The Role of Diltiazem in the

Management of Emergency
Hypertension

SYAIFUL AZMI

SUB BAGIAN GINJAL HIPERTENSI

BAG ILMU PENYAKIT DALAM
FDOK UNAND / RSUP DR M DJAMIL
PADANG
Definition and classification of
Definition and classification of
hypertension:
hypertension: JNC
JNC VII
VII

Hypertension is defined as blood pressure

140/90 mmHg
Systolic Diastolic
Category
(mmHg) (mmHg)
Normal <120 and <80
Pre hypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Stage 2 hypertension 160 or 100

2
JNC VII. JAMA 2003;289:2560-2572
Pathogenesis
Pathogenesis ofof hypertension
hypertension
( Kaplan N, 2002 )
( Kaplan N, 2002 )

3
 Renin-angiotensin-aldosterone
Renin-angiotensin-aldosterone
system
system
Angiotensinogen
(-)
Renin
Renin
Angiotensin I Bradykinin
Angiotensin-
Angiotensin-
converting
converting
enzyme
enzyme
Angiotensin II Inactive kinins

AT1 AT2
BP
BP AT1 AT2
Vasoconstriction Vasodilation
Aldosterone secretion Inhibition of cell growth
Catecholamine release Cell differentiation
Proliferation Injury response
Hypertrophy Apoptosis

Ellis ML, et al. Pharmacotherapy 1996;16:849-860;

4
BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163
HIPERTENSI KRISIS
HIPERTENSI KRISIS
6
 PREVALENSI
PREVALENSI

11%%dari
daripopulasi
populasihipertensi
hipertensi
dewasa
dewasa

HipertensiEmergensi
Hipertensi Emergensi
>>50%
50%penderita
penderitadi
diICU
ICU
Karena terapi tak adekuat
Karena terapi tak adekuat

Pergolini MS. Clinter 160/2/2009

Mark PE Chest 131/6/2007

7
OTAK 45,3 %
Infark Serebri 24,5%
Ensefalopati 16,3%
Perdarahan 4,5%
JANTUNG 50,8%
Edem Paru 36,8%
Infark 12,0%
Diseksi Aorta 2,0%
EKLAMSI 4,5%
GINJAL 1%

8
 PROGNOSIS
PROGNOSIS

Angka kematian tinggi

Tanpa terapi : 1 year survival rate 10-
20%
Terapi adekuat : 5 year survival rate
50-60%

9
Kaplan, clinical hypertension
 Faktor
Faktor Risiko
Risiko

Tidak / Teratur minum obat

Hamil
Rangsangan simpatis yang tinggi
Trauma kepala
Luka bakar
Pheochromo cytoma
Penyakit parenkim ginjal
Penggunaan NAPZA

10
 DEFINISI
DEFINISI

KRISIS HIPERTENSI
Peningkatan tekanan darah mendadak (>
180/120 mmHg)
T.O.D +/-
KELUHAN +/-
PENANGGULANGAN SEGERA

11
 HYPERTENSIVE CRISIS

HYPERTENSIVE HYPERTENSIVE
EMERGENCY URGENCY

JNC VI, 1997

12
 KLASIFIKASI
KLASIFIKASI
HIPERTENSI URGENSI
TANPA GEJALA
Biasanya tekanan darah > 180/120
mmHg
Tanpa keluhan (sakit kepala/cemas)
TOD akut tidak ada

DGN GEJALA
Biasanya tekanan darah > 180/120
mmHg
Keluhan sakit kepala hebat, nafas
pendek, kardiovaskuler stabil
TOD akut tidak ada 13
 KLASIFIKASI
KLASIFIKASI

Hipertensi Emergensi
Biasanya tekanan darah > 220/140
mmHg
Keluhan TOD : sesak, nyeri dada,
nokturia, disartria, gangguan
kesadaran

14
15
16
17
Table 3 : Clinical Characteristics of the Hypertensive Emergency

Blood
Funduscopic Neurologic Cardiac Renal Gastrointestina
Pressure
Findings Status Findings Symptoms l Symptoms
(mmHg)

Headache,
Prominent
confusion,
apical
somnolence,
Usually Hemorrhage pulsation, Azotemia,
stupor, visual Nausea.
>220/140 s, exudates, cardiac proteinuria,
loss, seizures, vomiting
papiledema eniargement, oliguria
focal
congestive
neurologic
heart failure
deficits, coma

Sumber : Hebert e.j Prim Care 2008. 35 (3)

18
Table 4 : Clinical Manifestations of End-Organ Damage From
Hypertensive Emergency

Central Dizzness, NV, confusion, weakness,

nervous encephalopathy, ICH, SAH, ischemic stroke
system
Ocular hemorrhage, exudates, or
Eyes papiledema on fundoscopic exam, blurred
vision, loss of sight
Angina, ACS, LVF, PE, aortic dissection,
Heart
cardiogenic shock
Hematuria, proteinuria, pyelonephritis,
Kidneys
elevated SCr and BUN, ARF
ACS; acute coronary syndrome; ARF: acute renal failure: BUN: blood urea nitrogen: ICH: intracranial
hemorrhage; LVF: left ventricular failure; NV: nausea and vomiting: PE: pulmonary edema: SAH:
subarachnoid hemorrhage; SCr, serum creatinine

Pergolini MS. The Management of hypertensive crises. Clin Ter 2009. 160 (2)

19
 Treatment
Treatment of
of
hypertensive emergency
hypertensive emergency
21
 Table 6 : Treatment of Hypertensive Emergencies
Agent Onset/Duration of
Dosage Action (after Precautions
Parenteral
Vasodilators discontinuation)

Sodium 0.25-10 g/kg/min as Immediate/2-3 min Nausea, vomiting; prolonged use

Nitroprusside IV infusion after infusion may cause thiocyanate
intoxication,
methemoglobinemia, acidosis,
cyanide poisoning; bags, bottles,
delivery sets must be light
resistant

Nitroglycerin 5-100 g as IV 2-5 min/5-10 min Headache, tachycardia,

infusion vomiting; flushing.
Methemoglobinemia; requires
special delivery system because
of drug binding to PVC tubing

Nicardipine 5-15 mg/hr as IV 1-5 min/15-30 min, Tachycardia, nausea, vomiting,

infusion but may exceed 12 headache, increased intracranial
hr after prolonged pressure; hypotension may be
infusion protracted after prolonged
infusions

Fenoldopam 0.1-0.3 g/kg/min as IV <5 min/30 min Headache, tachycardia, flushing,

Mesylate infusinon local phlebitis, dizziness

Hydralazine 5-20 mg as IV bolus or 10 min IV/> 1 hr (IV); Tachycardia, headache,

10-40 mg IM; repeat 20-30 min IM/4-6 hr vomiting, aggravation of angina
every 4-6 hr (IM pectoris, sodium and water
Sumber : Hebert e.j Prim Care 2008. 35 (3)
pressure
22
retension, increased intracranial
 JNC
JNC VII
VII Recommendation:
Recommendation:

The Initial Goal of Therapy in

Hypertensive
Emergency Is to Reduce MABP by No
More
Than 25% (within minute to 1 hour), then
if
stable, to 160/100-110 within the next 2-6
JNC 7, The Lancet 2003
hours.
23
Consensus
Consensusininthe
thetreatment
treatmentofof
Crisis
CrisisHypertension
Hypertension(InaSH
(InaSH2008)
2008)

A.Blood Pressure reduction target of crisis

hypertensive patients:
Parenteral anti hypertension is given based on
the procedure of crisis hypertensive treatment
with MAP reduction 20-25% from the baseline
in the first hour.
Target of BP reduction is 160 mmHg for
Systolic and 90 mmHg for Diastolic.

Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008) 24

Calcium
Calcium Channel
Channel Blockers
Blockers

Which one for which

condition?
 Actions
Actionsof
ofCalcium
CalciumChannel
ChannelBlockers
Blockerson
on
Smooth
SmoothMuscle
Muscleand
andHeart
Heart
Calcium
Calcium Channel
Channel Blockers
Blockers

Slow
Slow Ca 2+ entry
Ca2+ entry

Smooth
Smooth muscle
muscle Heart
Heart muscle
muscle

Oesophagus
Oesophagus Blood
Blood Sinus
Sinus rate
rate Contractility
Contractility
Ureter
Ureter vessels
vessels AV
AV conduction
conduction Cardioprotection
Cardioprotection
Detrusor
Detrusor vesicae
vesicae
Uterus
Uterus Coronary
Coronary flow
flow
Intestine
Intestine Vasospasm
Vasospasm
Bronchi
Bronchi Organ
Organ protection
protection

Atherosclerosis
Atherosclerosis Blood
Blood pressure
pressure

26
Calcium
Calcium Channel
Channel Blockers
Blockers
(CCBs )
(CCBs )

Dihydropyridine ( DHP )
Nifedipine, Amlodipine, Nicardipine, etc.
N on-Dihydropyridine ( NDHP )
Diltiazem, Verapamil

OPIE, 2001

27
Calcium
CalciumChannel
ChannelBlockers
Blockers

Nicardipine Diltiazem
(dihydropyridine) (benzothiazepine)
Peripheral
Vasodilation1
+++++ +++
Coronary
Vasodilation2
+++++ +++
Suppression
of SA Node2 + +++++
Suppression
of AV Node2 0 ++++

Suppression
of Cardiac Contractility2 0 ++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547.

28
2. Adapted from Goodman and Gilmans: The Pharmacologic Basis of Therapeutics. 9th ed.
2001.
 NICARDIPINE
NICARDIPINEand
andDILTIAZEM
DILTIAZEM

NICARDIPINE DILTIAZEM

Target organ Arteriole (ca Arteriole (ca

Channel) Channel)
Clinical effect Vasodilatation : Vasodilatation :
BP decreased BP decreased
Heart Rate

29
Diltiazem
Diltiazem and
and Nicardipine
Nicardipine on
on HR
HR
of Hypertensive emergency
of Hypertensive emergency
patients
patients Heart Rate
(beat/minute)
< 60 60 - 80 > 80

Nicardipine I.V. Diltiazem I.V

30
 Pathophysiologic Effects Diltiazem
Pathophysiologic Effects Diltiazem

Potent vasodilator
Inhibits vascular smooth muscle contractility and
decreases peripheral vascular resistance
Coronary resistance
Dilates coronary arteries and increases coronary
blood flow
Heart rate
Rate-Pressure Product (HR x SBP) reduce
myocardial oxygen demand
Absence of reflex tachycardia
No adverse effects on glucose or
carbohydrate metabolism

Drugs. 1990;39:757. 31
Clinical
Clinical Data
Data
Diltiazem
DiltiazemInjection
Injectionon
on Haemodynamic
Haemodynamic
Control
Control

33
 Antihypertensive
Antihypertensivedrugs
drugsand
andHeart
HeartRate
Rate
250
29
200 27
Blood 205 * 24 14 14 12 9 9
Pressure mmHg
* * * 24.6%
150 * * * SBP
mmHg 154
* * mmHg
* * * * * mea
100 115.8 n
* DBP
mmHg * * 26.9%
Pulse * * * *
50 83.3
Rate mmHg
beats/min * * * * * * 8.9%
75 87.1 *
78.1
50

10 * P0.05 vs
Dose
infused pretreatment level
5
g/kg/min

0 0.5 1 2 3 4 5 6
Subjects: 29 severe systemic hypertension
Dosage : diltiazem initial dose less 10 g/kg/min, average infusion rate was 11 g/kg/min

Research. 1988: 43
34
Current Therapy
Antihypertensive drugs and Heart
Antihypertensive drugs and Heart
Rate
Rate
Diltiazem injection Drip infusion: 5~40
g/kg/min

Average BP reduced
224/119 mmHg to 170/95 mmHg (mean
change 27.3 9.0 %, P<0.001)

HR controlled

Subject : 11 patients with

hypertension
emergency
Design : Open study

Current Therapeutic Research.1987: 42:1223.

35
Antihypertensive
Antihypertensivedrugs
drugscause
causeincrease
increase
of
ofICP
ICP
Comparison of intracranial Comparison of Cerebral perfusion
pressure change by different pressure index (CPP index) by different
antihypertensives. antihypertensives.p<0.05
mmHg p<0.05
20 2.0 1.800.11
Change of intracranial pressure

17.0 1.630.13

14.2
1.5 1.330.07

CPP index
10
6.7
1.0

0 0.0
Herbesser i.v. Nitroglycerin i.v. Nicardipine i.v. Herbesser i.v. Nitroglycerin i.v. Nicardipine i.v.
CPP index=CPP/SBP
CPP index coming close to 1 indicates
less increase of intracranial pressure.
35 patients who had surgical evacuation of spontaneous intracerebral haematomas after cerebral
Target
hemorrhage
Medication
Herbesser i.v.: 12, Nitroglycerin i.v.: 13, Nicardipine i.v.:10
Methods Compare the intracranial pressure when the same blood pressure reduction level is achieved in each g
Hirayama A, Katayama Y, et al:Neurological Research 16; 97-99, 1994 36
 Diltiazem
Diltiazemi.v. i.v.reduced
reducedcardiac cardiacevent
event
rate
rate
in patients
in patients with
with unstable
unstable angina.
angina.
Nitroglycerin i.v. group (n=61)
Herbesser i.v. group (n=60) p=0.007**

40 38
p=0.02*
Incidence during i.v.(%)

30 28

20
15
10 10
10
5

0
Myocardial infarction refractory angina Myocardial infarction
+
refractory angina
Target 129 patients with unstable angina
Methods Randomized, double blind comparative trial
Diltiazem i.v. group (n=60) :25mg i.v.+5mg/h continuous i.v. (increase dose to 25mg/h)
Nitroglycerin i.v. group (n=61) : Physiologic saline i.v.+1mg/h continuous i.v. (increase do

Gobel E, et al. Lancet 346:1653-1657, 1995 37

HERBESSER
HERBESSER Injection

Injection
Dose
DoseFlow
FlowChart
Chart

Intravenous bolus Dose

injection calculati
on

0.2 mg / kgBW

Intravenous drip infusion 10-20 % MBP

( 5-15 g / kgBW / minute ) reduction
from baseline
Observe every 10-20 minutes

Stable BP

Switch to oral HERBESSER CD 200

38
TABEL ALUR DOSIS PENGGUNAAN HERBESSER-INJ DRIP
TABEL ALUR DOSIS PENGGUNAAN HERBESSER-INJ DRIP
INTRAVENA
INTRAVENA

39
 HERBESSE
TERDAFTA

HERBESSE
R
DI DPHO
ASKES
R
R Injection
Injection50
Intravenous Diltiazem
50
HCl 50 mg

Effective in Controlling Blood

Pressure with Target Organ Protection:
Predictable Onset of Action
Anti Ischemic and Arrhythmic Effect
Heart & Brain Protection.
Easy to Use

40
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