Compare and contrast the pharmacology of dobutamine and levosimendan.
The objective of this question was that candidates relay a detailed knowledge of both drugs with respect to their individual pharmacology highlighting the important clinical aspects of each drug (e.g., mechanism of action, metabolism, duration of effect). Then an integration of this knowledge was in the contrast section where the better candidates highlighted features of the drug that would influence when or why one may use it with respect to the second agent. Tabular answers of the pharmacology of each drug without any integration or comparison scored less well. A detailed knowledge of both agents was expected to score well.
Because "the better candidates highlighted features of the drug that would influence when or why one may use it with respect to the second agent", and everybody should want to be the better candidate, the basic outline here has been interrupted with an "applications" row.
|Chemistry||Synthetic catecholamine||Pyridazinone-dinitrile derivative|
|Routes of administration||IV||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 = 10.14; sparingly soluble in water||pKa 6.3, minimally water soluble|
|Distribution||VOD = 0.2 L/kg, i.e. essentially confined to the circulating volume. Protein binding is unknown- presumably, minimal||VOD = 0.3 L/kg; 99% protein-bound|
|Target receptor||Dobutamine is a racemic mixture of stereoisomers; net effect is a partial alpha-1 agonist effect, a full beta-1 agonist effect, and a weak beta-2 agonist effect||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||Levosimendan itself has a half life of around 1 hour, but OR1896 has a half-life of over 80 hours.|
|Time course of action||Very short acting, very rapid onset of effect||Effect takes ~3 days to develop, and lasts for two-three weeks|
|Mechanism of action||By binding to the beta-1 receptor, dobutamine causes an increase in intracellular cAMp, which leads to increased calcium availability inside the cardiac myocytes, and therefore increased contractility and pacemaker automaticity||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 heart rate, increased contractility, increased lusitopy; decreased peripheral vascular resistance due to beta-2 effect||Increased cardiac contractility, increased heart rate, significant arterial and venous vasodilation (including pulmonary arterial vasodilation), decreased afterload, increased arrhythmogenicity. Purported cardioprotective effect.|
LV systolic failure
Scenarios where chronotropy is desirable (eg. AR)
Scenarios where coronary artery supply is sufficient (eg. after revascularisation)
Scenarios where pulmonary arterial vasodilation is desirable
Scenarios where coronary artery supply is suspect (eg. before revascularisation)
|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.
RUFFOLO Jr, ROBERT R. "The pharmacology of dobutamine." The American journal of the medical sciences 294.4 (1987): 244-248.
Tuttle RR, Mills J (January 1975). "Dobutamine: development of a new catecholamine to selectively increase cardiac contractility". Circ Res 36 (1): 185–96.