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.
e By self-report.
Bulletin of the World Health Organization, 2001, 79 (6)
 Hemodynamic, neurohumoral, and renal changes in
experimental obesity caused by a high fat diet and in
human obesity
Model Arterial SNS PRA Na+reabsorb- GFR Insulin
pressure activity activity tion 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,-melanocyte-
stimulating 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 Effects of Insufficient Sleep on
sleep-insufficient day and a normal workday Autonomic Nervous System Activity

Urinary excretion Normal Sleep- P

norepinephrine Workday Insufficient
nmol/g Day

Sleep period 12439 16878 <.05

Waking hours 23049 270 68 <.05

24 Hours 19446 22358 <.05

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

Sleep duration to risk of hypertension incidence: a meta-
analysis 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
 All Htn CAD
Drug Stroke or CHF
Resistant TIA Nieto Shafer
Javaheri
Htn
Basetti JAMA Card 1999
Circ 1999
Logan 2000
Sleep,
J Htn 2001 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

 Guidelines Worldwide Acknowledge That Most Patients
Need Combination Therapy to Achieve BP Goals

Most patients with hypertension will require two or more

JNC VII

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
ESH/ESC

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
NICE

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

The Japanese Society of

Hypertension Committee for The use of two or three drugs in combination is often necessary
JSH

Guidelines for the

Management of Hypertension
to achieve the target BP control
2009 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
Natriuresis sodium balance
reinforces the
effects of the
ARB

Vasodilation
Arterial Arterial +
Venous

CCB ARB
SNS RAS RAS SNS
Arteriodilation Arterio- and venodilation
Effective in low-renin patients Effective in high-renin patients
No renal or congestive heart failure benefits Congestive heart failure and renal benefits
Peripheral edema Attenuates peripheral edema
Reduces cardiac ischemia 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%)

0.16
Benazepril/HCTZ (679 patients with events: 11.8%)
Cumulative event rate

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 6 12 18 24 30 36 42
Patients at risk (N)
Benazepril/amlodipine 5,512 5,317 5,141 4,959 4,739 2,826 1,447
Benazepril/HCTZ 5,483 5,274 5,082 4,892 4,655 2,749 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 berlebih-
lebihan 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
Number of antihypertensive agents
Trial 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

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

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, Lewis EJ, et al. N Engl J Med 2001;345:851-860;
systolic blood pressure 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, Real and theoretical links connecting

obesity to hypertension.
hyperinsulinemia,hypertension

Curr Diab Rev. 2010; 6: 58-67 Goodfriend T L , and Calhoun D A Hypertension.

2004;43:518-524