Compare and contrast the pharmacology of adrenaline,  dopamine and dobutamine when used by infusion for the treatment of septic shock.

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College Answer

No human clinical trials have demonstrated any benefit to any particular vasoactive drug or combination in sepsis.

Adrenaline: endogenous adrenergic agonist, opaque ampoule (usually 1:1000 solution), administered  diluted   as   infusion,  rapidly  inactivated  by  liver   (Catechol  O-Methyl Transferase  and  Mono-Amine Oxidase),  duration  of  action  minutes,  activates  alpha-1,alpha-2, beta-1 and beta-2 receptors. Causes initial dose dependent increase in heart rate, cardiac output.   Blood pressure may not increase initially (beta-2 effects: smooth muscle vasodilatation, but also propensity for hypokalaemia, hypophosphataemia, hyperglycemia and increased lactate).   In higher doses vasoconstriction predominates.   May cause pulmonary arterial vasoconstriction. Dose range is unit dependant (eg. 1-30 microgram/min [0.01-0.5 microgram/kg/min]).  Caution with MOA inhibitors.  Central venous access for safety.

Dopamine: endogenous adrenergic agonist, ampoule 200mg/5 mL (with meta-bisulfite), administered  diluted   as   infusion,  rapidly  inactivated  by  liver   (Catechol  O-Methyl Transferase and Mono-Amine Oxidase), duration of action < 10 minutes.   At increasing dose range activates dopaminergic receptors (0.5 – 2 microgram/kg/min)(dopa-1 = sphlanchnic  vasodilatation  and   diuresis),   beta-1   receptors   (2-10   microgram/kg/min: increased heart rate, cardiac output), and finally alpha receptor activation (>10 microgram/kg/min: vasoconstriction, blood pressure elevation).   Indirect action also via release of noradrenaline.  May cause pulmonary arterial vasoconstriction and interacts with pituitary hormone release.   Caution with MAO inhibitors and phenytoin (hypotension, bardycardia). Central venous access required for safety.

Dobutamine:  exogenous  adrenergic  agonist  compound  resembling  dopamine.  Ampoule

250mg/20 mL (with meta-bisulfite) containing racemic mixture of levo and dextro enantiomers, administered diluted as infusion, rapidly inactivated (methylated and conjugated), with duration of action minutes.  Levo: alpha-1 agonist (pressor effect), with modest beta-2 effects. Dextro: beta-1 and beta-2 agonist with alpha-1 blocking activity. Combination of effects complex, but usually inotropic with some vasodilatation (ie. blood pressure may fall, and in sepsis commonly requires an additional vasoconstrictor eg. noradrenaline); pulmonary arterial vasodilatation rather than vasoconstriction.  Dose range

2.5 to 40 microgram/kg/min.  Overall vasodilation means can be administered safely via a peripheral vein.

Discussion

Again, a question where the answer works better as a table.

Features

Dopamine

Dobutamine

Adrenaline

Class

Endogenous catecholamine

Synthetic catecholamine

Endogenous catecholamine

Pharmacokinetics

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Receptor activity

Predominantly alpha-1 agonist activity;
Some beta-1 and beta-2 effects at high doses

Predominantly beta-1 receptor agonist at low doses, with more alpha-effects  as dose escalates
D-1 receptor agonist at low doses

Mixed non-selective alpha and beta agonist

Mechanism

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins

Increases intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins.

Additionally, the beta-effects increase intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Benefits in sepsis

Maintenance of vascular smooth muscle tone to maintain normotension

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Adverse effects

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

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

The beta-2 vasodilatory effect may result in a decrease of blood pressure, which would be counterproductive in sepsis.

Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

Lactic acidosis develops due to beta-2 and beta-3 effects

References

Beale, Richard J., et al. "Vasopressor and inotropic support in septic shock: an evidence-based review." Critical care medicine 32.11 (2004): S455-S465.

Oba, Yuji, and Nazir A. Lone. "Mortality benefit of vasopressor and inotropic agents in septic shock: A Bayesian network meta-analysis of randomized controlled trials." Journal of critical care 29.5 (2014): 706-710.

Wilkman, E., et al. "Association between inotrope treatment and 90‐day mortality in patients with septic shock." Acta Anaesthesiologica Scandinavica 57.4 (2013): 431-442.