1. Severe Hypertension: Disease State Awareness

2. Hypertensive Crisis: JNC-7 definitions Chobanian AV et al. Hypertension. 2003;42:1206-1252. Hypertensive Crisis Operating room post-anesthesia care Emergency department Intensive care unit 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 Hypertensive urgency Hypertensive emergency Perioperative hypertension

4. Severe Hypertension: Clinical Outcomes Aortic Dissection Stroke, Encepha- lopathy Myocardial Infarction Renal Dysfunction CHF and Pulmonary Edema Severe HTN

11. Severe Hypertension: Treatment Options

13. IV Antihypertensive Utilization Trends All Patients Treated with Drug Thomson Patient Level Data. 2006

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

23. 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.

27. Vascular and Myocardial Inhibitory Potency of Various Calcium Antagonists* 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 pIC 50 IC 50 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

28. Clevidipine Clinical Development Tolerability, Safety, PK Dose Response ESCAPE: Efficacy Clevidipine vs Placebo VELOCITY: Severe Hypertension PK, Metabolism, Rates and Routes of Excretion PK/BP ESCAPE: Efficacy Clevidipine vs Placebo PK PK/PD: Clevidipine vs Placebo ECLIPSE: Safety vs NTG QTc Study ECLIPSE: 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 I N=89 Phase II N=300 Healthy Volunteers Patients: Mild to Moderate Hypertension N=86 Phase III N=1821 Perioperative Hypertension N=1721 Severe Hypertension N=100 Patients: Perioperative N=214 Data on file. The Medicines Company.

30. Clevidipine: Linear Dose Response Bailey JM et al. Anesthesiology. 2002;96:1086-1094. 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. 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 Responders* (%) n=0 n=1 n=4 n=6 n=9

33. Clevidipine: Rapid Offset Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001. N=12 normal volunteers 100 90 80 70 60 50 40 – 5 0 5 10 15 20 35 MAP (mm Hg) Time (min) 25 30 Clevidipine Infusion MAP

34. Clevidipine: Hemodynamics * 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 0 C1 0.375 0.75 1.5 3 C2 10 6 2 mcg/kg/min Central Venous Pressure C2 Systemic Vascular Resistance 1400 Units 1200 1000 0 C1 0.375 0.75 1.5 3 ‡ † † † mcg/kg/min C2 Mean Arterial Pressure 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 † 90 80 70 * † † C1 0.375 0.75 1.5 3 mcg/kg/min mm Hg

35. Clevidipine: Hemodynamics * 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. Stroke Volume Cardiac Output * 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 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/beat 70 65 0 C1 0.375 0.75 1.5 3 † * Infusion Rate (µg • kg –1 • min –1 )

36. Clevidipine: Effect on Heart Rate Preoperative HR Changes in Non-Anesthetized Patients N=53 Postoperative HR Changes in Anesthetized Patients N=61 Levy JH et al. Anesth Analg . 2007;105:918-925. Singla N et al. Anesthesiology. 2005;103:A292. 10 5 0 – 5 0 5 10 15 20 25 30 % Change From Baseline Time (min) HR 5 0 – 5 0 5 10 15 20 25 30 % Change From Baseline Time (min) HR HR change for patients during the 30-minute treatment period HR change for patients during the 30-minute treatment period