Compare and contrast adrenaline and levosimendan
A basic and fundamental question which required candidates to present their answer in a
coherent fashion (a table worked best), as well as demonstrate sufficient knowledge. The
majority of candidates did so, and so scored well. Candidates tended to struggle most with
levosimendan. Candidates also confused the use of the terms “elimination” and
“metabolism”, often using them interchangeably.
Even though "coherent fashion" is not what Deranged Physiology routinely does, it was worth having a go:
|Chemistry||Endogenous catecholamine||Pyridazinone-dinitrile derivative|
|Routes of administration||IV, IM, subcutaneous, nebulised, topical, as eye drops and directly into the ETT during an arrest||IV|
|Absorption||Basically zero oral availabilty due to destruction by brush border enzymes in the gut (COMT and MAO)||High oral bioavailability (85%)|
|Solubility||pKa of 9.69; minimal water slubility||pKa 6.3, minimally water soluble|
|Distribution||VOD = 0.1-0.2 L/kg; 12% protein-bound||VOD = 0.3 L/kg; 99% protein-bound|
|Target receptor||All adrenoceptors, with some selectivity for beta-1 and beta-2 at lower doses||Troponin C|
|Metabolism||Metabolised rapidly and completely by COMT and MAO||Metabolised mainly by the liver (95% into inactive metabolites, and 5% into OR1896 which has a long half-life and potent activity)|
|Elimination||Metabolites are renally excreted. Half-life is ~2 minutes||Eliminated mainly as renally excreted metabolites|
|Time course of action||Very short acting, very rapid onset of effect||Levosimendan itself has a half life of around 1 hour, but OR1896 has a half-life of over 80 hours.|
|Mechanism of action||By binding to the alpha-1 receptor, adrenaline increases the release of a secondary messenger (inositol triphosphate, IP3) which results in the release of calcium into the cytosol, and thus enhanced smooth muscle contractility. By binding to beta-1 and beta-2 receptors, it increases cAMP, whcih as a second messenger mediates the other cardiovascular clinical 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 cardiac contractility, increased heart rate, some peripheral vasodilation, decreased afterload, hyperglycaemia, hyperlactataemia, hypokalemia, increased arrhythmogenicity||Increased cardiac contractility, increased heart rate, significant arterial and venous vasodilation (including pulmonary arterial vasodilation), decreased afterload, increased arrhythmogenicity. Purported cardioprotective effect.|
|Single best reference for further information||TGA PI document||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.
Gorain, Bapi, et al. "Pharmacology of Adrenaline, Noradrenaline, and Their Receptors." Frontiers in Pharmacology of Neurotransmitters. Springer, Singapore, 2020. 107-142.