LEVOSIMENDAN

• A calcium sensitizer which has been used in short term treatment of Acute Decompensated Heart Failure.

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• 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.

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