Question 14

Compare and contrast the pharmacology of dobutamine and milrinone

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College Answer

Many candidates presented their information in a tabular form and this worked well as it allowed 
direct comparison between the two drugs. Most candidates did not mention that dobutamine was 
a racemic mixture of [+] and [-] isomers. Also that the [+] isomer was a potent β1 agonist and α1 
antagonist, while the [-] isomer was an α1 agonist. The administration of the racemic mixture 
results in the overall β1 agonism responsible for its activity and also its mild β2 agonist effect. 
While most candidates stated that milrinone was an inodilator details on its mechanism of action 
as a selective phosphodiesterase type III inhibitor were on the whole vague. Within the cytoplasm 
of the cardiac myocyte milrinone inhibits the enzyme PDE 3 which results in the inhibition of the 
breakdown of cyclic AMP which in turn results in elevated cellular levels of cAMP. These 
elevated levels of cAMP in turn activate cAMP dependant protein kinases with a resultant 
increase in the influx of Ca2+ into the cell via the sarcolemma. Also uptake of Ca2+ by the 
sarcoplasmic reticulum is increased. The overall effect is an increase in intracellular Ca2+ which 
increases myocardial contractility. Milrinone also has lusitropic action, inducing left ventricular 
relaxation. This probably occurs as a result of the inhibition of SR membrane bound PDE3. 
Milrinone also cause peripheral vasodilatation by inhibiting PDE3 in vascular smooth muscle cells 
which again results in elevated cAMP levels.In vascular smooth muscle cAMP normally inhibits 
myosin light chain kinase the enzyme that is responsible for phosphorylating smooth muscle 
myosin and causing muscle contraction.

Many candidates did not emphasize how very different the pharmacokinetics of these two drugs 
were. Milrinone has a much longer half life than dobutamine and because of its predominant 
renal excretion accumulates in renal failure. 


This is an excellent college answer, and it would be reasonable to simply organise it into a table.

Name Dobutamine Milrinone
Class Inotrope Ino-dilator
Chemistry Synthetic catecholamine Biperidine
Routes of administration IV IV; but can also be administed as a nebulised aerosol, and had initially been marked as an oral preparation
Absorption Basically zero oral availabilty due to destruction by brush border enzymes in the gut (COMT and MAO) Well absorbed orally; 92% oral bioavailability
Solubility pKa = 10.14; sparingly soluble in water pKa 4.6 and 8.5; good solublity at physiological pH
Distribution VOD = 0.2 L/kg, i.e. essentially confined to the circulating volume. Protein binding is unknown- presumably, minimal 0.38L/kg; 70% 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 Phosphodiesterase 3
Metabolism Metabolised rapidly and completely by COMT and MAO Mostly cleared renally; of the free fraction some undergoes hepatic metabolism into an inactive o-glucouronide, and the rest is excreted unchanged at a rate which varies depending on renal blood flow
Elimination Metabolites are renally excreted. Half-life is ~2 minutes Half life is 2.3 hours in patients with heart failure, slightly less in normal healthy adults and longer in patients with renal dysfunction
Time course of action Very short acting, very rapid onset of effect Onset of action is usually within 5-15minutes
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 Increases cyclic AMP by inhibiting phosphodiesterase 3, which is responsible for cAMP catabolism. Selective for vascular smooth muscle and cardiac muscle.
Clinical effects Increased heart rate, increased contractility, increased lusitopy; decreased peripheral vascular resistance due to beta-2 effect Improved ventricular contractility; decreased systemic vascular resistance; decreased pulmonary vascular resistance; tachycardia; propensity to arrhythmias.
Single best reference for further information TGA PI document Canadian (Novopharm) product pamphlet for milrinone lactate


Edelson, J., et al. "Pharmacokinetics of the bipyridines amrinone and milrinone."Circulation 73.3 Pt 2 (1986): III145.

Alousi, A. A., and D. C. Johnson. "Pharmacology of the bipyridines: amrinone and milrinone." Circulation 73.3 Pt 2 (1986): III10.

RUFFOLO Jr, ROBERT R. "The pharmacology of dobutamine." The American journal of the medical sciences 294.4 (1987): 244-248.