Drotaverini hydrochloridum

Pharmacotherapeutic group: drugs for functional gastrointestinal disorders, papaverine and derivatives, drotaverine, ATC code: A03AD02. The pronounced spasmolytic activity of drotaverine is mediated through 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 in turn initiates the cascade of mechanisms described below. Elevated cAMP levels activate cAMP-dependent protein kinase, which phosphorylates myosin light chain kinase (MLCK). Phosphorylation of MLCK reduces its affinity for the Ca²⁺–calmodulin complex, and the resulting 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 reduction of cytoplasmic calcium counteracts the relaxant effect of drotaverine and thus accounts for its antagonistic actions. In vitro, drotaverine inhibits PDE IV without affecting the PDE III or PDE V isoenzymes. PDE IV appears to be a particularly important enzyme in reducing the contractile activity of smooth muscle, suggesting that selective PDE IV inhibitors may be effective in the treatment of disorders involving hypermotility and a 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 agent without significant cardiovascular effects, while retaining pronounced therapeutic activity in the gastrointestinal area.