable angina of instability or nonQ-wave Future high-risk MI lesion

Acute MI

Adapted from Yeghiazarians et al. N Engl J Med. 2000;342:101-114.

Myocardial infraction Sudden death Coronary thrombosis Arrhytmia & loss of muscle

Myocardial ischaemia Remodelling Coronary artery disease Ventricular dilation Atherosclerosis, left Ventricular hypertrophy Heart failure Risk factors (hypertension, lowdensity lipoprotein, diabetes mellitus, etc)

Endstage heart disease

Figure 232-1. Patterns of ventricular hypertrophy. Specific patterns of ventricular remodeling occur in response to the imposed augmentation in work load. A pattern of hypertrophic growth characterized as concentric, in which increased mass is out of proportion to chamber volume, is particularly effective in reducing systolic wall stress (s) under conditions of heightened pressure load. In contrast, in volume overload conditions, in which the major stimulus is diastolic loading, a predominant finding is a great increase in the cavity size or volume. Although there can be extensive increases in mass, the relationship between mass and volume is either preserved or, in severe cases, reduced. The fundamental response is generated by cellular hypertrophy. However, the configuration of the new contractile tissue is specific and offsets the mechanical stimulus. [Modified from W Grossman et al in NR Alpert (ed): Perspectives in Cardiovascular Research. Myocardial Hypertrophy and Failure, vol 7. New York, Raven Press, 1993, with permission.]

Development of heart failure in the hypertensive patient

Sustained pressure overload
Genetic factors Mechanical stretch neurohormonal signalling Co-morbidities

Diastolic dysfunction Altered expression of contractility regulating genes Systolic dysfunction Heart Failure

Compensated concentric or eccentric hypertrophy

Microvascular abnormalities Apoptosis necrosis

Ischaemia

Cell loss

Decompensated concentric hypertrophy Decompensated eccentric hypertrophy

BP
A
Systolic dysfunction

B LVH
Diastolic dysfunction

Ejection fraction End diastolic volume LV dilation

Ventricular arrhytmias

Ejection fraction or End diastolic volume or LV size normal

Low cardiac output syncrome

LV filling pressure

BP = arterial blood pressure LVH = left ventricular hypertrophy

Pulmonary venous Congestion Dyspnea

Characteristics of concentric (CON) vs eccentric (ECC) hypertrophy and failure

Parameter CON hypertrophy
PLC (ANG II, a1, ET)

ECC hypertrophy
Cytokines (CT-1, ? TNF-a)

Failure

1. Chamber size 2. Wall thickness 3. Myocyte length 4. Myocyte cross-sectional area 5. Sarcomere assembly signalling

The hypertension to heart failure continuum

Hypertension Coronary artery disease
Coronary risk factors

LV hypertrophy
LV dilation
Diastolic Remodelling

Myocardial infarction
LV damage Systolic

LV dysfunction

Heart failure
Symptoms Decreased tissue perfusion Increased hospitalisations Death

Prognosis of Heart Failure Community Studies

100 90 Reported Framingham 1993 Hillingdon 1998

80 70 60 50 40

50% Survival

0 1 3 Months Hillingdon (n = 220) Framingham Women (n = 321) Framingham Men (n = 331)

12

24

Mortality in patients with heart failure in the Framingham study

Mortality at time from diagnosis of HF
2 years 6 years

Men

Women

37% 82%

33% 67%

Kannel (1991)

Hypertension and Stroke

Influence of antihypertensive therapy on the incidence of stroke and coronary events

Trial Numbers of events (or group of trials) (treated : control) Odds ratios and confidence limits (treated : control)
Treatment better Treatment worse

Reduction and SD

HDFP trial MRC trial 12 others All trials

Strokes 102 : 158 60 : 109 127 : 217 (Heterogeneity X2=0.85 NS) CHD events 275 : 343 222 : 234 174 : 194 (Heterogeneity X2=2.3 NS)

42% SD 6 2p<0.0001

HDFP trial MRC trial 12 others All trials

14% SD 5 2p<0.01 Differences in stroke and in CHD risk associated epidemiologically with a long-term difference of 56 mmHg DBP: 0.5 1.0 1.5

Stroke CHD 3540% 2025%

Reduction in stroke and coronary events in the HDFP trial, the MRC trial and in 12 other, smaller, randomised trials of antihypertensive therapy (mean DBP difference 56 mmHg for 5 years)

Collins (1990)

Hipertensi menyebabkan :
Deg. hyaline (lipohialinosis) arteriol otak infark lakuner Deg. Otot Polos arteriol otak berry aneurysm perdarahan subkortikal hipertensif Plak pada arteri basal otak karotis interna bifukarsio karotis trombosis dan emboli arteri otak

Hypertension and Renal Damage

Age-adjusted relative risk of end-stage renal disease due to any cause in the MRFIT study
Age-adjusted relative risk

25
20 15 10 5 1.0 0 SBP <12 0 DBP and <80 1.2 120 129 and <84 1.9 130 139 and <90 6.0 3.1 140 159 and <100 160 179 and <110
n=332 544 men aged 3557 years

22.1

11.2

180 210 209 and/or and 120 <120 Klag (1991)

1.HT TD a.afferen gelung glomerulus dan a.efferen meningkat

2.AT2 penyempitan a.afferen hipertensi glomeruler glomerulusklelorosis dan proteinuria. Protenuria diserap tubulus fibrosis interstitium gagal ginjal

DASH indicates Dietary Approaches to Stop Hypertension. *For overall cardiovascular risk reduction, stop smoking. The effects of implementing these modifications are dose- and time-dependent and could be greater for some individuals.

Therapy of Hypertension

Hypertension Treatments
Rules of Halves
50 % not diagnosed Hypertension

50 % Diagnosis

50 % not treated

50 % Treated

50 % 7 million pts poorly controlled

Hypertension in practice 2nd, Beevers & MacGregor

50 % well treated (12.5 % of all hypertensives)

Antihypertensive therapy and the prevention of cardiovascular complications

Cumulative incidence of cardiovascular complications in hypertensive patients with diastolic blood pressure of 90114 mmHg
Complications with lethal outcome (%) All cardiovascular complications (%) 60 50 40 30 60 50 40 30 20 Control Treated

20
10 0 0 1 2 3 4 5 Observation period (years)

10
0 0 1 2 3 4 5 Observation period (years)

Veterans Administration Cooperative Study Group (1970)

Blood pressure threshold levels for initiating antihypertensive therapy

Country/ organisation Diastolic blood pressure (mmHg) 95 95 90 95 UK New Zealand 100 100 Systolic blood pressure (mmHg) 160 160 140 150 160 170 Observation period (months) 36 36 36 36 36 6 90 90 90 Threshold value with additional risk factors (mmHg) 140/90

WHO/ISH Germany USA*

*Two different opinions are reflected for the USA in the JNC V

AUTOREGULATION
BLOOD PRESURE = CARDIAC OUTPUT Hypertension = Increased CO X and or PERIPHERAL RESISTANCE Increased PR

Preload

Contractillity

Function constriction

Structural hypertrophy

Fluid Volume

Venous Contractillity Sympathetic Renin nervous over anglotensin activity excess Cell Hyper membrane Insullinemia alteration Endothelum derived factors Stress Genetic alteration Genetic alteration Obesity

Renal sodium retention Excess sodium infake

Decreased filtration surface

Classes of antihypertensive agents

Diuretics
thiazides and related agents loop diuretics K+-sparing diuretics

Vasodilators
arterial dilators arterial and venous dilators

Ca2+ channel blockers

Sympatholytic drugs
centrally acting agents adrenergic neurone-blocking agents adrenergic antagonists a1 adrenergic antagonists multiple-action neurohormonal antagonists

ACE inhibitors Angiotensin II receptor antagonists

Goodman and Gilman (1996)

PHYSIOLOGICAL ACTIONS OF ADRENERGIC RECEPTORS

ORGAN RECEPTOR TYPE

RESPONSE TO STIMULATE

Heart SA node Atria 1 1 1 1 1 2 / 2 / 2 / Increased heart rate Increased contractility and

conduction velocity
AV node His-Purkinje System Ventricles Arteries Periphera Coronary Carotid Increased automaticity and conduction velocity Increased automaticity and conduction velocity Automaticity, contractility and conduction velocity Dilatation/Contraction Dilatation/Contraction Dilatation/Contraction

BETA-ADRENOCEPTOR BLOCKING DRUGS

Nonselective

Selective

With alpha-Blocking Activity

SA
Nadolol Propranolol Timolol Satolol Tertalolol

+ ISA
Pindolol Carteolol Penbutolol Alprenolol Oxprenolol Dilevalol

ISA
Atenolol Esmolol Metoprolol Bevantolol Bisoprolol Betaxolol

+ ISA

Labetalol Bucindolol Carvedilol

Acebutol (Practolol) Celiprolol

lanjutan

lanjutan

Source: Physicians Desk Reference. 57th ed. Montvale, NJ: Thomson PDR; 2003. *In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval (trough effect). BP should be measured just prior to dosing to determine if satisfactory BP control is obtained. Accordingly, an increase in dosage or frequency may need to be considered. These dosages may vary from those listed in the Physicians Desk Reference, 57th ed. Available now or soon to become available in generic preparations.

SEKIAN & TERIMA KASIH