LEVOSIMENDAN
May 31, 2015
LEVOSIMENDAN
• A calcium sensitizer which has been used in short term treatment of Acute Decompensated Heart Failure.
Actions
• Primary mechanism:
• In diastole the binding pocket is not exposed.
• In systole Ca2+ binds to troponin C and exposes a hydrophobic binding pocket. Levosimendan stabilizes troponin C and prolongs the binding of Ca2+ & hence prolongs the systolic actin-myosin interaction
• 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)
Role of K+ ATP channel activation
Mitochondrial K+ATP channels (mKATP)
- act as “guardians of cellular integrity” by stabilizing mitochondrial metabolism during ischemia.
- 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 of mPTP
SARCOLEMMAL MEMBRANE KATP channels
Activation:
- potassium ion efflux and membrane hyper-polarisation
- 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
Advantages of Levosimendan1) levosimendan enhances myocardial force without increasing
intracellular Ca2+ concentrations, which, in context with neutral effects on myocardial oxygen demand and heart rhythm, should be of benefit compared with catecholamines or PDE III inhibitors.
2) Second, levosimendan does not impair myocardial relaxation, a possible limitation of other Ca2+ sensitizers.
3) Third, stimulation of ATP-sensitive potassium channels improves coronary blood flow, reduces preload and afterload, and may exert anti-ischemic actions.
• At therapeutic dosages levosimendan enhances myocardial contractility without increasing oxygen requirements, and causes coronary and systemic vasodilation.
• Clinical effects prolonged due to active metabolite OR-1896
• Half life- 80hrs• The short half-life (about 1 hour) of the parent drug,
Levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV).
• Dosing as indicated by clinical experience-
Loading dose of 6-24µg/kg followed by
infusion of < 0.4µg/kg/h
Pharmacodynamics
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
Unlike other +ve Inotropic agents
(increase intracellular cAMP)
- not associated with increased incidence of arrhythmias leading to cardiovascular mortality.
*ROLE IN ISCHAEMIA-REPERFUSION INJURY
(during ischemia, acidosis decreases calcium sensitivity in the failing heart)
- levosimendan has potential to preserve contractile function
(unique myofilament action)
Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed
CLINICAL APPLICATIONS
1. HEART FAILURE- • beneficial effect on survival in acute De-compensated
failure compared to dobutamine.
2. INOPROTECTION- • positive inotropy +activation of KATP channels
- cardiogenic shock
- evolving myocardial infarction
- perioperative ischaemia
- emergence from CPB
3. Catecholamine resistant SEPSIS
Adverse Drug Reaction
• Common (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea
• The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairment, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and/or history of torsades de pointes.
THANK YOU…