Prevention and Awareness of Asthma

Severe Hypertension: Disease State Awareness

Hypertensive Crisis: JNC-7 definitions

Hypertensive emergency

Severe elevation in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction

Hypertensive urgency

Severe elevation in BP without progressive target organ dysfunction

Chobanian AV et al. Hypertension. 2003;42:1206-1252.

Hypertensive Crisis

Hypertensive urgency

Hypertensive emergency

Perioperative hypertension

Operating roompost-

anesthesia care

Emergencydepartment

Intensive care

unit

Severe Hypertension: Epidemiology

● Hypertensive emergency1

– Hypertension affects approximately 50 million people in the USA and approximately 1 billion people worldwide.

– Estimates are that approximately 1% of these patients will develop hypertensive crisis at some point in their lives

– Hospital admissions for hypertensive emergency tripled from 1983 to 1990 (from 23,000/yr to 73,000/yr) in the USA.

● Perioperative hypertension– Frequently occurs with cardiovascular surgery (30%–80%)2,3

80% incidence following carotid endarterectomy

– Preoperative incidence: 2,4

50% of cardiac surgery patients25% of non-cardiac surgery patients

– Intraoperative incidence:2

50% of patients undergoing cardiac surgery

1. Varon J, Marik PE. Crit icalCare. 2003 7:374-384 2. Cheung AT. J Card Surg. 2006;21:S8-S143. Oparil S et al. Am J Hypertens. 1999;12:653-664. 4. Goldman L et al. N Engl J Med. 1977;297:845-850

AorticDissection

AorticDissection

Stroke,Encepha-lopathy

Stroke,Encepha-lopathy

MyocardialInfarction

MyocardialInfarction

Renal Dysfunction

Renal Dysfunction

CHF andPulmonary

Edema

CHF andPulmonary

Edema

SevereHTN

SevereHTN

Severe Hypertension: Clinical Outcomes

Severe Hypertension: End-Organ Damage

End-Organ Damage Type No. of Cases (%)

Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy 18 (16.3)

Acute Pulmonary Edema 24 (22.5)Acute CHF 15 (14.3)Acute MI 13 (12)

Aortic Dissection 2 (2)

Eclampsia 5 (4.5)

Zampaglione, B. Hypertension 1996;27:144-147.

108 Hypertensive Emergencies*

*All Caucasians

Acute Condition Death Rehospitalization

ACS1,2,3 5-7% 30%

CHF4 8.5% 26%

Severe Hypertension5 7-9% 37%

Severe Hypertension: Short-Term (Up to 6 months) Outcomes

1. OASIS-5 NEJM 2006. 2. GUSTO IIb NEJM 1996.3. GRACE JAMA 2007.4. IMPACT-HF J Cardiac Failure 2004.5. Kleinschmidt, SAEM, STAT registry, 2008

Severe Hypertension: May Occur Throughout the Hospital

●ED

●MICU

●SICU

●OR

●PACU

Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.

Severe Hypertension: Etiologies

●Medical– Uncontrolled HTN

- Noncompliance– Drug-induced HTN

- Cocaine, amphetamines- Drug withdrawal- Drug-drug interactions

– Endocrine disorders

●Surgical– Cardiac surgery

– Major vascular surgery

- Carotid endarterectomy

- Aortic surgery

– Neurosurgery

– Head and neck surgery

– Renal transplantation

– Major trauma – burns or head injury

Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.

Treatment Goals for Hypertensive Emergency

●Reduce MAP by ≤ 25% during the first minute to 1 hour

● If stable, reduce BP to 160/100-110 mmHg in next 2-6 hours

●Gradual reductions toward normal BP over next 24-48 hours

●Excessive falls in BP may cause renal, cerebral, or coronary ischemia

●Conditions requiring special management– Ischemic stroke– Stroke eligible for thrombolytic agents– Aortic dissection

Chobanian AV et al. Hypertension. 2003;42:1206-1252.

Use of Intravenous (IV) Antihypertensive Therapy

●Hypertensive emergency

●Hypertensive urgency when oral therapy is not feasible

●Perioperative hypertension

●Special patient populations– Hemorrhagic stroke– Ischemic stroke prior to thrombolytics– Aortic dissection– NPO patient

Chobanian AV, et al. Hypertension. 2003;42:1206-1252.Varon J, Marik PE. CHEST. 2000;118:214-227.Varon J, Marik PE. Crit Care. 2003;7:374-384.

Severe Hypertension: Treatment Options

Goals of an Ideal Agent for Treatment of Severe Hypertension

– Rapid onset of action– Short acting– Easily titratable– Require minimal dosage adjustments– Minimal risk of hypotension (“overshoot”)– Lack significant side effects– Mild reduction in myocardial contractility– Vascular effects confined to arteriolar bed– Easy conversion to oral agents– Low cost, including drug and monitoring costs

Feneck R. Drugs. 2007;67:2023-2044.Oparil S et al. Am J Hypertens. 1999;12:653-664.Rynn KO et al. J Pharm Pract. 2005;18:363-376.

IV Antihypertensive Utilization Trends

1,200,4441,133,717

8,288

139,104

240,785

735,647

502,518

312,432

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

Nitroglycerin Labetalol Hydralazine Enalaprilat Esmolol SNP Nicardipine Fenoldopam

2004 2005 2006

All Patients Treated with Drug

Thomson Patient Level Data. 2006

IV Antihypertensive Agents

Agent Onset/Duration

Elimination Half-Life Adverse Events Cautions/Concerns

Enalaprilat <15 min/12–24 h 11 h

Precipitous fall in BP in high-renin states, headache, cough, renal

failure, hyperkalemia, angioedema

Avoid in acute MI, long duration of action

Esmolol 1–2 min/10–30 min 2–9 min

Heart block, hypotension, nausea, bronchospasm, overt heart failure,

cardiogenic shock

Reduces cardiac output, which may impair organ perfusion

Fenoldopam mesylate

5–15 min/30 min–4 h 5 min

Tachycardia, headache, nausea, dizziness, flushing, hypotension, increased intraocular pressure

Caution with glaucoma

Hydralazine 10–20 min/1–4 h 1 h Marked hypotension, tachycardia,

flushing

Avoid in aortic dissection, MI, severe renal disease; prolonged and

unpredictable effects; difficult to titrate

Labetalol <5 min/3–6 h 5.5 h

Bradycardia (heart block), overt heart failure, cardiogenic shock,

edema, nausea, vomiting

Avoid in acute heart failure; severe bradycardia; heart block, asthma

Nicardipine 5–15 min/15 min–6 h 44.8 min

Tachycardia, headache, nausea, flushing, thrombophlebitis,

hypotension, vomiting

Avoid in acute heart failure; caution with coronary ischemia; long duration

of action

Nitroglycerin 2–5 min/5–10 min 1–4 min

Flushing, headache, vomiting, hypotension, methemoglobinemia,

decreased arterial resistance, reflex tachycardia

Reduction in preload and cardiac output undesirable in patients with compromised renal and cerebral

perfusion

Sodium nitroprusside

Immediate/2–3 min 2–3 min

Nausea, muscle twitching, sweating, thiocyanate and cyanide

intoxication, hypotension

Increases intracranial pressure; may reduce coronary perfusion pressure (coronary “steal”); cyanide toxicity

Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Rynn KO et al. J Pharm Pract. 2005;18:363-376.

Enalaprilat

●ACE Inhibitor – Reduces vasoconstriction and circulating catecholamine levels – Balanced reduction in afterload and pre-load– Reduces CVP, PCWP, SVR, with minimal effect on CO, HR

●Pharmacokinetics– Moderate to slow onset of action– Longer duration of action– Full effect may not be seen for 24 hours

●May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash

Rynn KO et al. J Pharm Pract. 2005;18:363-376.

Esmolol

●B1 selective adrenergic blocker– Reduction in heart rate (HR) and cardiac output (CO)– May see increase in PCWP, CVP, and SVR

●Rapid onset and short duration of action

●Elimination via plasma esterases

●May cause bradycardia, bronchospasm, seizures, and pulmonary edema


Labetalol

●Non-selective adrenergic blocker– Alpha-1, Beta-1, Beta-2– 1:7 ratio of alpha:beta effects– Reduces SVR with little effects on HR, CO– Little to no effect on cerebral blood flow

●Moderate onset, long duration of action

●Commonly used in HTN emergency and in ICH

●Generally given by IV bolus in ED, OR; IV infusion used in ICU

●May cause bronchospasm, bradycardia, heart block, delayed hypotension


-Blocker vs Combined - and -Blocker

Parameters Esmolol -Blocker

Labetalol - and -Blocker

Administration BolusContinuous infusion

BolusContinuous infusion

Onset Rapid (60 s)2 Intermediate (peak 5-15 min)2

Offset (Duration of action) Rapid (10-20 min)2 Slower (2-4 h)2

HR Decreased +/-

SVR 0 Decreased

Cardiac output Decreased +/-

Myocardial O2 balance Positive Positive

Contraindications Sinus bradycardiaHeart block >1°

Overt heart failureCardiogenic shock

Severe bradycardiaHeart block >1°

Overt heart failureCardiogenic shock

1. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:215-268.

2. Varon J, Malik PE. Chest. 2000;118:214-227.

Nitroglycerin

●At lower doses, works primarily by ↓ preload– Reduces CVP, PCWP

●At higher doses, works primarily by ↓ afterload– Some reduction in SVR, further reduction PCWP– Increase HR

●Administered as continuous infusion; onset of action 2-5 min; duration of action 5-10 min

●Useful in managing BP – Angina patients: improved coronary blood flow– Pulmonary edema/heart failure: decreasing preload

●Limitations: tachyphylaxis, headache, significant hypotensive effects in patients who are hypovolemic, caution in RCA IHD


Hydralazine

●Directly relaxes arteriolar smooth muscle – reduction in afterload– Reduces SVR– Increases HR

●Used primarily in management of preeclampsia and eclampsia although some use in the OR, in combination with pure beta-blockers in patients who are difficult to control

●Moderate onset; long duration of action

●Limitations: – reflex tachycardia often dose limiting– use associated with lupus-like syndrome


Sodium Nitroprusside

●Arterial and venous vasodilator– ↓Preload and afterload– Reduces SVR, CVP– Increases HR

●Onset: Immediate

●Duration of action: 1-2 min

●Adverse effects– Tachycardia, nausea, vomiting, muscle twitching, sweating,

thiocyanate and cyanide intoxication, coronary steal, maldistribution of blood flow

●Light sensitive: requires special delivery system


Nicardipine

●Dihydropyridine calcium channel blocker– Coronary and cerebral arterial vasodilation – No negative inotropic or dromotropic effects– Reduces SVR, little to no effect on HR/CO

●Onset: 5-15 min

●Duration of action: 15 min-6 hours

●Adverse effects: – Tachycardia (+/-), headache, flushing, local phlebitis– Fluid load may be an issue for some patients

Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Rynn KO et al. J Pharm Pract. 2005;18:363-376.

Cleviprex (clevidipine butyrate)

Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Please see full prescribing information.

Clevidipine: Overview

● Dihydropyridine calcium channel blocker (CCB)

● T½ ≈ 1 min

● Selective arteriolar dilation↓ Systemic vascular resistance↓ Afterload↑ Stroke volume↑ Cardiac output

● No venous dilation– No effect on cardiac filling pressure

● No effect on HR

● Clevidipine is selective for vascular as opposed to myocardial smooth muscle

Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.

Clevidipine: Metabolized by Plasma and Tissue Esterases

Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite and formaldehyde

+OH

OHH

O

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

Esterases +O

O

NH

Cl

O

O

Cl

H

Primary metabolite

Reproduced from: Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67.

Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

Clevidipine: Pharmacokinetics

Clevidipine Product Information August 2008; The Medicines Company

●Clevidipine butyrate is >99.5% bound to proteins in plasma at 37°C

●Carboxylic acid metabolite is inactive as an antihypertensive

● In vitro studies show that clevidipine butyrate and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme

●83% of the drug is excreted in the urine or feces, with the major fraction (63-74%) excreted in urine

Vascular and Myocardial Inhibitory Potency of Various Calcium Antagonists*

pIC50 IC50

Compounds Vascular Myocardial Selectivity Ratio

Verapamil 6.6 6.46 1.4

Diltiazem 6.36 5.5 7

Nifedipine 7.62 6.47 14

Felodipine 7.47 5.40 118

Clevidipine 6.37 4.69 48

Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.

In vitro studies comparing effects of calcium antagonists on isolated rat portal vein (vascular) vs. left ventricular rat papillary muscle (myocardial)

*Clinical significance of selectivity is unknown

Clevidipine Clinical Development

Tolerability, Safety, PK

Dose ResponseESCAPE: Efficacy

Clevidipine vs Placebo

VELOCITY: Severe Hypertension

PK, Metabolism, Rates and Routes

of ExcretionPK/BP

ESCAPE: EfficacyClevidipine vs Placebo

PKPK/PD:

Clevidipine vs Placebo

ECLIPSE: Safety vs NTG

QTc StudyECLIPSE:

Safety vs SNP

ECLIPSE: Safety vs NIC

Dose Response:Clevidipine vs Placebo

Hemodynamics:Clevidipine vs SNP

BP, HR:Clevidipine vs SNP

BP, Dose/PK

BP: Clevidipine vs Placebo

Phase IN=89

Phase II N=300

Healthy VolunteersPatients: Mild to

Moderate HypertensionN=86

Phase III N=1821

Perioperative Hypertension

N=1721

SevereHypertension

N=100

Patients: Perioperative

N=214

Data on file. The Medicines Company.

*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion.

Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.

Clevidipine: Linear Pharmacokinetics

At steady state, there is a linear relationship between dosage and arterial blood concentrations

120

100

80

60

40

20

0

0 5 10 15 20 35

Cle

vid

ipin

e C

on

ce

ntr

ati

on

at

Cs

s (

nm

ol/

L)*

Dose Rate (nmol/kg/min)25 30

N=12 normal volunteers

Bailey JM et al. Anesthesiology. 2002;96:1086-1094.

Clevidipine: Linear Dose Response

n=19

Infusion Rate (mcg/kg/min)

0

10

20

30

40

50

60

70

80

90

100

0 0.05 0.18 0.32 1.37 3.19

Re

sp

on

de

rs*

(%)

n=0

n=1

n=4

n=6

n=9

Phase II dose-ranging study in cardiac surgery patients with hypertension

*Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration.

Reproduced from Ericsson H et al. Anesthesiology. 2000;92:993-1001.

*Accounts for 85-90% of clevidipine butyrate elimination. Clevidipine Product Information August 2008; The Medicines Company

Clevidipine: Ultrashort Half-Life

●Approximate initial phase half-life: 1 min*

Triphasic Elimination

arterial measurements

venous measurements

Representative subject – normal volunteer Graph developed from mean concentrations following 7 nmol/kg/min dose given over a 20 minute period;.

Levy JH et al. Anesth Analg. 2007;1-5:918-925

10

5

0

–5

–10

–15

–20

–25

–300 5 10 15 20 25 30

Me

an

% C

ha

ng

e F

rom

Ba

se

lin

e

Time (min)

Systolic Blood Pressure

Clevidipine: Rapid Onset

BP-lowering effects seen within 1-2 min of clevidipine infusion

N=105

Clevidipine: Rapid Offset

Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.

100

90

80

70

60

50

40–5 0 5 10 15 20 35

MA

P (

mm

Hg

)

Time (min)

25 30

Clevidipine InfusionMAP

N=12 normal volunteers

*P<0.05, †P<0.001, ‡P<0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg /min–1 and post-drug control. Values are mean ± SEM.

Adapted from: Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

12

mm

Hg 8

4

0C1 0.3750.75 1.5 3 C2

10

6

2

mcg/kg/min

Central Venous Pressure

Clevidipine: Hemodynamics

C2

Systemic Vascular Resistance

1400

Un

its 1200

1000

0C1 0.375 0.75 1.5 3

‡†

††

mcg/kg/minC2

Mean Arterial Pressure

†

90

80

70

*†

†

C1 0.375 0.751.5 3mcg/kg/min

mm

Hg

Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients

C1 is baseline/control before CLV administered C2 is post-CLV control after CLV discontinued

*P<0.05. †P<0.001.SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

Clevidipine: Hemodynamics

Stroke VolumeCardiac Output

L •

min

–1

0

1

2

3

4

5

6

C1 0.375 0.75 1.5 3 C2

Infusion Rate(µg • kg–1 • min–1)

C2

75

mL

/be

at

70

65

0C1 0.375 0.75 1.5 3

†*

Infusion Rate(µg • kg–1 • min–1)

*

Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients

C1 is baseline/control before CLV administered C2 is post-CLV control after CLV discontinued

Preoperative HR Changes in Non-Anesthetized Patients

N=53

Postoperative HR Changesin Anesthetized Patients

N=61

Clevidipine: Effect on Heart Rate

10

5

0

–5

0 5 10 15 20 25 30

% C

ha

ng

e F

rom

Ba

se

lin

e

Time (min)

HR5

0

–5

0 5 10 15 20 25 30%

Ch

an

ge

Fro

m B

as

eli

ne

Time (min)

HR

HR change for patients during the 30-minute treatment period

HR change for patients during the 30-minute treatment period

Levy JH et al. Anesth Analg. 2007;105:918-925.Singla N et al. Anesthesiology. 2005;103:A292.

Clevidipine: Pharmacodynamics


● Clevidipine is titrated to the desired reduction in blood pressure. The infusion rate for which half the maximal effect is observed is approximately 10 mg/hr.

● Onset: In the perioperative patient population, clevidipine produces a 4-5% reduction in SBP within 2-4 min of starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr).

● Offset: In most patients, full recovery of blood pressure is achieved within 5-15 minutes after the infusion is stopped.

● Duration of effect: In studies up to 72 hours, there was no evidence of tolerance; in these studies, if patients were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following discontinuation of clevidipine therapy.

Clevidipine: Pharmacodynamics


●Hemodynamics: Clevidipine causes a dose-dependant decrease in systemic vascular resistance

●Heart rate: An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate can be pronounced. If this occurs, decrease the dose of clevidipine.

●Electrophysiologic effects: In healthy volunteers, clevidipine butyrate or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady state), did not prolong cardiac repolarization.

IMPORTANT SAFETY INFORMATION

● Cleviprex is intended for intravenous use. Titrate drug depending on the response of the individual patient to achieve the desired blood pressure reduction. Monitor blood pressure and heart rate continually during infusion, and then until vital signs are stable. Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped.

● Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products; defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia; and in patients with severe aortic stenosis.

● Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal.



IMPORTANT SAFETY INFORMATION:continued

● Most common adverse reactions (> 2%) are headache, nausea, and vomiting.

● Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

● Maintain aseptic technique while handling Cleviprex. Cleviprex contains phospholipids and can support microbial growth. Do not use if contamination is suspected. Once the stopper is punctured, use and discard within 4 hours.



Prevention and Awareness of Asthma

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