Quaternary ammonium derivatives as spasmolytics for irritable bowel syndrome.
Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.
Evangelista
S
S
Menarini Ricerche SpA, Preclinical Development, Florence, Italy. sevangelista@menarini-ricerche.it
D002086:Butylscopolammonium Bromide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010276:Parasympatholytics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012602:Scopolamine Derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D009025:Morpholines; D010276:Parasympatholytics; D000644:Quaternary Ammonium Compounds; D012602:Scopolamine Derivatives; C016859:cimetropium; C013934:octylonium; D002086:Butylscopolammonium Bromide; C013199:pinaverium