Management of

Hypertension
and
Emergency Hipertension,
Focus on : Diltiazem Hcl

RESTO SOEUL PALACE

SEMARANG, 25 Mei 2016
Dr. Hadi Sulistyanto Sp.PD, MH Kes,FINASIM
Hipertensi

 Suatu peningkatan tekanan darah

melebihi normal yang dapat
meningkatkan resiko kerusakan organ,
seperti pembuluh darah, jantung,
otak, ginjal, mata serta kematian.
 Di Indonesia , prevalensi 6 – 15 % .
Terendah di Lembah Baliem 0.6 %,
Tertinggi di Silungkang 19.4 %.
Etiologi Hipertensi:
Berdasarkan penyebabnya dapat dibedakan :
• Primer (essential)
– tidak ada penyebab yang spesifik yang dapat
diidentifikasi
– 95% dari kasus hipertensi
• Sekunder
– diketahui penyebabnya
– 5% dari kasus hipertensi
– penyakit ginjal merupakan penyebab dari 90%
kasus hipertensi sekunder
JNC VII : Classification of Blood Pressure for
Adult Aged 18 Years or Older
Initial Drug Therapy
BP SBP DBP Lifestyle Without
With Compelling
Classification mmHg mmHg Modification Compelling
Indication
Indication
< 120
Normal < 80 Encourage - -
and
No Drug(s) for the
Pre- 120-139
80-89 Yes antihypretensive compelling
hypretension or
drug indicated indication
Diuretics and/or
Drug(s) for the
Stage 1 140-159 ACE-I, ARB, Beta-
90-99 Yes compelling
hypertension or blocker, CCB, or
indication
combination
Diuretic and Drug(s) for the
Stage 2 > 160
> 100 Yes other compelling
hypretension or
combination indication

JNC VII, 2003

 The World Hypertension Population
Aged 65 Years or More is Increasing
Millions % of total population
700 649 9 8.3
8
600 6.7 6.6
7
500 6 5.4
403
400 5
298
300 4
3
200 165
2
100 1
0 0
1960 1980 2000 2020 1960 1980 2000 2020

WHO, 1990
 Penyakit CV: Masalah Yang
Berakibat Fatal
Kondisi Ibu Hamil
Lain-lain dan Persalinan
dan defisiensi
Peny.Infeksi &
nutrisi parasit

Kecelakaan
Kanker
Peny.Respirasi
Non infeksi

Infeksi Respirasi
Diduga 38% dari
CV kematian th 2005

WHO World Health Report, 2005

 Component of Cardiovascular Risk
Stratification in Patient with Hypertension
Major Risk Factors Target Organ Damage
• Smoking • Heart
• Dyslipidemia LVH
• Diabetes mellitus Angina / prior MI
• Age ( men > 55 years Prior Coronary
and women > 65 years ) Revascularization
• Family history of CVD Heart Failure
Men < 55 years or • Brain
Women < 65 years Stroke or TIA
• Chronic Kidney Disease
• Peripheral Arterial Disease
• Retinopathy.
JNC. VII, 2003
 Komplikasi Hipertensi
Eyes Brain Kerusakan Target Organ!!
retinopathy stroke

Kerusakan yang disebabkan

Heart oleh hipertensi tergantung :
ischaemic heart disease
Kidneys left ventricular hypertrophy • Besarnya peningkatan
renal failure heart failure tekanan darah
• Lamanya kondisi tekanan
darah yang tidak
terdiagnosis dan tidak
Peripheral arterial disease
diobati
 Treatment of Hypertension
Background

• Hypertension is the major risk factor for coronary heart

disease and congestive heart failure
• Hypertension is second only to diabetes as the cause of
renal failure
• In a recent meta analysis, treating hypertension reduced
the incidence of stroke by 38% and coronary heart disease
by 16%
• In a US survey, only 21% of hypertensive patients had their
blood pressure controlled at <140/90 mmHg
 Istilah dalam Hipertensi.
 Hipertensi refrakter  respon pengobatan tidak
memuaskan & TD > 220/110 mmHg, walaupun sdh
diberikan terapi yg adekuat.
 Hipertensi akselerasi  TD Diastolik >120 mmHg yg
disertai dengan kelainan funduskopi.
 Hipertensi Maligna  Ps dgn hip. Akselerasi dgn TD
diastolik >130, disertai papiledema, TIK ,GGA atau
kematian apabila tidak mendapat pengobatan.
 Hipertensi ensepalopati  pe tiba-tiba disertai sakit
kepala sangat hebat, penurunan kesadaran, reversibe
bila TD turun.
 Difinisi
KRISIS HIPERTENSI
 Suatu keadaan klinis yang ditandai
oleh tekanan darah yang tinggi
dengan kemungkinan akan timbulnya
atau telah terjadinya kelainan target
organ.
 Dibagi 2 :
– Hipertensi darurat (emergency)
– Hipertensi mendesak (urgensi)
EDUCATION IS KEY
Prevalensi

 1-5 % dari kasus hipertensi

 Sebab :
– Pengobatan tidak adekuat.
– Ketidakpatuhan minum obat.
– Kurangnya kesadaran penderita tentang
resiko dari hipertensi.
– Faktor ekonomi
 HYPERTENSION CRISIS
A severe elevation in BP, generally a SBP > 220 mm Hg and / or
DBP > 120 mm Hg. ( JNC-VI, 1997 )

 HYPERTENSIVE EMERGENCIES
Severe elevation in BP complicated by acute target organ dysfunction,
such as coronary ischemia, stroke, intracerebral hemorrhage,
pulmonary oedema, or acute renal failure.

 HYPERTENSIVE URGENCIES
Severe elevations in BP without evidence of target organ deterioration.

Colhum DA. Oparil S, New Engl. J. Med, 323 : 1177, 1990

 Hipertensi emergensi
– Kenaikan TD sangat tinggi terdapat
kelainan/kerusakan target organ yg
bersifat progresif.
– Penurunan cepat (menit-jam).
 Hipertensi Urgensi
– Kenaikan TD sangat tinggi tanpa disertai
kelainan/kerusakan target organ yg
progresif.
– Penurunan lebih lambat (jam-hari).
 Patofisiologi
 Teori Over Regulation
TD  spasme yg berat  arteriole aliran drh
ke otak  iskemi.
Pe permebilitas kapiler  pecahnya kapiler,
edema otak, perdarahan otak, mikro infark.
 Teori Breakthrough of cerebral Autoregulation
Bila TD mencapai batas tertentu  mikro infark,
edema otak, ptechie, hemorhages.
 Patofisiologi
Odema otak
Overautoregulation
spasme arteriole

Ptechie
hemorhages
TD naik Hipertensi
medadak ensefalopati
Mikro infark

Breakthrought Nekrosis
autoregulation vaskuler
 Algorithm for Treatment of hypertension
Lifestyle Modifications

Not at Goal BP ( <140/ 90 mmHg or <130/80 mmHg

for those with diabetes or chronic kidney disease )

Initial Drug Choices

Hypertension without Hypertension with

Compelling Indication Compelling Indication

Stage 1 Hypertension Stage 2 Hypertension Drug for the compelling

(Systolic BP 140-159 mmHg or diastolic (Systolic BP > 160 mmHg or diastolic indication
BP 90-99 mmHg) BP > 100 mmHg) Other AH drug ( Diuretic
Thiazide , ACE-I, ARB, B-Blocker, CCB, 2 drug combination ( Thiazide and ACE- ACE-I , ARB, B-Blocker,
or combination I or ARB or B-Blocker or CCB ) CCB) as needed

Not at Goal BP

Optimize dosages or Add Drugs Until Goal BP is Achieved

Consider Consultation With hypertension Specialist
JNC. VII, 2003
 Goal of Hypertension Therapy

“ the reduction of cardiovascular and

renal morbidity and mortality ”

BP Target
Normal : 140 / 90 mm Hg
Diabetes or chronic kidney disease : 130 / 80 mm Hg

JNC. VII, 2003

 Target Anti hipertensi
1. Menurunkan tekanan darah
2. Menjaga aliran darah cerebral

3. Mencegah kerusakan target organ

4. Menghindari peningkatan tekanan

intracranial
 Hypertension Crisis
DBP >120 mmHg
URGENCY
 BP within hours < 24 hours
( PARENTERAL / ORAL )
1. KAPLAN NM., Lancet 344:1335,1994
2. KAPLAN NM., 8th edition., 2002 p : 339-40
EMERGENCY
 BP within minutes < 1 hours
( PARENTERAL )
- Accelerated malignant hypertension
- Hypertensive encephalopathy
- Intracerebral / Subarachnoid hemorrhage
- Acute aortic dissection
- Acute left ventricular failure
- Acute myocardial infarction
- Acute glomerulonephritis
- Eclampsia
- Severe epistaxis
- Perioperative hypertension, etc
Hipertensi Urgensi.
 Tanda dan Gejala :

– TD > 180/110 mmHg

– Sakit kepala hebat, sesak nafas.
– Pf ; tdk ada gangguan target organ.
– Th/ obat oral jangka pendek
 CCB
 Ace inh
 Adrenergik sentral (klonidin)
 B Bloker

– Periksa ulang dlm 24 jam.

Hipertensi Emergensi.
 Tanda dan gejala:

– TD> 220/120 mmHg

– Sesak nafas, nyeri dada, kacau, gangguan
bicara, gangguan kesadaran, mual muntah.
– Pem. Fisik ; ensefalopati, edema paru, gang. Fs
ginjal, CVA, iskhemia jantung.
– Th/ obat intra vena
 Herbesser 5-15 ug/kg/mnt  1-5 ug/kg/mnt
 Klonidine
 Nitrogliserine
 Nikardipine
– Lab; proteinuria, uremia
– Rawat ICU
 Parenteral Drugs for Treatment of
Hypertensive Emergencies ( Vasodilators )
Drugs Onset of action Duration of action
Nicardipine * 5 min 1 hr
Sodium Nitropruside immediate 1-2 min
Fenoldopam < 5 min 30 min
Nitroglycerin * 2-5 min 2-3 min
Enalaprilat 15-30 min 6 hr
Hydralazine 10-20 min 4-6 hr
HERBESSER
Diltiazem * Injection 5 min 30 min
Trimetaphan 5-10 min 10 min

* Available in Indonesia
 Intravenous Drugs for Hypertensive
Emergencies Available in Indonesia

Vasodilators
• Clonidine
• Nitroglycerin
• Sodium Nitroprusside
Ca-Antagonist
• Nicardipine Hydrochloride
• Diltiazem Hydrochloride
 COMMONLY USED DRUG IN
HYPERTENSIVE EMERGENCY

CLONIDINE I.V.
• Reduce peripheral sympathetic tone by central
stimulation of 2- receptor.

• Unpredictable onset of action.

• Adverse effect : sedation, dry mouth, constipation

and a tendency to a overshoot or rebound
hypertension on withdrawn.

W.H. Frishman, et al., Cardiovascular Pharmacotherapy, 1996

 COMMONLY USED DRUG IN
HYPERTENSIVE EMERGENCY

DILTIAZEM I.V. ( HERBESSER Injection )

• Useful for hypertensive emergency and urgency.
• Acts as Non-dihydropyridine calcium channel blockers.
• Dose-dependent :
Predictable onset of action
Rapidly reduced BP.
No rebound on withdrawn
• Adverse effect : bradycardia, hypotension, headache,
flushing.
• Has antiischemic and antiarrhythmic effect (class-IV)
Organ Target HER CLON NTG NIFE
Cardioprotective
Heart rate
Ischemic

Dilate: coroner ++ - ++ +
Anti-

collateral ++ - - -
Antiarrhytmic + - - -
Antivasospasm ++ - - +
Renoprotective
Afferent + - - +
RBF - -
Efferent + - - -
CGP - -
Cerebroprotective
CBF
Epstein M, 1991, Bakris GL, 1993, Mancia G, 1996, Messerly FH, 1996
 Herbesser Injection
Indikasi
1. Takiaritmia ( supraventrikuler ) atau Tachyarrhythmia ( supraventricular )
2. Pengobatan darurat untuk hipertensi abnormal selama operasi
3. Hipertensi emergensi atau Hypertensive urgensi
4. Angina tidak stabil atau Unstable Angina

CONTRAINDICATION
1. Patient’s with severe hypotension
Patient’s with 2nd or 3rd degree of AV-block or sick sinus
syndrome ( sinus bradycardia less than 50 beats / minute )
2. Patient’s with severe congestive heart failure
3. Patient’s with severe cardiomyopathy
4. Patient’s with history of Hypersensitivity to diltiazem
5. Pregnant women or woman who may possibly be pregnant.
 Kesimpulan :
 Penting bedakan hipertensi urgensi dan
emergensi  Pemilihan obat anti hipertensi yang
tepat.
 Penurunan TD kira2 25% dari MAP / tdk lebih
rendah dari 160/100 mmHg.
 Pada Hipertensi Krisis Pemakaian obat anti
hipertensi parenteral lebih baik dibandingkan oral.
 Diltiazem injeksi ( Herbesser inj R ),rupakan
salah satu Drug of choice th/ Hipertensi
Emergency,selain th/konvensional lain.
MANTENANCE HIPERTENSI DENGAN
HERBESSER CD 100,200 MG
 Point to Ponder about Herbesser:

• Effective in the treatment of Hypertension

• Cerebral Protection (Stroke Prevention &
Less ICP Increase)
• Heart Protection (Decrease Heart rate,
Coronary Dilation, Reduce IHD Syndrome)
• Kidney Protection (Dilation of Afferent &
Efferent, Decrease Proteinuria, Inhibit
Nephropathy Progression )
a.s.200
3
Hypertension Efficacy of HERBESSER® CD
Clinical Effect of Diltiazem Hydrochloride Sustained Released Preparation (HERBESSER® CD)
on Essential Hypertension
– A Double Blind Study with Diltiazem Hydrochloride Current Product

** : p<0.01 (vs baseline) Mean + S.D. n = 37 Subject : Essential hypertension ( mild to moderate ) 53 cases
Method : HERBESSER® CD 100-200 mg once a day for 12 weeks

K. Arakawa et al, J. Clinical Therapeutics & Medicines 1989 ; 5: 171

 Risk Factor 1 : HYPERTENSION
DILTIAZEM AS EFFECTIVE AS CONVENTIONAL THERAPY IN
MEAN BLOOD PRESSURE REDUCTION
Blood Pressure (mmHg)

BASELINE END OF STUDY

180
* RESULTS FROM NORDIL STUDY
170 173.5 173.4 Diltiazem
160
*
20.3/18.7 mmHg
150 152.2 149.1 Diuretic and β-blocker
140
23.3/18.7 mmHg
130

120
Baseline
110 105.7
105.8
*
SR diltiazem once daily
100
Conventional
90 87.6 87.4 * p<0.001 for intra-group comparisons
*
versus baseline Lancet 2000; 356: 359-65
80
Risk Factor 3 : DIABETES MELLITUS
DILTIAZEM REDUCED NEW DIABETES MELLITUS BY 13%
COMPARE WITH CONVENTIONAL THERAPY
11 - RESULTS FROM NORDIL STUDY
10.8
Event rate per 1000

Occurrence of Diabetes mellitus

Patient-years

10 - 13%
reduction

9.4
9-

8-
Diuretics & Diltiazem
Beta-blockers Relative risk (95% CI) = 0.87 (0.73-1.04) P =
Lancet 2000; 356: 359-65
 NORDIL Study
NORDIL STUDY : showed Diltiazem group had a 20% lower rate
of all stroke than Diuretics and -Blockers

The Lancet, Vol 356, July 29, 2000

 Differential Effects of CCB Therapy inType 2 Diabetics with
Nephropathy

10 SBP DBP 100 D 24 h proteinuira

Proteinuria reduction vs baseline

BP reduction vs baseline (mmHg)

0 0

-10 -100

(mg/day)
-20 -200

* *
-30 -300

-40 -400
*
-50 * -500

*
Nifedipine GITS (n = 10) *p<0.05
Diltiazem CD (n = 11)

Smith et al. Kidney Int. 1998;54:889-896.

 HERBESSER
HERBESSERCD
CD 200 100

Controlled Dose Diltiazem HCl 100 mg & 200

mg

 Effective in controlling both systolic and diastolic

blood pressure.
 Kidney protection effect : decreasing proteinuria.
 Heart protection effect : anti ischaemic and
arrhytmia.
 Brain protection effect : stroke prevention.