Levosimendan

Chemical

A calcium sensitizer inotropic agent

Presentation

Clear, yellow solution 2.5mg/mL in 5 & 10mL ampoules

Which needs to be diluted prior to administration

Route/Dose

IV infusion

Load: 6 – 12mcg/kg over 10 mins

Infusion: 0.1 – 0.2mcg/kg/min

MoA

INOTROPY

  • ↑affinity of TnC for Ca2+
  • Directly stabilizes the TnC – Ca2+ conformation
  • Magnifies the contraction produced when Ca2+ binds TnC
  • Levo’s binding to TnC is directly dependent on cytosolic Ca2+ (∴ it’s significantly weaker with minimal Ca2+ sensitization during diastole)

VASODILATION

Large conductance vessels

  • Opens KCA (Ca2+ activated) & KV (voltage dependent Ca2+ ch)
  • K exits
  • ↓intrac. K+ = HYPERPOLARISATION
  • Inhibits inward Ca2+ current via L-type Ca2+ channel
  • ↓intrac. Ca2
  • Relaxation of vessel

Resistance vessels

  • Opens KATP channels → K exits
  • ↓intrac. K+ = HYPERPOLARISATION
  • Promotes Na/Ca2+ exchanger → Ca2+ exits
  • ↓intrac. Ca2 = relaxation of vessels

PD

CVS

  • ↑myocardial contractility without ↑myocardial O2 consumption
  • ↑CO (↑SV + ↑HR)
  • Coronary + peripheral VD
  • ↓SVR

GU: ↑UO + GFR 2° ↑CO

PK

A

Good oral absorption but administered IV

D

97% PPB → albumin

VD 0.2L/kg

M

95% → liver → hepatic conjugation to cysteine conjugates

5% → intestinal reduction → activate metabolites OR-1855 & OR-1896

E

55% renally excreted

44% faecally excreted

t ½ B = 3hrs

Active metabolites OR-1855 & OR-1896 reach peak plasma [  ] 2 days after infusion cessation → excreted in urine

Adverse Effects

  • Hypotension 2° ↓SVR
  • Headache, Dizziness, N&V 2° ↓ blood
  • Small no’s of ↓K & arrhythmia reported
  • Expensive
Levosimendan