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.