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LEVOSIMENDAN

LEVOSIMENDAN. www.anaesthesia.co.in. email: anaesthesia.co.in@gmail.com. PERIOPERATIVE CARDIAC DYSFUNCTION During anaesthesia - Vasodilatation Volume shifts, blood loss Pain Hypothermia Increased myocardial work Release of inflammatory mediators Sympathetic NS activation

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LEVOSIMENDAN

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  1. LEVOSIMENDAN www.anaesthesia.co.in email: anaesthesia.co.in@gmail.com

  2. PERIOPERATIVE CARDIAC DYSFUNCTION During anaesthesia- • Vasodilatation • Volume shifts, blood loss • Pain • Hypothermia • Increased myocardial work • Release of inflammatory mediators • Sympathetic NS activation • Patient profile- pre-existing CAD PREDISPOSE TO MYOCARDIAL ISCHAEMIA

  3. MANAGEMENT OF PERIOPERATIVE CARDIAC FAILURE • Afterload reduction- vasodilators • Maintenance of coronary perfusion- adequate MAP (fluids, vasoconstrictors) • Augmentation of cardiac contractility- infusion of inotropic drugs

  4. HOWEVER, Short term infusion of inotropic drugs • Not associated with improved long term prognosis • Long term use associated with arrhythmias, sudden death, increased mortality • Most increase cardiac contractility by increasing cAMP levels * intracellular calcium overload * increased myocardial O2 consumption * myocardial cell death (apoptosis)

  5. LEVOSIMENDAN • Novel cardioprotectiveinotrope • (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrile

  6. Active enantiomer of simendan • Clear yellow liquid for intravenous infusion Pharmacokinetics • clinical effects prolonged due to active metabolite OR-1896 • Half life- 80hrs • Potentiates hemodynamics after cessation of parent drug • Dosing as indicated by clinical experience- Loading dose of 6-24µg/kg followed by infusion of < 0.4µg/kg/h

  7. ISCHAEMIC PRE-CONDITIONING • Adaptive cellular response to ischaemia which protects the cell from further ischaemic insult, slows the rate of cell death and preserves organ function. • Levosimendan mimics ischaemic preconditioning - protection to heart during ischaemia- reperfusion states - improve haemodynamic state in heart failure - augments myocardial contractility without increasing myosin ATPase activity or oxygen consumption

  8. MECHANISM OF ACTION 1. Enhances myocardial contractility by sensitizing myofilaments to intracellular calcium - binds to troponin C, stabilizes calcium-bound conformation and prolongs the systolic actin-myosin interaction 2. Role of KATP channel activation MITOCHONDRIAL KATP channels (mKATP) - act as “guardians of cellular integrity” by stabilizing mitochondrial metabolism during ischaemia - opening of mitochondrial permeability transition pore (mPTP) in response to ischaemic stress : central mechanism in cell damage - levosimendan activates mKATP channels *stabilise mitochondrial metabolism *maintain closure of ofmPTP

  9. SARCOLEMMAL MEMBRANE KATP channels Activation: - potassium ion efflux and membrane hyperpolarisation - inhibit inward L-type calcium current, lower intracellular calcium current, » vasodilatation in arteries, arterioles and veins * acts as an vasodilator agent on systemic vasculature and microcirculation * Key role in maintaining basal tone of coronary vasculature

  10. 3) EFFECT ON LUSITROPHY • Diastolic dysfunction –major component of heart failure, present in up to 50% patients • Levosimendan does not appear to worsen lusitrophy due to its stabilizing action of the calcium-troponin C complex (and not increasing the binding affinity of calcium to troponin C)

  11. 4) PHOSPHODIESTERASE INHIBITION At conc. >0.3µM - inhibits PDE III in vitro - role of cAMP ? • however, III & IV isoforms not simultaneously inhibited. Thus unlikely to be primary mechanism of action. • In clinical practice, plasma levels less than 100ng/ml recommended.

  12. Cardiovascular effects of levosimendan: Increase in -HR -CO -LV stroke volume Decrease in -LV EDP -SVR Also… • Increase blood flow to renal medulla & small intestine • Improved gastric mucosal oxygenation

  13. * Unlike other positive inotropic agents (increase intracellular cAMP) - not associated with increased incidence of arrhythmias leading to cardiovascular mortality. *ROLE IN ISCHAEMIA-REPERFUSION INJURY (during ischaemia, acidosis decreases calcium sensitivity in the failing heart) - levosimendan has potential to preserve contractile function (unique myofilament action)

  14. CLINICAL APPLICATIONS • HEART FAILURE- • beneficial effect on survival in acute decompensated failure compared to dobutamine at 31 and 108 days 2. INOPROTECTION- • positive inotropy +activation of KATP channels - cardiogenic shock - evolving myocardial infarction - perioperativeischaemia - emergence from CPB 3. Catecholamine resistant SEPSIS

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