Drotaverini hydrochloridum

Pharmacotherapeutic group: drugs for functional gastrointestinal disorders, papaverine and derivatives, drotaverine, ATC code: A03AD02. The pronounced spasmolytic action of drotaverine is based on inhibition of phosphodiesterase (PDE). Phosphodiesterase is the enzyme responsible for the hydrolysis of cAMP to AMP. Inhibition of this enzyme leads to an increase in cAMP concentration, which initiates the entire cascade of mechanisms described below. A high cAMP concentration activates cAMP-dependent protein kinase, which phosphorylates myosin light chain kinase (MLCK). Phosphorylation of MLCK reduces its affinity for the Ca2+–calmodulin complex, and the inactive form of MLCK maintains the muscle in a relaxed state. cAMP also influences the cytoplasmic Ca2+ concentration by stimulating the transport of calcium ions into the extracellular space and into the sarcoplasmic reticulum. This reduction of cytoplasmic calcium counteracts the relaxant effect of drotaverine and thus accounts for its antagonistic actions. In vitro, drotaverine inhibits PDE IV without further effect on the PDE III and PDE V isoenzymes. PDE IV appears to be a very important enzyme for reducing the contractile activity of smooth muscle, suggesting that selective PDE IV inhibitors could be effective in the treatment of hypermotility disorders and a wide range of conditions associated with spastic states of the gastrointestinal tract. The enzyme primarily responsible for cAMP hydrolysis in cardiac and vascular muscle is PDE III, which explains why drotaverine is an effective spasmolytic without serious cardiovascular effects and with marked therapeutic activity in this area.