Mechanism of action of inotropic drugs

The following drugs are correctly paired with their mechanism of action EXCEPT

which one?

a) Dopexamine – dopamine and beta-adrenergic agonist

b) Prenalterol – beta-adrenergic agonist

c) Digoxin – inhibition of sodium–potassium ATPase pump

d) Bucladesine – phosphodiesterase inhibitor

e) Istaroxime – calcium channel stimulator

Answer: e

Explanation

There are a number of inotropic drugs currently under investigation. Very few of these

will ever make it into mainstream clinical practice, and finding an agent that is both

effective and safe when administered in the short or long term seems a long way off.

The commonest inotropic agents currently in use work either by dopamine or adrenergic

agonism or a combination of both. All of these agents have significant side

effects. Several new classes of inotrope are under development including calcium

channel stimulators, sodium channel stimulators, new sodium–potassium ATPase

pump inhibitors, anti-endothelin agents, myosin activators, synthetic atrial natriuretic

peptides, vasopressin antagonists and sodium–calcium exchange inhibitors. Within

critical care a number of agents have been trialled with varying degrees of success.

Most data exist about the phosphodiesterase inhibitors, e.g. amrinone, milrinone and

bucladesine. They work by inhibiting type III phosphodiesterase thus preventing

degradation of cAMP. As well as having an inotropic effect they cause vasodilation

making their use somewhat challenging. Istaroxime, a sodium–potassium ATPase

inhibitor has some promising animal data behind it. CK-1827452 is a cardiac myosin

receptor entering human trials. Unlike the beta-adrenergic receptor agonists and

phosphodiesterase inhibitors it does not increase intracellular calcium concentration

or shorten ejection systolic time, so may have a much better safety profile. Ularitide

 (a synthetic atrial natriuretic peptide) has been used in the treatment of acute heart

failure with mixed success. A number of other agents are entering phase I clinical trials.

Reference

Tavares M, Rezlan E, Vostroknoutova I, Khouadja H, Mebazza A. New

pharmacologic therapies for acute heart failure. Crit Care Med 2008; 36(1 Suppl):

S112–20.