+++ ++ +++++ ++++ Nicardipine

Report
An update in the
management of
Hypertensive Emergency
In Patients with Acute
Heart Failure
Yerizal Karani
Acute Heart failure
Acute Heart
Failure
ESC Guideline. For diagnosis and treatment of
Acute and chronic HF. 2008
Major Drugs for the Treatment of
Acute Heart Failure
Classification
Diuretics
Heart
stimulators
Vasodilators
Generic Name
Loop diuretic
Furosemide
Digitalis
Digoxin
Methyldigoxin
Digitoxin
Catecholamines
Dopamine
Dobutamine
Norepinephrine
Epinephrine
Phosphodiesterase
-inhibitors
Amrinone
Milrinone
Nitrates
Nitroglycerin
Sodium nitroprusside
Isosorbide dinitrate
Hypertensive Emergency
Definitions

A hypertensive emergency is a situation that requires immediate
reduction in blood pressure (BP) with parenteral agents because
of acute or progressing target organ damage.

A hypertensive urgency is a situation with markedly elevated BP
but without severe symptoms or progressive target organ
damage, wherein the BP should be reduced within hours, often
with oral agents.
Kaplan, 2002
Hypertensive Crises
Hypertensive Urgency
Markedly elevated BP
Without severe symptoms or
progressive target organ damage
BP should be reduced within hours
Oral agents
Hypertensive Emergency
Markedly elevated BP
With acute or progressing
target organ damage
BP should be reduced immediate
Parenteral agents
Kaplan NM ,Hypertensive Crises in : Clinical hypertension 9th Ed,
Lippincott Williams & Wilkins 2006:609-630
HTN Crisis Definitions
 Severe
(stage 2) acute elevation of BP
SBP ≤160 mmHg
DBP ≤100 mmHg
 Hypertensive
Urgency
No evidence of organ failure
BP reduction over several hours to days
Oral treatment adequate
HTN Crisis Definitions

Hypertensive emergency
Severely elevated BP (>180/120mmHg)
Acute onset
Evidence of target-organ damage
BRAIN, HEART, KIDNEYS, RETINA
HYPERTENSIVE EMERGENCY
Accelerated-malignant hypertension with papilledema
Cerebrovascular conditions
Hypertensive brain infarction with severe hypertension
Intracerebral hemorrhage
Subarachnoid hemorrhage
Head trauma
Cardiac conditions
Acute aortic dissection
Acute left ventricular failure
Acute or impending myocardial infarction
After coronary bypass surgery
Renal conditions
Acute glomerulonephritis
Renovascular hypertension
Renal crises from collagen-vascular diseases
Severe hypertension after kidney transplantation
Hypertensive emergency (cont’d)
Excess circulating catecholamines
Pheochromocytoma crisis
Food or drug interactions with monoamine oxidase inhibitors
Sympathomimetic drug use (cocaine)
Rebound hypertension after sudden cessation of antihypertensive drugs
automatic hyperreflexia after spinal cord injury
Eclampsia
Surgical conditions
Severe hypertension in patients requiring immediate surgey
Postoperative hypertension
Postoperative bleeding from vascular suture lines
Severe body burns
Severe epistaxis
Thrombotic thrombocytopenic purpura
Pathophysiology

circulating cathecolamines
 Activation
 Altered
of the renin-angiotensin-aldosterone axis
baroreceptor function
Pathophysiology
vascular resistance

Endothelial damage

Arteriolar fibrinoid necrosis

Loss of autoregulatory function

Target organ ischemia
Management of Hypertensive emergency
General principle :
• the goal is, inhibit the progression of organ damage
• parenteral drugs must be used
• balance the benefit and the organ perfusion,
particularly brain, myocardium and kidney
Therapeutic guidelines
• do not lower BP more than 25% over the first 1 hour
unless necessary to protect other organs
• reduce the SBP of 160 mmHg, DBP of 100 mmHg, or
MAP of 120 mmHg, in the first 24 hours
• begin the concomitant long-term therapy soon after the
initial emergency treatment
• attempt the established normotension within e few days
Parenteral Drugs for Treatment of
Hypertensive Emergencies based on JNC 7
Drugs
Dose
Onset
Duration of
Action
Sodium
nitroprusside
0.25-10 ugr/kg/min
Immediate
1-2 minutes after
infusion stopped
Nitroglycerin
5-500 ug/min
1-3 minutes
5-10 minutes
Labetolol HCl
20-80 mg every 10-15 min
or 0.5-2 mg/min
5-10 minutes
3-6 minutes
Fenoldopan HCl
0.1-0.3 ug/kg/min
<5 minutes
30-60 minutes
Nicardipine HCl
5-15 mg/h
5-10 minutes
15-90 minutes
Esmolol HCl
250-500 ug/kg/min IV
bolus, then 50-100
ug/kg/min by infusion;
may repeat bolus after 5
minutes or increase
infusion to 300 ug/min
1-2 minutes
10-30 minutes
Chobanian AV et al, The JNC 7 report, JAMA 2003;389-2560-70
Parenteral Drugs for Treatment of
Hypertensive Emergencies based on CHEST 2007
Acute Pulmonary edema /
Systolic dysfunction
Nicardipine, fenoldopam, or nitropruside combined with
nitrogliceryn and loop diuretic
Acute Pulmonary edema/
Diastolic dysfunction
Esmolol, metoprolol, labetalol, verapamil, combined with
low dose of nitrogliceryn and loop diuretics
Acute Ischemia Coroner
Labetalol or esmolol combined with diuretics
Hypertensive encephalopaty
Nicardipine, labetalol, fenoldopam
Acute Aorta Dissection
Labetalol or combined Nicardipine and esmolol or combine
nitropruside with esmolol or IV metoprolol
Preeclampsia, eclampsia
Labetalol or nicardipine
Acute Renal failure /
microangiopathic anemia
Nicardipine or fenoldopam
Sympathetic crises/ cocaine
oveerdose
Verapamil, diltiazem, or nicardipine combined with
benzodiazepin
Acute postoperative
hypertension
Esmolol, Nicardipine, Labetalol
Acute ischemic stroke/
intracerebral bleeding
Nicardipine, labetalol, fenoldopam
Marik Paul E, Varon Joseph, CHEST 2007;131:1949-62
Nitroglycerin
Nitroglycerin is a potent venodilator and only at high doses affect
arterial tone. It reduces BP by reducing cardiac
ouput and preload which are undesirable effects in patient with
compromised cerebral and renal perfusion
Nifedipine
Nifedipine has been widely used via oral or sublingual
administration in the management of hypertensive
emergencies. This mode of administration has not been
approved by FDA and since JNC VI because it may cause
sudden uncontrolled and severe reductions in blood pressure
may precipitate cerebral, renal, and myocardial ischemia that
have been associated with fatal outcomes
Clonidine
 Central
alfa blocker, sedative effect
 CI : in patient with Cerebrovascular accident
 Rebound effect
USE OF NICARDIPINE
• Nicardipine :
. Dihydropiridine class of CCB
• Reduce peripheral resistance --- blood pressure
• water soluble, light insensitive, -- can be
parenteraly used (deference with nifedipine /
sodium nitroprusid)
Calcium Channel Blocker Mechanism
Ca++

Blocking
effect of CCB
Ca++

Ca++ plus Calmodulin

Myosin Kinase
Ca++ plus Calmodulin

Myosin Kinase

  
Actin-Myosin Interaction
 Contraction


Ca++
Ca++
NICARDIPINE
CHARACTERISTIC
1.VASOSELECTIVITY
Nicardipine selectivity 30.000 x in smooth muscle cells
blood vessels compared with myocardium
2. Myocardial depression (-)
3. Negative inotropic (-)
4. Rapid and stable antihypertensive effects, reduce blood
pressure gradually < 25% in 2 hours, minimal effects to
heart rate
5. Increase blood flow in major organ : Renal, coroner,
cerebral
Actions to increase organ blood flow
Pharmacodynamic action
Perdipine: 3 g/kg/min  20 min
⊿%)
Blood flow change rate
60
40
Mean blood
pressure
Vertebral
artery
blood flow
Renal
blood flow
Coronary
blood flow
(Hypertensive patients, n = 9)
Baseline value
Mean blood pressure
Mean blood pressure
change rate
20
0
-10
103  11 mmHg
Vertebral artery
blood flow
183  65 mL/min
Renal artery
blood flow
563  29mL/min
Coronary artery
blood flow
121  42 mL/min
-20
(⊿%)
(Shoji Suzuki, et al., The 20th Annual Scientific Meeting of the Japanese Society of Hypertension: 1997)
Tissue selectivity between
Calcium Antagonist
Bristow et al. Br J Pharmacol1984; 309:82
Comparison between Calcium Antagonist
Drug
Coronary
Vasodilation
Suppression
of Cardiac
Contractility
Suppression
of SA Node
Suppression
of AV Node
Verapamil
(phenylalkylamine)
++++
++++
+++++
+++++
Diltiazem
(benzothiazepin)
+++
++
+++++
++++
Nicardipine
(dihydropyridine )
+++++
0
+
0
Kerins DM. Goodman Gilman’s.10th ed.2001:843-70
Perdipine Injection
- Clinical data for Acute Heart Failure -
Comparison Study with Placebo in
Patients with AHF
Subjects:
Patients with acute heart failure with CI  2.5 L/min/m2,
PCWP  15 mmHg, and SBP  100 mmHg (n=81)

Design:
Multicenter, randomized, placebo-controlled, double-blind
comparative study

Treatment:
Enrolled patients were randomly allocated to receive either
1) Intravenous infusion of nicardipine 1 g/kg/min for 1 hour
or
2) Intravenous infusion of placebo for 1 hour

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Changes in Arterial Pressure Following
IV-Infusion of Nicardipine and Placebo
(mmHg)
200
Nicardipine
(n=28)
175
150
NS
NS
NS
*: p<0.05
**: p<0.01
(vs baseline)
125
**
**
**
100
NS
NS
Placebo
(n=28)
NS
75
**
**
**
50
Baseline 15
30
60
(min)
[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Changes in Cardiac Index (CI) Following
IV-Infusion of Nicardipine and Placebo
(L/min/m2)
5
Nicardipine
(n=28)
4
Placebo
(n=28)
3
**
2
**
NS
**
NS
*: p<0.05
**: p<0.01
(vs baseline)
NS
1
0
Baseline 15
30
60
(min)
[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Changes in Pulmonary Capillary Wedge Pressure
(PCWP) Following IV-Infusion of
(mmHg)
Nicardipine and Placebo
40
Nicardipine
(n=20)
30
NS
NS
Placebo
(n=19)
NS
*: p<0.05
**: p<0.01
(vs baseline)
20
*
*
**
10
0
Baseline
15
30
60
(min)
[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Changes in Pulmonary Vascular Resistance (PVR)
Following IV-Infusion of Nicardipine and Placebo
(dyne・sec/cm5)
Nicardipine
(n=28)
3000
NS
NS
NS
Placebo
(n=29)
2000
**
**
**
1000
*: p<0.05
**: p<0.01
(vs baseline)
0
Baseline 15
30
60
(min)
[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Changes in Pulmonary Capillary Wedge
Pressure (PCWP) and Cardiac Index (CI)
(L/min/m2)
Nicardipine
(n=20)
3.4
60 min
3.0
Placebo
(n=19)
30 min
2.6
15 min
(Mean±SD)
Baseline
Baseline
2.2
15 min
1.8
30 min
0
60 min
14
18
22
26
30
34
Pulmonary Capillary Wedge Pressure (PCWP)
38(mmHg)
[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]
Comparison Study with
Intravenous Diltiazem
Subjects:
Patients requiring a rapid reduction in BP (DBP  115 mmHg)
Design:
Multicenter, randomized, single-blind comparative study
Dosage
Nicardipine: Started at 0.5 g/kg/min
 Increased up to 10 g/kg/min if necessary
Diltiazem: Started at 5 g/kg/min
 Increased up to 15 g/kg/min if necessary
Duration of drug administration
Dose titration: 1 hour
Maintenance infusion: 24 hours
Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437
Stability of antihypertensive effect
better than Diltiazem
Stability Effect
120
100
%
80
Perdipine
Diltiazem
95.8
69
60
40
24.1
20
4.2
0
6.8
0
Stable
Slightly unstable
Undeterminable
Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437
Nicardipine vs Nitrovasodilators
Drug
Nicardipine
(Perdipine® IV)
Nitroprusside
Nitroglycerin
Rapid Onset of Peak Effect
++++
++++
+++
Afterload Reduction
++++
++++
+
Preload Reduction
0
++
++++
Coronary Steal Reported
0
+
0
Coronary Dilation: Large Vessel
+++
+
++++
Coronary Dilation: Small Vessel
+++
+/-
+/-
Tachycardia
+
++
++
Potential for Symptomatic
Hypotension
+
++
+++
++++
++
+++
0
++++
0
Ease of Administration
Cyanide Toxicity
Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25.
DOSIS
PERDIPINE
DIV
(g/kg/min)
Bolus
(g/kg)
Acute hypertensive crises during surgery
2 - 10
10 – 30
Hypertensive emergencies
0.5 – 6
Acute hypertensive crises during surgery
Hypertensive emergencies
0.5
1
2
6
(g/kg/min)
10
Dosage and Administration
Start with the lowest dose.
Eg 0.5 mcg/BW/min  15 drops  monitoring, if in 5-15
minutes there’s no significant blood pressure reducing 
Increasing drip until 20 drop , and then can be increased
until desirable blood pressure achieved ( about 3-5 drops
each after monitoring)
Monitoring blood pressure and heart rate frequently
Before choose to switch to oral, 1 hour before Perdipine
is stopped, give oral drugs and Perdipine is tappered of
TAKE HOME MESSAGES

Hypertensive Crises:
urgent situation
need rapid management to prevent organ damage

Antihypertensive agent:
should be fast action
parenteral
titratable
TAKE HOME MESSAGES

Nicardipine (Perdipine ®):
Calcium Antagonist recommended by JNC 7, AHA,
2007, CHEST 2007 to manage hypertensive
emergency

Nicardipine (Perdipine ®):
has favorable antiischemic
increase myocardial oxygen supply
increase cardiac index
 in patients with acute heart failure
THANK YOU FOR YOUR ATTENTION
TAKE CARE OF YOUR HEART

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