Cardiac glycosides are the time-honored treatment for CHF, having been used for
centuries. Nonetheless, since the administration of cardiac glycosides is beset with
problems of toxicity, new druggable targets and new drugs are currently being evalu-
ated as potential new leads in the pharmacotherapeutic treatment of CHF. Initial work has
focused on less toxic compounds with positive ionotropic effects on the heart. Drugs
that inhibit phosphodiesterases, the family of enzymes that inactivate cAMP and cGMP,
have been evaluated. Chemically, bipyridine derivatives, including amrinone (7.51) and
milrinone (7.52), have been developed. Although efficacious, their use is plagued with
problems of toxicity, leading to their relegation to only limited intravenous use for an
acute exacerbation of heart failure. Another possible therapeutic avenue is afforded by
selective β 1 adrenergic receptor agonists that have the ability to exert a positive inotropic
effect via a messenger-mediated mechanism. Dobutamine (7.53) is a selective β 1 agonist
with a demonstrated capacity to increase cardiac output. Finally, it is possible to treat
CHF using non-cardiac strategies. Since CHF involves the inability of the heart
to cope with fluid loads, diuretics and ACE inhibitors have been shown to have some
therapeutic efficacy.
7.7 Targeting Cellular Cytoplasmic Structures
The cytoplasm contains a number of functional organelles. Probably the most impor-
tant of these are the mitochondria, the energy-producing units within the cell. Drugs
that target mitochondria are discussed in section 7.7.1. Other organelles include the
rough endoplasmic reticulum, Golgi apparatus, and lysosomes. Traditionally, structures
such as these have been relatively ignored in drug design when compared to the atten-
tion lavished on the cell membrane and the cell nucleus. Furthermore, the importance
of these organelles in human disease processes is only recently being more fully appre-
ciated. For example, recent studies have suggested that anti-Golgi autoantibodies may
ENDOGENOUS CELLULAR STRUCTURES 439