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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 Blockers
Slow Ca2+ entry
Smooth muscle

Heart muscle

Oesophagus Ureter Detrusor vesicae Uterus Intestine Bronchi

Blood vessels
Coronary flow Vasospasm Organ protection

Sinus rate AV conduction

Contractility Cardioprotection

Atherosclerosis

Blood pressure

Calcium Channel Blockers ( CCBs )

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

OPIE, 2001

Calcium Channel Blockers


Nicardipine
(dihydropyridine) Peripheral Vasodilation1 Coronary Vasodilation2 Suppression of SA Node2 Suppression of AV Node2 Suppression of Cardiac Contractility2

Diltiazem
(benzothiazepine)

+++++
+++++ + 0 0

+++
+++ +++++ ++++ ++

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

NICARDIPINE and DILTIAZEM


NICARDIPINE
Target organ Arteriole (ca Channel)

DILTIAZEM
Arteriole (ca Channel)

Clinical effect Heart Rate

Vasodilatation : BP decreased

Vasodilatation : BP decreased

Diltiazem and Nicardipine on HR of Hypertensive emergency patients


Heart Rate (beat/minute)
< 60 60 - 80 > 80

Nicardivine I.V.

Diltiazem I.V

Clinical Data

Diltiazem Injection on Haemodynamic Control

Antihypertensive drugs and Heart Rate


250

250 200 150 100

29
200

Blood Pressure mmHg

205
mmHg

27 * *

24 * * *

14 * * *

14 * * *

150

12 * * *

9 * * *

9 * SBP 24.6% 154


mmHg

100

115.8
mmHg

Pulse Rate beats/min

50 100 50

* mean * DBP 26.9% 83.3


mmHg

75 50 10 5

75

87.1

* 78.1

8.9%

50

15

10

Dose infused g/kg/min

* P0.05 vs
pretreatment level

0 0

0.5

0.5

Subjects: 29 severe systemic hypertension Dosage : diltiazem initial dose less 10 g/kg/min, average infusion rate was 11 g/kg/min

16
Current Therapy Research. 1988:

Antihypertensive drugs and Heart 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
17 Current Therapeutic Research.1987: 42:1223.

Antihypertensive drugs cause increase of ICP


Comparison of intracranial pressure change by different antihypertensives.
mmHg 20 Change of intracranial pressure 17.0 14.2 CPP index 1.5 1.330.07

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


p<0.05 p<0.05 2.0 1.800.11 1.630.13

10 6.7

1.0

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

0.0

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.

Target Medication Methods

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

Diltiazem i.v. reduced cardiac event rate in patients with unstable angina.
Nitroglycerin i.v. group (n=61) Herbesser i.v. group (n=60) p=0.007** 38

40
Incidence during i.v.(%) 30

p=0.02* 28

20
10 0 Myocardial infarction refractory angina 10 5 10

15

Target Methods

129 patients with unstable angina

Myocardial infarction + refractory angina

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 dose to 5mg)
Gobel E, et al. Lancet 346:1653-1657, 1995

HERBESSER

Injection
Dose calculation

Dose Flow Chart


Intravenous bolus injection 0.2 mg / kgBW

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


Stable BP

10-20 % MBP reduction from baseline

Observe every 10-20 minutes

Switch to oral HERBESSER CD 200

TABEL ALUR DOSIS PENGGUNAAN HERBESSER-INJ DRIP INTRAVENA


Dosis
m cg/kg/m nt

Berat
kg

Laju Infusi
m g/jam

Mikrodrip
tetes/m enit

Dosis
m cg/kg/m nt

Berat
kg

Laju Infusi
m g/jam

Mikrodrip
tetes/m enit

Dosis
m cg/kg/m nt

Berat
kg

Laju Infusi
m g/jam

Mikrodrip
tetes/m enit

1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5

50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100

3 4 4 5 5 6 6 7 8 10 11 12 9 11 13 14 16 18 12 14 17 19 22 24 15 18 21 24 27 30

3 4 4 5 5 6 6 7 8 10 11 12 9 11 13 14 16 18 12 14 17 19 22 24 15 18 21 24 27 30 I D C W

6 6 6 6 6 6 7 7 7 7 7 7 8 8 8 8 8 8 9 9 9 9 9 9 10 10 10 10 10 10

50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100

18 22 25 29 32 36 21 25 29 34 38 42 24 29 34 38 43 48 27 32 38 43 49 54 30 36 42 48 54 60

18 22 25 29 32 36 21 25 29 34 38 42 24 29 34 38 43 48 27 32 38 43 49 54 30 36 42 48 54 60

11 11 11 11 11 11 12 12 12 12 12 12 13 13 13 13 13 13 14 14 14 14 14 14 15 15 15 15 15 15

50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100 50 60 70 80 90 100

33 40 46 53 59 66 36 43 50 58 65 72 39 47 55 62 70 78 42 50 59 67 76 84 45 54 63 72 81 90

33 40 46 53 59 66 36 43 50 58 65 72 39 47 55 62 70 78 42 50 59 67 76 84 45 54 63 72 81 90

Contoh Perhitungan : Keterangan simbol : I = Infusion rate D = Dosis (mcg/kg/menit) C = Konsentrasi (%) W = Berat Badan (kg)

= ? = 5 mcg/kg/menit = 0.1 % (gr/ml) = 50 kg

50 mg/50 ml ~ 100 mg/100 ml

Infusion Pump : = 0.25 ml/menit x 60 = 15 ml/jam Mikrodrip : = 0.25 ml/menit x 60 = 15 tetes/menit

Rumus / Formula : I = D/C x W I = 5 mcg/kg/mnt / ( 50 mg/ 50 ml ) x 50 kg = 0.005 mg/kg/mnt x ( 50 ml/ 50 mg ) x 50 kg = 0.25 ml/menit

TERDAFTAR DI DPHO

ASKES

HERBESSER
Injection 50
Intravenous Diltiazem 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

Thank You