A drug to be used in Decompensated Heart Failure which has inotropic effect with Cardioprotective action and periphera vasodilatation effect

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

3. Actions

4. • 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

5. • 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)

6. 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

7. 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

8. Advantages of Levosimendan
1) 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.

9. • At therapeutic dosages levosimendan
enhances myocardial contractility without
increasing oxygen requirements, and causes
coronary and systemic vasodilation.

10. • 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

11. 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

12. 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

13. 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

14. 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

15. • The use of levosimendan is contraindicated in
patients with: moderate-to-severe renal
impairment, severe hepatic impairment, sever
e ventricular filling or outflow
obstruction, severe hypotension and tachycar
dia, and/or history of torsades de pointes.

16. THANK YOU…