The Role of Diltiazem in the Management of Emergency

Hypertension

JNC VII 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 hours.

JNC 7, The Lancet 2003

Consensus in the treatment of Crisis Hypertension (InaSH 2008)

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)

Drugs used in the emergency hypertension (InaSH 2008)

B. Diltiazem (Herbesser) IV (50 mg/ampul)– Diltiazem 10mg IV given by bolus in 1-3 menit

followed by drip infusion 50 mg/jam in 20 menit.

– When the BP reduction achieve at >20% from the baseline, the dosage is adjusted to 30 mg/jam until the BP reduction target achieved.

– Followed by maintenance dosage 5-10 mg/jam, observed in 4 hours, if stabil switch to oral.

– Precaution to the patients with AV Block and Heart Failure.

•Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008)

Management of Hypertension in the stroke acute patient

I. Guidance in the acute ischemic stroke:1.Management of HypertensionBlood

Pressure elevation:• For patient with Diastolic Blood Pressure >

140 mmhg (or > 110 mmhg if in trombolytic treatment) is treated as emergency hypertensive patient and should receive drip continue; nikardipin, diltiazem, nimodipine, etc.

Guideline Stroke PERDOSSI 2011, BAB V hal 46.

Drugs used in the treatment of emergency hypertension (InaSH 2008, CHEST 2007)

• Clonidin (Catapres) IV (150 mcg/ampul)• Diltiazem (Herbesser IV); 50 mg/ampul Nicardipin (Perdipin IV (2 mg dan 10 mg/ampul) Labetalol (Normodyne) IV* Nitroprusside (Nitropress, Nipride) lV Nitroprusside in drip infus with dosage dosis

0.25-10.00 mcg/kg/menit Nitogliserin (nitrat)

•Chest 2007;131;1949-1962•Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008)

Calcium Channel Blockers

Which one for which condition?

Actions of Calcium Channel Blockers on Smooth Muscle and Heart

Calcium Channel BlockersCalcium Channel Blockers

Slow Ca2+ entrySlow Ca2+ entry

Smooth muscleSmooth muscle Heart muscleHeart muscle

Oesophagus Ureter Detrusor vesicae Uterus Intestine Bronchi

Oesophagus Ureter Detrusor vesicae Uterus Intestine Bronchi

Blood vessels Blood vessels

Coronary flow Vasospasm Organ protection

Coronary flow Vasospasm Organ protection

AtherosclerosisAtherosclerosis Blood pressureBlood pressure

Sinus rate AV conduction

Sinus rate AV conduction

Contractility Cardioprotection

Contractility Cardioprotection

Dihydropyridine ( DHP ) Nifedipine, Amlodipine, Felodipine Non-Dihydropyridine ( NDHP ) Diltiazem, Verapamil

OPIE, 2001

Calcium Channel Blockers ( CCBs )

Calcium Channel Blockers

Nicardipine(dihydropyridine)

Diltiazem(benzothiazepine)

Peripheral Vasodilation1 +++++ +++

CoronaryVasodilation2 +++++ +++

Suppressionof SA Node2 + +++++

Suppressionof AV Node2 0 ++++

Suppressionof Cardiac Contractility2 0 ++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547. 2. Adapted from Goodman and Gilman’s: The Pharmacologic Basis of Therapeutics. 9th ed. 2001.

NICARDIPINE and DILTIAZEM

NICARDIPINE DILTIAZEM

Target organ Arteriole (ca Channel)

Arteriole (ca Channel)

Clinical effect Vasodilatation : BP decreased

Vasodilatation : BP decreased

Heart Rate ↑ ↓

Diltiazem and Nicardipine on HR of Hypertensive emergency patients

Nicardivine I.V. Diltiazem I.V

< 60 60 - 80 > 80

Heart Rate (beat/minute)

Clinical Data

Diltiazem Injection on Haemodynamic Control

50

100

150

200

250

50

75

100

0

5

10

15

0 0.5 1 2 3 4 5 6

250

200

150

100

50

75

50

0

10

5

0.5 1 2 3 4 5 6

Dose infused

g/kg/min

Pulse Rate

beats/min

Blood Pressure mmHg

2927

*24*

14*

14*

12*

9*

9*

* * * * * * *

* * * * * **

*******

* P0.05 vs

pretreatment level

Subjects: 29 severe systemic hypertension

Dosage : diltiazem initial dose less 10 g/kg/min, average infusion rate was 11 g/kg/min

Current Therapy Research. 1988: 43

SBP

mean

DBP

24.6%24.6%

26.9%26.9%

8.9%8.9%

205 mmHg

115.8 mmHg

154mmHg

83.3mmHg

87.178.1

Antihypertensive drugs and Heart Rate

16

Subject : 11 patients with hypertension emergency Design : Open study

Diltiazem injection Drip infusion: 5~40 μg/kg/min

Average BP reduced

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

HR controlled

17Current Therapeutic Research.1987: 42:1223.

Antihypertensive drugs and Heart Rate

Nicardipine i.v.

Hirayama A, Katayama Y, et al:Neurological Research 16; 97-99, 1994

35 patients who had surgical evacuation of spontaneous intracerebral haematomas after cerebral hemorrhage

Herbesser i.v.: 12, Nitroglycerin i.v.: 13, Nicardipine i.v.:10

Compare the intracranial pressure when the same blood pressure reduction level is achieved in each group.

①CPP index= CPP/ SBP△ △②CPP index coming close to 1 indicates less increase of intracranial pressure.

Comparison of intracranial pressure change by different antihypertensives.

Ch

an

ge

of

intr

acr

an

ial

pre

ssu

re

Comparison of Cerebral perfusion pressure index (CPP index) by different antihypertensives.

CP

P in

de

x

Herbesser i.v. Nitroglycerin i.v. Nicardipine i.v.Herbesser i.v. Nitroglycerin i.v.

20

10

0

2.0

1.5

0.0

1.06.7

14.2

17.0

1.33±0.07

1.80±0.11

1.63±0.13

p<0.05

p<0.05

（ mmHg ）

Target

Medication

Methods

Antihypertensive drugs cause increase of ICP

Diltiazem i.v. reduced cardiac event rate Diltiazem i.v. reduced cardiac event rate in patients with unstable angina.in patients with unstable angina.

Target

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

Nitroglycerin i.v. group (n=61)

Herbesser i.v. group (n=60)

Inci

denc

e du

ring

i.v.(

%)

40

30

20

10

0Myocardial infarction refractory angina Myocardial infarction

+refractory angina

10

5

28

10

38

15

p=0.02*

p=0.007**

Methods

129 patients with unstable angina

Randomized, double blind comparative trialDiltiazem 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 dose to 5mg)

Intravenous bolus injectionIntravenous bolus injection0.2 mg / kgBW0.2 mg / kgBW

Intravenous drip infusion Intravenous drip infusion ( 5-15 µg / kgBW / minute )( 5-15 µg / kgBW / minute )

10-20 % MBP reductionfrom baseline

Switch to oral HERBESSERSwitch to oral HERBESSER®® CD 200 CD 200

HERBESSERHERBESSER Injection InjectionDose Flow ChartDose Flow Chart

Stable BP

Observe every 10-20 minutes

Dose calculation

Dosis Berat Laju Infusi Mikrodrip Dosis Berat Laju Infusi Mikrodrip Dosis Berat Laju Infusi Mikrodripmcg/kg/mnt kg mg/jam tetes/menit mcg/kg/mnt kg mg/jam tetes/menit mcg/kg/mnt kg mg/jam tetes/menit

1 50 3 3 6 50 18 18 11 50 33 331 60 4 4 6 60 22 22 11 60 40 401 70 4 4 6 70 25 25 11 70 46 461 80 5 5 6 80 29 29 11 80 53 531 90 5 5 6 90 32 32 11 90 59 591 100 6 6 6 100 36 36 11 100 66 662 50 6 6 7 50 21 21 12 50 36 362 60 7 7 7 60 25 25 12 60 43 432 70 8 8 7 70 29 29 12 70 50 502 80 10 10 7 80 34 34 12 80 58 582 90 11 11 7 90 38 38 12 90 65 652 100 12 12 7 100 42 42 12 100 72 723 50 9 9 8 50 24 24 13 50 39 393 60 11 11 8 60 29 29 13 60 47 473 70 13 13 8 70 34 34 13 70 55 553 80 14 14 8 80 38 38 13 80 62 623 90 16 16 8 90 43 43 13 90 70 703 100 18 18 8 100 48 48 13 100 78 784 50 12 12 9 50 27 27 14 50 42 424 60 14 14 9 60 32 32 14 60 50 504 70 17 17 9 70 38 38 14 70 59 594 80 19 19 9 80 43 43 14 80 67 674 90 22 22 9 90 49 49 14 90 76 764 100 24 24 9 100 54 54 14 100 84 845 50 15 15 10 50 30 30 15 50 45 455 60 18 18 10 60 36 36 15 60 54 545 70 21 21 10 70 42 42 15 70 63 635 80 24 24 10 80 48 48 15 80 72 725 90 27 27 10 90 54 54 15 90 81 815 100 30 30 10 100 60 60 15 100 90 90

Contoh Perhitungan : I = ? Infusion Pump :Keterangan simbol : D = 5 mcg/kg/menit = 0.25 ml/menit x 60I = Infusion rate C = 0.1 % (gr/ml) 50 mg/50 ml ~ 100 mg/100 ml = 15 ml/jamD = Dosis (mcg/kg/menit) W = 50 kgC = Konsentrasi (%) Mikrodrip :W = Berat Badan (kg) Rumus / Formula : I = D/C x W = 0.25 ml/menit x 60

I = 5 mcg/kg/mnt / ( 50 mg/ 50 ml ) x 50 kg = 15 tetes/menit = 0.005 mg/kg/mnt x ( 50 ml/ 50 mg ) x 50 kg = 0.25 ml/menit

TABEL ALUR DOSIS PENGGUNAAN HERBESSER-INJ DRIP INTRAVENA

Effective in Controlling Blood Pressure with Target Organ Protection:

Predictable Onset of Action

Anti Ischemic and Arrhythmic Effect

Heart & Brain Protection.

Easy to Use

Intravenous Diltiazem HCl 50 mg

TERDAFTAR DI DPHO

ASKES HERBESSER Injection 50

®

Thank You