Drotaverini hydrochloridum

Pharmacotherapeutic group: drugs for functional gastrointestinal disorders, papaverine and derivatives, drotaverine, ATC code: A03AD02. The pronounced spasmolytic activity of drotaverine is based on the 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 cascade of mechanisms described below. A high concentration of cAMP 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 cytoplasmic Ca2+ concentration by stimulating the transport of calcium ions into the extracellular space and into the sarcoplasmic reticulum. This decrease in cytoplasmic calcium ion concentration 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 particularly important enzyme in reducing the contractile activity of smooth muscle, which suggests that selective PDE IV inhibitors could be effective in the treatment of hypermotility disorders and a range of conditions associated with spastic states of the gastrointestinal tract. The enzyme primarily responsible for the hydrolysis of cAMP in cardiac and vascular muscle is PDE III, which explains why drotaverine is an effective spasmolytic without serious cardiovascular effects and with pronounced therapeutic activity in this field.