Comparative pharmacology of inotropes and vasopressors

By Alex Yartsev - 07/12/2015

The college has historically asked a series of questions comparing vasopressors and inotropes to one another, presumably to see who among the trainees could explain why they use vasopressin and not phenylephrine (for example). So far, the drugs discussed in such question have been limited to levosimendan, dobutamine, noradrenaline, phenylephrine, vasopressin and dopamine. Of these questions, none have been repeated since 2008, suggesting that the college have decided to stop putting them into the fellowship papers. Some might argue that pharmacokinetics and pharmacodynamics belong in the primary exam, and the fellows should be busy analysing the published evidence of efficacy, clinical trials and suchlike. Other might point out that most of the evidence generated by ICU studies is negative or inconclusive, and that the application of basic sciences still determines much of what happens with ICU drugs.

Question 13 from the second paper of 2008 (Levosimendan vs dobutamine)
Question 18 from the second paper of 2005 (noradrenaline, vasopressin and phenylephrine)
Question 9 from the first paper of 2004 (noradrenaline, vasopressin and phenylephrine)
Question 8 from the second paper of 2000 (dopamine and dobutamine.)

In each of the above, a tabulated comparison is available. In order to simplify revision, all those tables were concocted into the summary offered below. Additionally, detailed monographs on some of these drugs are available in the "Fluid Resuscitation, Vasopressors and Inotropes" section of this site.

In the context of pre-exam revision, these probably represent a pointless digression.

A Comparison of Selected Inotropes
Features	Dobutamine	Levosimendan	Dopamine
Class of drug	Synthetic catecholamine	Calcium sensitizer	Endogenous catecholamine
Administration	IV infusion 5-15mcg/kg/min	IV infusion 0.05-0.2mcg/kg/min	1-5 mcg/kg/min IV (low dose) 5-15 mcg/kg/min IV (medium dose) 20-50 mcg/kg/min IV (high dose)
Pharmacokinetics	Rapidly metabolised by COMT; Half-life ~ 5 minutes No active metabolites	Excreted into the small intestine Slowly eliminated metabolites (half life ~ 80 hours)	Half-life 2-3minutes Metabolised by MAO and COMT
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	Predominantly beta-1 receptor agonist at low doses, with more alpha-effects as dose escalates D-1 receptor agonist at low doses
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)	increases heart rate and contractility by increasing the intracellular levels of cAMP, thus increasing the availablility of intracellular calcium. Low dose: increases renal blood flow Medium dose: inotrope and chronotrope (beta High dose: vasopressor Beta1 effects: 2-10 mcg/kg/min Alpha effects: >10 mcg/kg/min Dopaminergic effects: 0.5-2 mcg/kg/min
Adverse effects	Arrhythmia Hypotension Increased cardiac metabolic demand, thus potentially exacerbating ischaemia Ventricular arrhythmias	Arrhythmia Hypotension Ventricular arrhythmias	Arrhythmogenic at the high doses required for treatment of severe sepsis Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena No evidence for any renal protective effects

A Comparison of Selected Vasopressors
Features	Noradrenaline	Phenylephrine	Vasopressin
Class	Endogenous catecholamine	Phenylethylamine	Endocrine nonapeptide
Pharmacokinetics	Half-life 2-3minutes Metabolised by MAO and COMT	Half-life 5-10 minutes	0.002 units /kg/min; or, 2-2.4 units/hr
Receptor activity	Predominantly alpha-1 agonist activity; Some beta-1 and beta-2 effects at high doses Affinity for receptors decreases in acidosis	Strongly selective for alpha-1 receptors Affinity for receptors decreases in acidosis	Acts on V1 receptors (for vasopressor activity) and on V2 receptors (for antidiuretic activity). Some crossover with oxytocin with respect to uterine contraction. Affinity for receptors is unchanged by acidosis
Mechanism	Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins	Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins	V1 effect is by Gq-protein coupled receptors, which also increases intracellular IP3. V2 effect is via Gs-protein coupled receptors, and cAMP.
Clinical effects	Arterial and venous vasoconstriction Reflex bradycardia Increased afterload and preload	Arterial and venous vasoconstriction Reflex bradycardia Increased afterload and preload	Arterial and venous vasoconstriction Reflex bradycardia Increased afterload and preload Increased resoprtion of water in the cortical collecting duct

References

Goldberg, L. L. "Dopamine: Clinical uses of an endogenous catecholamine." New England Journal of Medicine 291.11 (1974): 707-10.

Holmes, Cheryl L., Donald W. Landry, and John T. Granton. "Science review: Vasopressin and the cardiovascular system part 1–receptor physiology." Critical care 7.6 (2003): 427.

Holmes, Cheryl L., Donald W. Landry, and John T. Granton. "Science Review: Vasopressin and the cardiovascular system part 2-clinical physiology." CRITICAL CARE-LONDON- 8.1 (2004): 15-24.

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