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NEW CONCEPTS IN VASOACTIVE THERAPY

NEW CONCEPTS IN VASOACTIVE THERAPY. Jerrold H Levy, MD Professor of Anesthesiology Deputy Chairman for Research Emory University School of Medicine Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia. VASOACTIVE THERAPY. Vasodilators. Beta Blockers

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NEW CONCEPTS IN VASOACTIVE THERAPY

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  1. NEW CONCEPTS IN VASOACTIVE THERAPY Jerrold H Levy, MD Professor of Anesthesiology Deputy Chairman for Research Emory University School of Medicine Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

  2. VASOACTIVE THERAPY Vasodilators Beta Blockers Other agents BP = SVR X CO (SV x HR) Inotropes Vasoconstrictors

  3. PHARMACOLOGIC APPROACHES FORBIVENTRICULAR DYSFUNCTION PERIOPERATIVELY AND IN THE ICU • Pulmonary vasodilators • PDE inhibitors • Inhaled NO • Prostaglandins • New agents Nesiritide, Levosimendan • Vasodilator therapy • Inotropic agents • Catecholamines • Phosphodiesterase inhibitors • Digoxin, calcium, T3 Bailey JM, Levy JH: Cardiac surgical pharmacology. Edmunds H (ed), McGraw Hill, New York, pp. 225-254, 1997. Levy JH: Milrinone. Ann Thorac Surg 2002;73:325-30. Levy JH: Postoperative circulatory control. Cardiac Anesthesia, 1233-1258, 4th Edition, W.B. Saunders, Philadelphia, 1998.

  4. VASODILATORS(1) • ACE inhibitors • Adenosine • A-II antagonists • Alpha1 adrenergic antagonists • Alpha2 adrenergic agonists • BNP (nesiritide) • Beta2 adrenergic agonists

  5. VASODILATORS(2) • Calcium channel blockers • Dopamine1 agonists • Hydralazine • Nitrovasodilators • Nitric oxide • Phosphodiesterase inhibitors • Prostaglandins

  6. SELECTIVE VASODILATORS • Nitroglycerin: due to selective metabolism to nitric oxide • Inhaled nitric oxide: due to optimizing ventilation/perfusion ratios and minimizing intrapulmonary shunting

  7. Mechanisms of Nitrate Tolerance • Decreased bioconversion to nitric oxide1 • Cellular depletion of sulfhydryl groups2,3 • Neurohumoral adaptations4 • Superoxide anion production5 • Upregulation of endothelin 16 1. Münzel T. Am J Cardiol. 1996;77:24C-30C. 2. Parker JD, Parker JO. N Engl J Med. 1998;338:520-531. 3. Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715. 4. Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303. 5. Münzel T, et al. J Clin Invest. 1995;95:187-194. 6. Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.

  8. NO+ CN CN CN Fe++ CN CN NitrovasodilatorsSodiumNitroprusside Na+ Na+

  9. NITROPRUSSIDE THERAPY • Potent venodilator/arterial vasodilator • Cardiac output is often affected due to venodilation • Volume replacement is often required for venodilation

  10. Nitroglycerin Efficacy in CHF ±1 Tachycardia2 Tachyphylaxis3 Neurohormonal activation due to reflexive sympathetic activity4 Nitroprusside Difficult titration Arterial line monitoring due to excessive hypotension risk3 Tachycardia3 Coronary steal3 Pulmonary shunting3 Thiocyanate toxicity3 Neurohormonal activation due to reflexive sympathetic activity4,5 Limitations of Nitrovasodilators for Acute Heart Failure 1 Publication Committee for the VMAC Investigators. JAMA 2002; 287 (12): 1531-40. 2 Robertson R, et al. ''Chapter 32: Drugs Used for the Treatment of Myocardial Ischemia'' in Pharmacologic Basis of Therapeutics,Goodman and Gilman, Eds. 9th. Edition 1996, McGraw-Hill. 3 Kelly and T Smith, ‘‘Chapter 34: Pharmacologic Treatment of Heart Failure’‘, in The Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds. 1996 McGraw-Hill. 4 Abraham W. Natriuretic peptides in heart failure. Heart Failure 1996; 12:391-393. 5 J Oates, J. Chapter 33: Antihypertensive Agents and Drug Treatment of Hypertension’‘, in The Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds. 1996 McGraw-Hill.

  11. MAINSTAY VASOACTIVE THERAPY FOR ACUTE HEART FAILURE IN CRITICALLY ILL PATIENTS • Diuretics • Dobutamine • Enalaprilat • Milrinone • Nesiritide • Nitrovasodilators

  12. MAINSTAY IV THERAPY FOR HYPERTENSION IN CRITICALLY ILL PATIENTS • Beta adrenergic blockers • Dihydropyridine (DHP) calcium channel blockers (Nicardipine IV) • Enalaprilat • Hydralazine • Nitrovasodilators (nitroprusside and nitroglycerin

  13. IV DHP CALCIUM CHANNEL BLOCKERS • 1st generation: nifedipine • 2nd generation: nicardipine, isradipine • 3rd generation: clevidipine

  14. DHP CALCIUM CHANNEL BLOCKERS:CLINICAL APPLICATIONS • No effects on SA/AV node • No myocardial depression • Cerebral and coronary vasodilator • Important applications in the ICU and perioperative management of neuro and CV disease. Has also been reported for pregnancy induced hypertension • Nicardipine is the first IV drug of this class available in the US (94)

  15. HEMODYNAMIC EFFECTS OF IV NICARDIPINE ControlNicardipine HR 71 ± 13 70 ± 14 MAP 107 ± 14 80 ± 9 PAOP 9 ± 4 8 ± 3 MPAP 15 ± 3 16 ± 4 RAP 8 ± 3 8 ± 2 CI 2.2 ± 0.3 2.8 ± 0.4 LV 1509 ± 376 1680 ± 485 LVEF 57 ± 9 68 ± 7 Lambert CR: Am J Cardiol 1993;71:420

  16. HEMODYNAMIC EFFECTS OF IV ISRADIPINE Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256

  17. Should a moratorium be placed on sublingual nifedipine capsules given more hypertensive emergencies and pseudo emergencies?Gross et al: JAMA 1996:276;1342-3

  18. Nicardipine IV Dosing (PI) • Initiation: 5 mg/hr (50 ml/hr) • Titration for gradual BP reduction:  rate 2.5 mg/hr (25 ml/hr) q 15 min to a maximum of 15 mg/hr (150 ml/hr) until blood pressure reduction achieved • For more rapid BP reduction:  rate 2.5 mg/hr (25 ml/hr) q 5 min to a maximum of 15 mg/hr (150 ml/hr) until blood pressure reduction achieved • Maintenance: Following achievement of BP goal, adjust infusion rate to 3 mg/hr, (30 ml/hr)

  19. Nicardipine IV Dosing (FRANCE) • For hypertensive urgency, Rx should be adapted so BP decrease is not >25% in 1 hr to avoid myocardial, cerebral or renal ischemia. • Rapid effect: 1 mg/min to 10 mg • Progressive effect: 8-15 mg/h to 30 min, then 2 to 4 mg/h maintenance • Infant: 1 to 2 mg/m2 of body surface in 5 minutes. Ref: http://www.biam2.org/www/Spe4359.html#Voie

  20. Clevidipine in CABG: a dose-finding study. Bailey JM et al:Anesthesiology 2002;96:1086 • Clevidipine, an ultrashort acting agent, decreased MAP and SVR, without changes in heart rate, CVP, PAOP, or CI at increasing doses. • The early phase of drug disposition had a half-life of 0.6 min. The context-sensitive half-time <2 min for up to 12 h of administration. • CONCLUSION: Clevidipine is a dihydropyridine CCB that lowers BP without changing heart rate, CI, or cardiac filling pressures.

  21. Fenoldopam (Corlopam) • Selective vascular DA1 agonist • Produces arterial vasodilation, increases renal perfusion, and natruresis • Short duration of action/half life • Approved in June 1997 • Expense and potency are major issues

  22. NOVEL AGENTS: Nesiritide(Human B-type Natriuretic Peptide)

  23. Natriuretic Peptides: The Heart as a Secretory Organ • Secretory granules found on EM of atria. Kisch, Exp Med Surg 1956 • Balloon catheter in atria of dogs resulted in diuresis: Henry and Pearce, J Exp Phys 1956 • Homogenized atrium injected IV cuases natriuresis, diuresis. De- Bold, Life Sciences, 1981 • ANP identified in 1984. Kangawa • BNP identified in 1988 in porcine brain. Nature, 1988 • Amino acid sequence and DNA clones: Sudoh et al, 1988 and Seilhamer et al, 1989

  24. Natriuretic Peptides

  25. I S R S D S M S K G R L G H G F R C R S S C L K V G K P M S S V Q G hBNP for Rx of decompensated heart failureNesiritide (h-BNP) is identical to the endogenous naturally occurring hormone, with identical pharmacological profile • 32 amino acid sequence • Recombinant technology using E-coli NOTE: hBNP affects assay for BNP, but can still use proBNP or one of the proANP assays

  26. Physiology of Natriuretic Peptides Cardiac Wall Stress + - Urodilatin ANP+BNP Neutral Endopeptidases NPR-B ?NPR-D Clearance NPR-A/NPR-B CNP NPR-C Decreased Blood Pressure Increased Na/H20 Excretion Decreased Vascular Growth Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:1307-1310

  27. Systemic Hemodynamic Preload reduction1,5 Afterload reduction1,5 Increased CI1,5 No tachycardia1,5 Coronary Arteries Vasodilates2,3 Neurohormonal Decrease endothelin-14 Inhibit RAA axis1,5 Decrease norepinephrine5 Renal Diureses and natriuresis1 Increased filtration fraction6 GFR effect variable6 B-Type Natriuretic Peptide (BNP) Physiologic Effects 1Colucci WS, et al. NEJM 2000; 343(4):246-253 2 Kato H. Yasue H. Yoshimura M.Tanaka H. Miyao Y. Okumura K. Am Heart J 1994; 128: 1098-1104 3 Okumura K, et al. J Am Coll Cardiol 1995 Feb;25(2):342-8. 4Aronson D, et al. J Am Coll Cardiol, February 2001. Abstract from Poster Session 1046 5Abraham WT, et al. J Card Failure 1998; 4(1): 37-44 6Jensen KT, et al. Clinic Sci 1999;96:5-15

  28. Clearance Pathways Vascular Smooth Muscle Cell GC= Guanylate Cyclase GC-A GTP G/C cGMP GC-B Biological Effects G/C hBNP ? NP-C NP=neutral endopeptidase Clearance receptor clearance pathway Nakao et al Can J Physiol Pharmacol, 1991, 69: 1500-1506

  29. Neurohumoral Activation in Heart Failure Myocardial injury Fall in LV performance ANP BNP Activation of RAAS, SNS, ET, and others - Peripheral vasoconstriction Hemodynamic alterations Myocardial toxicity Remodeling and progressive worsening of LV function - Heart failure symptoms Morbidity and mortality

  30. The Natriuretic Peptide System is Overwhelmed in Acute Decompensated Heart Failure ANP BNP Endothelin Aldosterone Angiotensin II Epinephrine Adapted from Burnett JC, J Hypertens 1999

  31. Natriuretic Peptide System Sympatho-inhibitory ANP BNP • Anti-fibrotic • Lusitropic • Vasodilation • veins • arteries • coronaries • pulmonary ET inhibition Vasodilation ANP ANP BNP BNP ANP CNP BNP ANP Aldosteroneinhibition BNP Antiproliferationeffect Natriuresis Renin inhibition

  32. I S R S D S M S K G R L G H G F R C R S S C L K V G K P M S S V Q G Pharmacologic Actions of Human BNP Hemodynamic veins  arteries  coronary arteries Neurohumoral aldosterone endothelin-1 norepinephrine • Cardiac • lusitropic • anti-fibrotic • anti-remodeling Renal  diuresis natriuresis 

  33. Nesiritide Reconstitution and Standard Dosing • 1.5 mg vial reconstituted with 5 mL NS, 1/2NS, 1/4NS, or D5W • Add 5 mL from reconstituted vial into 250 mL bag for a final concentration of 6 mg/mL • Administration via peripheral IV or non-heparin coated central line catheter Standard Dosing: 2 mcg/kg bolus + 0.01 mcg/kg/min continuous infusion • Bolus volume (ml): Patient weight (Kg) / 3 • Infusion (ml/hour): 0.1 x patient weight (Kg) • Duration: Dependent on clinical need – NO maximum duration NB: Most patients are expected to be managed without dose adjustment

  34. Nesiritide Clinical Summary • Nine clinical trials in CHF. Over 900 CHF patients studied. • Trials included patients with ACS, renal disease, serious arrhythmias • Studied with a wide variety of concomitant medications Summary of Trial Data: • Improves hemodynamics and CHF symptoms such as dyspnea • Decreases diuretic need and/or increases urine output • Suppresses neurohormones • More effective than IV NTG • No tachyphylaxis • No tachycardic or proarrhythmic effects • Can be used safely with b-blockers • Hypotension is the major side effect

  35. NOVEL AGENTS: Levosimendan

  36. Calcium Sensitisation by Levosimendan • Enhanced contractility of myocardial cell by amplifying trigger for contraction with no change in total intracellular Ca2+

  37. Effects of Opening ATP-Sensitive Potassium Channels • Reduces preload and afterload • Increased coronary blood flow(Lilleberg et al. Eur Heart J. 1998;19:660-668.) • Anti-ischemic effect(Kersten et al. Anesth Analg. 2000;90:5-11;Kaheinen et al. J Cardiovasc Pharmacol. 2001;37:367-374.)

  38. Opening of ATP-Sensitive Potassium Channels • Activation of KATP channels in coronary vascular smooth muscle (Kaheinen J Cardiovasc Pharmacol. 2001;37:367-374.) • Results in venous, arterial, andsystemic vasodilation

  39. Pharmacokinetic Profile • Active drug (t1/2= 1h) • Rapid onset of action • Titratability • Active metabolite (t1/2= ~80h) • Sustained hemodynamic response

  40. VasoactiveTherapy.com

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