Phosphodiesterase inhibitors Anagrelide

The drug, a structural combination of cilostamide [211] and anagrelide (155), is a potent and selective inhibitor of cyclic AMP phosphodiesterase. The acyl guanidine unit is both weakly basic (pK 3.5) and weakly acidic (pKa 11.3), but the solubility of the compound is too low for it to be physiologically useful [209, 212]. 

Anagrelide should not be used with other phosphodiesterase III inhibitors (e.g. milrinone) because of the potential for increased inotropic effects. Inhibitors of CYP1A2 (e.g. fluvoxamine) are predicted to increase anagrelide levels. Some caution might be required with concurrent aspirin and other platelet inhibitors. Whether anagrelide inhibits theophylline metabolism to a clinically relevant extent is not known. No pharmacokinetic interaction occurs with digoxin or warfarin. 

Anagrelide is a cyclic AMP phosphodiesterase III inhibitor, and consequently has positive inotropic effects. The manufacturer recommends against its concurrent use with other phosphodiesterase III inhibitors, because of the potential increased inotropic effects, and they specifically mention amrlnone, cllostazol, enoximone, milrinone, and olprinone. ... 

Mid-ventricular takotsubo syndrome (see also p. 313) has also been described in a 75-year-old woman taking anagrelide [139" ]. The authors hypothesized that accumulation of anagrelide, a phosphodiesterase type II inhibitor, had caused major inotropic stimulation and sympathetic hyperactivation in a vulnerable myocardium. 

---