Why hard to control blood pressure ?

Atma Gunawan

Top 10 causes of death

WHO media center, May 2014

Top 10 causes of death

Hypertension !

WHO media center, May 2014

World Health Day 2013

(WHO press release, April 2013)

Reasons for Lack of Responsiveness to

Hypertension Therapy or May as the Causes
Patient factors : obesity , high salt diet, non adherence
Misdiagnosis : white coat hypertension, mask hypertension, non dipping

hypertension, pseudohypertension
Secondary hypertension : sleep disturbances, renal parenchymal
disease,primary aldosteronism, renal artery stenosis, cushing disease,
pheochromocytoma.
Drug-related causes : late to start a combination, inappropriate
combinations, doses too low, Rapid inactivation , Drug interactions
(Glucocorticoids, NSAIDs, phenothiazines, oral contraceptives,
Sympathomimetics, nasal decongestans, cyclosporine, erythropoetin)

Obesity

Pandemic obesity

May 29th 2014, 8:15 am

Increased prevalence of hypertension

and diabetes in US

JAMA, 2003; 289: 76-79

Obesity and hypertension

Framingham Heart Study suggest that 78% of new cases of

hypertension in men and 65% in women are related to excess

body weight
Every 10-pound weight gain is associated with an estimated
4.5-mm Hg increase in systolic blood pressure

Curr Opin Cardiol. 1996;11:490495.

Prev Med. 1987;16:234251

Correlates of prevalent hypertension among the study subjects: results

of multiple logistic regression analyses(a)

a Age, sex, marital status, religion, past history of smoking were not statistically significant
b BMI = body mass index.
c Figures in parentheses are standard errors.
d Figures in italics are 95% confidence intervals.
Bulletin of the World Health
e By self-report.

Organization, 2001, 79 (6)

Hemodynamic, neurohumoral, and renal changes in

experimental obesity caused by a high fat diet and in
human obesity
Model

Arterial
pressure

SNS
activity

PRA
activity

Na+reabsorbtion

GFR

Insulin
resistance

Obese
rabbits
(high fat
diet)

Obese
dogs
(high fat
diet)

Obese
humans

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO.

23, pp. 1727117276, June 4, 2010

Leptin-melanocortin
activation distinct areas of the
brain : Chronic Activation of the CNS
POMC-MC3/4R Pathway Causes SNS
Activation and Hypertension

POMC, pro-opiomelanocortin;
MC3/4R, melanocortin 3 and
melanocortin 4 receptor; ARC,
arcuate nucleus ; LH,lateral
hypothalamus; PVN,
paraventricular nucleus
DMV, dorsal motor nucleus of
the vagus; -MSH,-melanocytestimulating hormone.;; RSNA,
renal sympathetic nerve activity,
MAPK, mitogenactivated
protein kinase; NTS, nucleus
solitary tract;; Jak2 (Janus
tyrosine kinase 2)

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 23, pp.

1727117276, June 4, 2010

Resistant hypertension in visceral obesity

Methods
The survey was performed on 5065 hypertensive patients with visceral
obesity. BP control was analyzed on the basis of office and home BP
measurements
Results
The percentage of RH was 13.9%. RH was more frequent only in obese with
BMI35 and <40kg/m2 (16.2%) and in morbidly obese individuals (26.5%).
Patients with BMI35 and <40kg/m2 and with morbid obesity were receiving
three-drug therapy more frequently than patients with visceral obesity and
BMI<30kg/m2. A multiple regression analysis revealed that obesity was
associated with RH independent from longer than 5-year period of
antihypertensive therapy, diabetes, smoking cigarettes, cardiovascular
disease and heart failure. The analysis of home BP measurement revealed
that in 11.1% of patients RH was in fact white coat hypertension.

European Journal of Internal Medicine

Volume 23, Issue 7, Pages 643648, October 2012

Sleep disturbances

Short sleep
National surveys in USA have shown a decline in self-reported sleep

duration over the past 50 years by 1.5 to 2 hours.

>30% of Americans report sleeping less than 6 h/night
Short sleep : <5-6 h/day or per night
In children the definition of short sleep was <10 h/day or < 10 h
per night
Effect of short sleep :
- longer exposures to elevated SNS activity
- raise blood pressure and heart rate (non-dipping HT)
- increase aldosterone levels

ABPM on a sleep-insufficient day and a normal workday

recorded by portable multibiomedical (PMB)
Means of ambulatory blood pressure on a
sleep-insufficient day and a normal workday

Tochikubo et al. [16]. Hypertension 1996; 27: 1318-1324

Effects of Insufficient Sleep on

Autonomic Nervous System Activity
Urinary excretion Normal
norepinephrine Workday
nmol/g

SleepP
Insufficient
Day

Sleep period

12439

16878

<.05

Waking hours

23049

270 68

<.05

24 Hours

19446

22358

<.05

Sleep duration to risk of hypertension incidence: a metaanalysis of prospective cohort studies .

(a) Short sleep duration. (b) Long sleep duration

Hypertension Research (2013) 36, 985995

Baseline polysomnographic data of the subject

with normotension, controlled hypertension and resistant
hypertension

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 2 | FEBRUARY 2010

Meta-Analysis of Short Sleep Duration and Obesity in

Adults

SLEEP, Vol. 31, No. 5, 2008

Obstructive sleep apnea

At least 10 apneic and hypopneic episodes (min 10

seconds) per sleep hour
10% of 30-60 years of age (5% of woman and 15% of men)

Superimposed recordings of the electrooculogram (EOG),

electroencephalogram (EEG), electromyogram (EMG), ECG (EKG),
sympathetic nerve activity (SNA), respiration (RESP), and blood
pressure (BP) during REM sleep in a patient with OSA

Drug
Resistant
Htn
Logan

J Htn 2001

Stroke or
TIA
Basetti
Sleep,
1999

CHF

All Htn

CAD

Javaheri

Nieto

Shafer

Circ 1999

JAMA
2000

Card 1999

Treatment of sleep apnea

Behavioral factors :
- weight loss
- no alcohol and smoking,
and no sedatives before
sleep
- avoidance of supine sleep
- sleep position :lateral
decubitus
Spironolactone 25-50 mg/d
Nasal CPAP Continuous
positive airway pressure
Oral dental devices
Surgical procedures :
UPP, nasal
surgery,,tonsilectony,LAUP
Maxiofacial
surgery,tracheostomy

Late to start a combination

Inadequate Management of
Hypertension

40 % of patients had BP 160/90 mmHg

despite an average of more than 6
hypertension-related visits per year.
Increases in therapy/combination only
in 6,7 % of visits.
Physicians are NOT
AGGRESSIVE ENOUGH in
treating hypertension.
Berlowitz DR, et al. N Engl J Med, 1998

ESH/ESC

JNC VII

Guidelines Worldwide Acknowledge That Most Patients

Need Combination Therapy to Achieve BP Goals
Most patients with hypertension will require two or more
antihypertensive medications to achieve their BP goals
When BP is > 20/10 mmHg above goal, consideration should
be given to initiating therapy with two drugs

Combination treatment should be considered as first choice when there

is high CV risk
i.e., in individuals in whom BP is markedly above the
hypertension threshold (> 20/10 mmHg), or associated with
multiple risk factors sub-clinical organ damage, diabetes,
renal or CV disease

Many patients will require more than one drug to achieve adequate
BP control
Pathophysiological reasoning suggests that adding an ACE-I/ARB
to a CCB or a diuretic (or vice versa in the younger group) are
logical combinations

NICE
JSH

The Japanese Society of

Hypertension Committee for
Guidelines for the
Management of Hypertension
2009

The use of two or three drugs in combination is often necessary

to achieve the target BP control
A low dose of a diuretic should be included in this combination

Chobanian et al. JAMA. 2003;289:25602572; Mancia et al. Eur Heart J. 2007;28:14621536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3107.

Combination Therapy Versus Monotherapy in Reducing Blood

Pressure: Meta-analysis on 11,000 Participants from 42 Trials
Low-dose therapy has the advantage of reducing adverse effects that, with the exception of ACEI/ARB, are strongly dose related;
for 2 classes (thiazides and calcium channel blockers), for example, adverse effects are 80% lower at half-standard than standard
dose. The prevalence of adverse effects from combining 2 drugs at half-standard dose would therefore, for most
combinations, be lower than with 1 drug at standard dose.

The extra blood pressure reduction from combining drugs from 2 different classes is
approximately 5 times greater than doubling the dose of 1 drug
Wald et al. Am J Med 2009;122:290300

CCBs and ARBs Interact Synergistically on Vascular and Renal Function,

Sympathetic Nervous System and Renin-Angiotensin System Activity

negative
sodium balance
reinforces the
effects of the
ARB

Natriuresis

Vasodilation
Arterial

Arterial +
Venous

CCB

ARB

SNS RAS
Arteriodilation
Effective in low-renin patients
No renal or congestive heart failure benefits
Peripheral edema
Reduces cardiac ischemia

RAS SNS
Arterio- and venodilation
Effective in high-renin patients
Congestive heart failure and renal benefits
Attenuates peripheral edema
No effect on cardiac ischemia

SNS = sympathetic nervous system; RAS = renin-angiotensin system

ACCOMPLISH: Superior CV Outcomes with RAAS Blocker/Amlodipine

Versus RAAS Blocker/HCTZ Single-pill Combination-based Regimens
Benazepril/amlodipine (552 patients with events: 9.6%)
Benazepril/HCTZ (679 patients with events: 11.8%)

Cumulative event rate

0.16

0.12

20%

0.08

relative risk
reduction

0.04

HR 0.80 (95%CI 0.720.90); p<0.001

0
0

182

366

547

731

912

1,096

1,277

Time to first CV mortality/morbidity (days)

Months
0
Patients at risk (N)
Benazepril/amlodipine
Benazepril/HCTZ

12

18

24

30

36

42

5,512
5,483

5,317
5,274

5,141
5,082

4,959
4,892

4,739
4,655

2,826
2,749

1,447
1,390

ACCOMPLISH = Avoiding Cardiovascular events through COMbination therapy in Patients

LIving with Systolic Hypertension; CV = cardiovascular;
RAAS = renin-angiotensin-aldosterone system; HCTZ = hydrochlorothiazide

Jamerson et al. N Engl J Med 2008;359:241728

Messages
Obesitas, gangguan tidur, terlambat memulai kombinasi obat, adalah sebagian

dari penyebab mengapa hipertensi tidak terkontrol.

Penyebab hipertensi pada obesitas berkaitan dengan tingginya prevalensi sleep

apnea, peningkatan rangsangan saraf simpatis, retensi sodium, aktivasi renin

angiotensin dan meningkatnya resistensi insulin
Efek dari kurang tidur mengakibatkan aktivasi saraf simpatis berlebihan,

kenaikan kadar aldosteron, non-dipping hipertensi.

Kebanyakan trial menunjukan bahwa setidaknya dibutuhkan dua kombinasi

obat untuk mencapai target.

Kombinasi obat menciptakan efek sinergis, saling melengkapi dan menghasilkan

penurunan tekanan darah lebih besar dibandingkan monoterapi.

 Makan dan minumlah kalian, namun jangan berlebihlebihan karena Allah tidak mencintai orang-orang yang
berlebih-lebihan. (Al-Araf:31).
Dialah yang menjadikan untukmu malam (sebagai)
pakaian, dan tidur untuk istirahat, dan Dia menjadikan siang
untuk bangun berusaha (Al-Furqaan Ayat : 47)

Multiple antihypertensive agents

are needed to achieve target BP
Trial

Number of antihypertensive agents

Target BP (mmHg) 1
2
3
4

UKPDS

DBP <85

ABCD

DBP <75

MDRD

MAP <92

HOT

DBP <80

AASK

MAP <92

IDNT

SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP,

systolic blood pressure

Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;

Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404

Hospital discharges for cardiovascular disease (United States: 19702007).

Roger V L et al. Circulation. 2011;123:e18-e209

Obesity and hypertension

Obesity,
hyperinsulinemia,hypertension

Curr Diab Rev. 2010; 6: 58-67

Real and theoretical links connecting

obesity to hypertension.

Goodfriend T L , and Calhoun D A Hypertension.

2004;43:518-524