Question 10

Compare and contrast the mechanism of action, pharmacokinetics, pharmacodynamics, and adverse effects of digoxin and levosimendan.

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College Answer

This question provided candidates with a clear structure and headings that were often ignored. 
Candidates wasted time on pharmaceutics, derivation (“foxglove” mentioned often) and dosing – these  were not requested and scored no marks. Superficial answers such as “cardiac glycoside” or “calcium sensitiser” were not adequate. Responses such as “modest” for Vd are inadequate – marks could be gained for identifying at least the direction of the difference between the two agents. Likewise “hepatic metabolism and renal excretion” is inadequate. Both agents had quantitative and qualitative differences in outcome of metabolic products and the renal elimination of active drug. Confusing diagrams with inadequate labelling, arrows with two heads and the use of uncommon abbreviations without definition all served to confuse the examiners rather than help the candidate. Candidates should read the questions carefully.


Without overmuch bitterness, it must be said that digoxin is in fact a cardiac glycoside, and levosimendan is in fact a calcium sensitiser. The college clearly did not want any classification or chemical information for these drugs, as this was not asked for in the question stem.

  Digoxin Levosimendan
Routes of administration Oral and IV; theoretically also IM IV
Absorption Oral bioavailability 80% (some is secreted back into the gut lumen by P-glycoprotein, an enterocyte efflux pump) High oral bioavailability (85%)
Solubility pKa = 7.15; basically insoluble in water. pKa 6.3, minimally water soluble
Distribution VOD=5.1–7.4 L/kg; 25% protein-bound VOD = 0.3 L/kg; 99% protein-bound
Target receptor Digoxin inhibits Na+/K+ ATPase. Troponin C
Metabolism Hepatic metabolism accounts for only abut 16% of clearance Metabolised mainly by the liver (95% into inactive metabolites, and 5% into OR1896 which has a long half-life and potent activity)
Elimination Elimination is renal, as unchanged drug, and slow because of the large VOD. Half-life is about 36-44 hrs Eliminated mainly as renally excreted metabolites
Time course of action Onset of effect is relatively rapid with IV infusion, or delayed by 2-3 hrs following oral loading. Levosimendan itself has a half life of around 1 hour, but OR1896 has a half-life of over 80 hours.
Mechanism of action By inhibiting Na+/K+ ATPase, digoxin increases intracellular sodium, which increases sodium-calcium exchange by the Na+/Ca2+ exchanger (INCX) during Phase 1 of the cardiac action potential. The resulting increase in intracellular calcium promotes inotropy. It also acts as a vagotonic agent, which slows conduction through the AV node, and decreases the duration of the action potential mainly by reducing the duration of Phase 2. The slope of Phase 4 is increased, promoting automaticity, but then automaticity is overall suppressed by the vagotonic effects. By binding to troponin C, levosimendan stabilises its open state, allowing muscle contraction. This increases contractility. It also vasodilates by activating ATP-sensitive potassium channels in vascular smooth muscle (like hydralazine). Additionally, at high doses,it acts as a phosphodiesterase (PDE3) inhibitor.
Clinical effects Increased contractility, bradycadia, AV block, prolonged PR interval, shortened QT interval Increased cardiac contractility, increased heart rate, significant arterial and venous vasodilation (including pulmonary arterial vasodilation), decreased afterload. Purported cardioprotective effect.
Adverse effects tachyarrhythmias (including VF and Vt which can be bidirectional), nausea, anorexia, depressed level of consciousness, and arterial vasoconstriction. Toxicity is exacerbated by hypokalemia Vasodilation/hypotension, increased arrhythmogenicity.
Single best reference for further information FDA data sheet Antila et al (2007)


Antila, Saila, Stig Sundberg, and Lasse A. Lehtonen. "Clinical pharmacology of levosimendan." Clinical pharmacokinetics 46.7 (2007): 535-552.

Innes, Carmen A., and Antona J. Wagstaff. "Levosimendan." Drugs 63.23 (2003): 2651-2671.

Figgitt, David P., Peter S. Gillies, and Karen L. Goa. "Levosimendan." Drugs 61.5 (2001): 613-627.

Worthley, L. I., and A. W. Holt. "Digoxin in the critically ill patient." Critical Care and Resuscitation 1.3 (1999): 252.

Pashazadeh-Panahi, Paria, and Mohammad Hasanzadeh. "Digoxin as a glycosylated steroid-like therapeutic drug: Recent advances in the clinical pharmacology and bioassays of pharmaceutical compounds." Biomedicine & Pharmacotherapy 123 (2020): 109813.