Perdipine

Management of Hypertensive CrisisFOCUS ON PARENTERAL NICARDIPINE

COMPLICATIONS OF HYPERTENSION

Acute Complication

- Abruptly

- Related with accelerated

elevation of BP

- BP must be decreased

aggressively

Chronic complication

- Gradually

- Related with duration

of hypertension

- BP managed smartly

COMPLICATIONS OF HYPERTENSION

Acute Complication

- Abruptly

- Related with accelerated

elevation of BP

- BP must be decreased

aggressively

Chronic complication

- Gradually

- Related with duration

of hypertension

- BP managed smartly

Hypertensive Crisis

Definition :

Hypertensive crisis :

Severe elevation of blood pressure, which must be

reduced immediately

Classification :• Hypertensive emergency :

• accompanied by acute target organ damage

• BP must be reduced within minutes

• Hypertensive urgency :

• no acute organ damage

• BP must be reduced within hours

Clinical Hypertension, Kaplan 2003

Hypertensive Crises

Hypertensive EmergencyHypertensive Urgency

Markedly elevated BP Without severe symptoms or

progressive target organ damageBP should be reduced within hours

Oral agents

Markedly elevated BP With acute or progressing

target organ damageBP should be reduced immediate

Parenteral agents

Kaplan NM ,Hypertensive Crises in : Clinical hypertension 9 th Ed, Lippincott Williams & Wilkins 2006:609-630

Definition :

• Not determined by BP level, but rather the imminent

compromise vital organ function

• Formerly when :

• systolic 180 mm Hg

• diastolic ≥ 110 mm Hg

(stage III ESH)

The Kidney and Hypertension, Bakris,

2004

High blood pressure in asymptomatic chronic hypertension

IS NOT A HYPERTENSIVE CRISES

Precipitating factors in hypertensive crisis

1. Accelerated sudden rise in blood pressure in patient with preexisting essential hypertension

2. Renovascular hypertension

3. Glomerulonephritis-acute

4. Eclampsia

5. Pheochromocytoma

6. Antihypertensive withdrawl syndromes

7. Head injuries

8. Renin secreting tumors

9. Ingestion of cathecolamine precursor in patients taking MAO inhibitors

HYPERTENSIVE EMERGENCY

Accelerated-malignant hypertension with papilledemaCerebrovascular conditions

Hypertensive brain infarction with severe hypertensionIntracerebral hemorrhageSubarachnoid hemorrhageHead trauma

Cardiac conditionsAcute aortic dissectionAcute left ventricular failureAcute or impending myocardial infarctionAfter coronary bypass surgery

Renal conditionsAcute glomerulonephritis Renovascular hypertensionRenal crises from collagen-vascular diseasesSevere hypertension after kidney transplantation

Accelerated-malignant hypertension with papilledemaCerebrovascular conditions

Hypertensive brain infarction with severe hypertensionIntracerebral hemorrhageSubarachnoid hemorrhageHead trauma

Cardiac conditionsAcute aortic dissectionAcute left ventricular failureAcute or impending myocardial infarctionAfter coronary bypass surgery

Renal conditionsAcute glomerulonephritis Renovascular hypertensionRenal crises from collagen-vascular diseasesSevere 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

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

Sign and symptom in various types of hypertensive emergency

Type of hypertensive emergency

Typical symptoms Typical signs Comment

Acute stroke in evolution (thrombotic or embolic)

Weakness, altered motor skill(s)

Focal neruological deficit(s)

Hypertension not usually treated

Suibarachnoid hemorrhage Headache, delerium

Altered mental status, meningeal signs

Lumbar puncture typically shows xanthochromia or red blood cells

Acute head injury/trauma Headache, altered sensorium or motor skills

Lacerations, ecchymoses, altered mental status

Computed tomographic (CT) scan is helpful to determine extent of intracranial injury

Hypertensive encephalopathy

Headache, altered mental status

papilledema Usually a diagnosis of exclusion

Cardiac ischemia/infraction Chest discomfort, nausea, vomiting

Abnormal EKG (esp. T-wave elevations)

Type of hypertensive emergency

Typical symptoms Typical signs Comment

Acute left ventricular failure/pulmonary edema

Shortness of breath

Rales auscultated in chest

Aortic dissection Chest discomfort Widened aortic knob on chest x-ray

Echocardiogram, chest CT, or angiogram usually needed to confirm

Recent vascular surgery Bleeding, tenderness at suture lines

Bleeding at suture lines

Often require surgical revision of vascular anastamosis

Pheochromocytoma Headache, sweating, palpitations

Pallor, flushing, rare skin signs (phakomatoses)

Phentolamine is very useful

Drug related catecholamine excess state

Headache, palpilations

tachycardia History regarding drug exposure is key

Preeclampsia / eclampsia Headache, uterine irritability

Edema, hyperreflexia

New treatment guidelines exist

Sign and symptom in various types of hypertensive emergency (cont’d)

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

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

Pathways for management of patients with severe hypertension, defined as blood pressure (BP) in excess of 180/120 mmHg.

Severe HypertensionBP > 180 / 110

EncephalopathyProgressing target organ damage

Yes(HT Emergency)

No

New onset(HT Urgency)

Prior similar experience;Negative workup(Uncontrolled HT)

Admit to ICUBaseline lab

Baseline lab

Oral Rx

Reinstitute oral Rx

Follow closely

Parenteral Rx

Workup foridentifiable causes:

Renovascular HT

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

Drug I.V. Bolus Dose Continous Infus Rate

LabetalolNicardipineEsmololEnalaprilHydralazineNiprideNTG

5 – 20 mg every 15’NA250 ug/kg IVP loading dose1,25-5 mg IVP every 6 h5 – 20 mg IVP every 30’NANA

2 mg/min (max 300mg/d)5-15 mg/h25-300 ug/kg/mNA1,5-5 ug/kg/m0,1-10 ug/kg/m20-400 ug/m

AHA/ASA Guideline, 2007 update. Stroke. 2007;38: 2001-2023.

Parenteral Drugs for Treatment of Hypertensive Emergencies based on ASA Guideline

This parenteral drugs are approved for hypertensive emergency in acute ischemic stroke and intracerebral hemorrhage

Parenteral Drugs for Treatment of Hypertensive Emergencies based on CHEST 2007Acute 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 affectarterial tone. It reduces BP by reducing cardiacoutput and preload which are undesirable effects in patient withcompromised cerebral and renal perfusion

Nifedipine

Nifedipine has been widely used via oral or sublingualadministration in the management of hypertensiveemergencies. This mode of administration has not beenapproved by FDA and since JNC VI because it may causesudden uncontrolled and severe reductions in blood pressuremay precipitate cerebral, renal, and myocardial ischemia thathave been associated with fatal outcomes

Clonidine

Central alfa blocker, sedative effect

CI : in patient with Cerebrovascular accident

Rebound effect

• Nicardipine :

. Dihydropiridine class of CCB

• Reduce peripheral resistance --- blood pressure

• water soluble, light insensitive, -- can be

parenteraly used (deference with nifedipine /

sodium nitroprusid)

USE OF NICARDIPINE

Ca++ plus Calmodulin

Myosin Kinase

Ca++ plus Calmodulin

Actin-Myosin Interaction Contraction

Myosin Kinase

Ca++ Ca++

Blocking effect of CCB

Ca++ Ca++

Calcium Channel Blocker Mechanism

• peripheral vasodilatation• preserve or enhanced cardiac pump activity

------ improve tissue perfusion• fall in systemic blood pressure, maintain at desired

level• in comparison with sodium nitropruside – equally

effective, but no cyanide toxic effect in long term use • not associated adverse effect on cardiovascular and

renal function

PRIMARY HEMODYNAMIC OF NICARDIPINE EFFECT

NICARDIPINE

CHARACTERISTIC

1. VASOSELECTIVITYNicardipine 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

Perdipine: 3 g/kg/min 20 min

(Shoji Suzuki, et al., The 20th Annual Scientific Meeting of the Japanese Society of Hypertension: 1997)

60

40

20

0

-10

-20

Vertebral artery

blood flow

Renal blood flow

Coronary blood flow

Baseline value

121 42 mL/min

563 29mL/min

183 65 mL/min

103 11 mmHg

Coronary artery

blood flow

Renal artery

blood flow

Vertebral artery

blood flow

Mean blood pressure

⊿%)

( %)⊿

(Hypertensive patients, n = 9)

Pharmacodynamic action

Blo

od

flo

w c

ha

ng

e r

ate

Me

an

blo

od

pre

ss

ure

ch

an

ge

ra

te

Mean bloodpressure

Tissue selectivity betweenCalcium Antagonist

Bristow et al. Br J Pharmacol1984; 309:82

Comparison between Calcium Antagonist

Drug Coronary Vasodilation

Suppressionof Cardiac

Contractility

Suppressionof SA Node

Suppressionof AV Node

Verapamil(phenylalkylamine)

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

Diltiazem(benzothiazepin)

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

Nicardipine(dihydropyridine )

+++++ 0 + 0

Kerins DM. Goodman Gilman’s.10th ed.2001:843-70

Comparison Study with Intravenous Diltiazem

Subjects:Patients requiring a rapid reduction in BP (DBP 115 mmHg)

Design:Multicenter, randomized, single-blind comparative study

DosageNicardipine: Started at 0.5 g/kg/min

Increased up to 10 g/kg/min if necessaryDiltiazem: 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 Effect

0

69

24.1

6.8

95.8

4.2

0

20

40

60

80

100

120

Stable Slightly unstable Undeterminable

%

PerdipineDiltiazem

Stability of antihypertensive effect better than Diltiazem

Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

Nicardipine vs Nitrovasodilators

Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25.

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

+ ++ +++

Ease of Administration ++++ ++ +++

Cyanide Toxicity 0 ++++ 0

Actions to maintain urine volume

(Patients with post-operative systolic blood pressure of 150 mmHg, n = 10, Mean SEM)

Perdipine: 1 g/kg/min: Increased/decreased appropriately** p<0.01

Urinary volume (Eq/min) Urinary Na excretion(mL/min)

(Fumio Goto et al., Journal of Clinical and Experimental Medicine: 152 (3) 189, 1990)

†: Urine collected from 30 to 60 min after the start of administration

＊＊ 700

600

500

400

300

200

100

0

＊＊

4

3

2

1

0

5

After administrationBefore administration

After administrationBefore administration

Nicardipine increase Renal Blood Flow

Baba Tsuneharu, et al;AHA 1986; 111:552-57

708.9

885.5

0

100

200

300

400

500

600

700

800

900

1000

Control Nicardipine

p < 0.01

0

5

10

15

20

25

30

Baseline Maintenance

0

0,5

1

1,5

2

2,5

Baseline Maintenance

Renal function parameters before and after rapid control of hypertension with nicardipine infusion (J Int Med Res 2002: 30:337-345)..

Blo

od u

rea n

itro

gen (

mg/d

l)

Cre

ati

nin

e

(mg/d

l)

Perdipine for preeclampsia

DOSIS PERDIPINE

0.5 – 6Hypertensive emergencies

10 – 302 - 10Acute hypertensive crises during surgery

Bolus(g/kg)

DIV(g/kg/min)

(g/kg/min)0.5 1 2 6 10

Hypertensive emergencies

Acute hypertensive crises during surgery

Dosage and AdministrationStart 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

The 1st line treatment of Hypertensive Emergency

Sodium Chloride / NaCl

( OTSU-NS : 100/250/500 ml )

Dextrose 5%

( OTSU-D5 : 100 / 250 / 500 ml )

Glucose 5%

Potacol – R

Ringer Asetat

KN 1A / 1B / 4A

PERDIPINE ®

Could be used : Couldn’t be used :

Sodium bicarbonat Ringer Laktat

SUMMARY Hypertensive Crises is an urgent situation that need rapid

management to prevent organ damage

Antihypertensive agent that preffered in this condition

should be fast action, parenteral, and titratable

Nicardipine is the only Calcium Antagonist recommended by JNC 7, AHA, 2007, CHEST 2007 to manage hypertensive emergency

Nicardipine has favorable antiischemic profilebecause of an increase myocardial , brain, and kidney oxygen supply

THANK YOU FOR YOUR ATTENTION

TAKE CARE OF YOUR HEART, BRAIN, AND KIDNEY