Question 13

Compare and contrast the pharmacology of dobutamine and levosimendan

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College Answer

	LEVOSIMENDAN	DOBUTAMINE
Class	Calcium sensitiser	Synthetic catecholamine
Pharmacokinetics	Slower onset of action (requires loading dose) t1/2 of parent compound 1 h Metabolised by conjugation and acetylation Active metabolite with t1/2 80-96 h (Effects persist once infusion ceased for up to 7- 10 days)	Onset of action in 1 – 2 min t1/2 < 3min Metabolised by methylation and conjugation Excreted in urine and bile Inactive metabolites
Mechanism of action	Increases myocyte sensitivity to calcium by binding to troponin C Opens ATP-dependant K+ channels in vascular smooth muscle	Selective beta-1 and beta-2 receptor agonist
Therapeutic effects	Increased cardiac contractility Coronary, systemic and pulmonary vasodilation Reduced preload and afterload without impairing diastolic relaxation	Increased cardiac contractility Mild peripheral vasodilation
	LEVOSIMENDAN	DOBUTAMINE
Adverse effects	Hypotension Headache	Drug-induced myocardial ischaemia Rate/ rhythm disturbances Hypotension Hypertension in XS dose Tachyphylaxis
Contraindications	Hypersensitivity to levosimendan LV outflow tract obstruction Severe renal or hepatic failure Severe hypotension and tachycardia History of torsade de pointes	Hypersensitivity to dobutamine LV outflow tract obstruction

Discussion

With such a detailed and comprehensive college answer, one can do nothing more than to rewrite the table with less information, so as to render the information it contains more memorable.

Features	Dobutamine	Levosimendan
Class of drug	Synthetic catecholamine	Calcium sensitizer
Administration	IV infusion 5-15mcg/kg/min	IV infusion 0.05-0.2mcg/kg/min
Pharmacokinetics	Rapidly metabolised by COMT; Half-life ~ 5 minutes No active metabolites	Excreted into the small intestine Slowly eliminated metabolites (half life ~ 80 hours)

Mechanism of action	Activates beta-1 adrencoeptors and increases heart rate and contractility by increasing the intracellular levels of cAMP, thus increasing the availablility of intracellular calcium.	Enhances the affinity of contractile proteins (partiularly cardiac troponin C) for calcium, thereby increasing contractility without incurring additional ATP cost
Clinical effects	Increased inotoropy Increased chronotropy Peripheral vasodilation (beta-2 effect of one of the enantimers)	Increased inotropy Increased chronotropy Increased lusitropy Pulmonary vasodilation Peripheral vasodilation (by action on ATP-sensitive potassium channels in vascular smooth muscle)
Adverse effects	Arrhythmia Hypotension Increased cardiac metabolic demand, thus potentially exacerbating ischaemia	Arrhythmia Hypotension

References

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

Papp, Zoltán, et al. "Pharmacological mechanisms contributing to the clinical efficacy of levosimendan." Cardiovascular drug reviews 23.1 (2005): 71-98.

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