DEVELOPMENT AND INNOVATION IN CARDIOVASCULAR MEDICINE - Innovation in the Biopharmaceutical Industry - page 36

serious adverse effects of -2 mediated bron-

chodilatation, vasodilatation, and mobilisation of glucose and free fatty acids. The
introduction of

β -blockers are caused by blockade of β

-1 selective antagonists substantially reduced the risk of these side-
effects (Rolf Smith et al. , 1983; Head et al. , 1995), whereas

β

-2 specific agonists
have proved successful in treating asthma (Svedmyr, 1985). It is remarkable that
approximately two decades after the introduction of

β

β -blockers, chronically elevated

β -adrenergic activity was discovered to be one of several important neurohumoral

disturbances associated with an adverse prognosis in heart failure (Mark, 1995). This
in turn led to studies of -blockers in heart failure which showed a significant benefit

to survival (CIBIS Investigators and Committees, 1999). Thus,

β

-blocking drugs
possess a range of properties depending on their receptor specificity and molecular
characteristics. Developments in understanding receptor characteristics and inno-
vations in drug design, following the initial introduction of this class of drugs, have
substantially improved our ability to use these drugs to maximum benefit.

β

Calcium antagonists
It has been known since the late 19th century (Ringer, 1887) that calcium ions
play a critical role in the contraction of cardiac muscle. A similar role in smooth
muscle contraction was demonstrated later. Flekenstein (Byon and Fleckenstein,
1969) showed in 1968 that Verapamil has properties on cardiac muscle similar to
withdrawal of calcium ions. He later went on to demonstrate that its action was
due to a decoupling of the electromechanical process, and was specifically related
to antagonism of a calcium-specific action. These studies led to the introduction
of a new class of drugs; the calcium antagonists of which the prototype, Vera-
pamil, remains in use for the treatment of supraventricular dysrhythmias, angina
pectoris and hypertension. However, following the discovery of Verapamil it was
soon learned that its actions applied both to cardiac and to smooth muscle, and that
the availability of calcium antagonists with greater tissue specificity would be bene-
ficial. Calcium antagonists acting on cardiac muscle cause a negative inotropic effect
(Joshi et al. , 1981) and slow conduction through the atrioventricular node (Rinken-
berger et al. , 1980); whereas those acting on smooth muscle cause vasodilatation.
This understanding led the development of calcium antagonist drugs with greater
tissue specificity for cardiac or smooth muscle, and consequently to more precise
pharmacological action. In current practice, calcium antagonists acting on smooth
muscle are most widely used to treat hypertension. In contrast, for the treatment of
supraventricular dysrhythmias, cardiac-acting drugs such as Verapamil are needed.
The calcium antagonists are therefore a drug class, which was initially developed
on the basis of an understanding of electro mechanical coupling in muscular tis-
sues, and which has evolved as a result of innovations based on an understanding