EurJ Clin Pharmacol (1991) 41:313-316
© Springer-Verlag 1991
Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man I. Konrad-Dalhoff, A. R. Baunack, K.-D. R/imsch, G. Ahr, H. Kraft, H. Schmitz, T. R. Weihrauch, and J. Kuhlmann Institute of Clinical Pharmacology,Pharma Research Centre, Bayer AG, Wuppertal, FRG Received: November 8, 1990/Accepted: February 18, 1991
Summary. Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline ( - 15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24 % by nifedipine and 17 % by nimodipine, whereas the effects of nitrendipine (decrease of 15 % ) and nisoldipine (9 % ) were not significant. Nifedipine significantly decreased by 17 % the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r = 0.92, nitrendipine r = 0.80 and nisoldipine r = 0.79. Nimodipine showed no such correlation. It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus. Key words: Calciumantagonists, Oesophageal motility; oesophageal pharmaco-manometry, lower oesophageal sphincter pressure, healthy volunteers, dihydropyridines, nifedipine, nisoldipine, nitrendipine, nimodipine, side effects
The common treatment of spastic gastrointestinal motility disorders employs anticholinergic agents. Experimentally, glyceryl trinitrate and long-acting nitrates [1, 2] diminish the abnormal motility, but in practice their benefits are inconsistent. Interest has recently been focused on the calcium channel blockers. Calcium channel blocking drugs, which primarily are used in the treatment of cardiovascular diseases, may also have a role in the regulation of gastrointestinal tract function. The drugs reduce both normal and abnormal oesophageal contractions. Nifedipine caused a significant decrease in the amplitudes of oesophageal peristaltic contraction and lower oesophageal sphincter pressure (LESP) [3-5] in normal subjects as well as in patients with achalasia, nutcracker oesophagus and other motility disorders, some of which may even cause angina-like chest pain [6-8]. From animal model it is known that nisoldipine, a new calcium channel blocker, effectively inhibits oesophageal smooth muscle in the cat more powerfully and for a longer period than nifedipine [9]. The development of new dihydropyridine derivatives should make it possible to use more selective calcium channel blockers. The new antagonists may also have different potencies on smooth muscle in different organs, which means that comparative studies on a selected smooth muscle will be needed in order to rank the individual potency of new agents. The aim of the present investigation was to study the effects of four calcium antagonists of the dihydropyridine type, nifedipine, nitrendipine, nimodipine and nisoldipine, in haemodynamically active dosages, on oesophageal muscle function.
Subjects and Methods In the first study 12 healthy male volunteers received, according to a randomised, double blind, fourfold crossover design, a single oral dose of placebo solution 4 ml, nifedipine (Adalat ®) 20 mg, nitrendipine (Bayotensin®) 20 mg and nisoldipine (Baymycard®) 10 mg, each in 4 ml solution. Each subject had given written informed consent.
314
I. Konrad-Dalhoff et al.: Ca-Antagonists and oesophageal motility
LESP (mmHg)
30-
20 -
10"
I" -vv
© Springer-Verlag 1991
Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man I. Konrad-Dalhoff, A. R. Baunack, K.-D. R/imsch, G. Ahr, H. Kraft, H. Schmitz, T. R. Weihrauch, and J. Kuhlmann Institute of Clinical Pharmacology,Pharma Research Centre, Bayer AG, Wuppertal, FRG Received: November 8, 1990/Accepted: February 18, 1991
Summary. Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline ( - 15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24 % by nifedipine and 17 % by nimodipine, whereas the effects of nitrendipine (decrease of 15 % ) and nisoldipine (9 % ) were not significant. Nifedipine significantly decreased by 17 % the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r = 0.92, nitrendipine r = 0.80 and nisoldipine r = 0.79. Nimodipine showed no such correlation. It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus. Key words: Calciumantagonists, Oesophageal motility; oesophageal pharmaco-manometry, lower oesophageal sphincter pressure, healthy volunteers, dihydropyridines, nifedipine, nisoldipine, nitrendipine, nimodipine, side effects
The common treatment of spastic gastrointestinal motility disorders employs anticholinergic agents. Experimentally, glyceryl trinitrate and long-acting nitrates [1, 2] diminish the abnormal motility, but in practice their benefits are inconsistent. Interest has recently been focused on the calcium channel blockers. Calcium channel blocking drugs, which primarily are used in the treatment of cardiovascular diseases, may also have a role in the regulation of gastrointestinal tract function. The drugs reduce both normal and abnormal oesophageal contractions. Nifedipine caused a significant decrease in the amplitudes of oesophageal peristaltic contraction and lower oesophageal sphincter pressure (LESP) [3-5] in normal subjects as well as in patients with achalasia, nutcracker oesophagus and other motility disorders, some of which may even cause angina-like chest pain [6-8]. From animal model it is known that nisoldipine, a new calcium channel blocker, effectively inhibits oesophageal smooth muscle in the cat more powerfully and for a longer period than nifedipine [9]. The development of new dihydropyridine derivatives should make it possible to use more selective calcium channel blockers. The new antagonists may also have different potencies on smooth muscle in different organs, which means that comparative studies on a selected smooth muscle will be needed in order to rank the individual potency of new agents. The aim of the present investigation was to study the effects of four calcium antagonists of the dihydropyridine type, nifedipine, nitrendipine, nimodipine and nisoldipine, in haemodynamically active dosages, on oesophageal muscle function.
Subjects and Methods In the first study 12 healthy male volunteers received, according to a randomised, double blind, fourfold crossover design, a single oral dose of placebo solution 4 ml, nifedipine (Adalat ®) 20 mg, nitrendipine (Bayotensin®) 20 mg and nisoldipine (Baymycard®) 10 mg, each in 4 ml solution. Each subject had given written informed consent.
314
I. Konrad-Dalhoff et al.: Ca-Antagonists and oesophageal motility
LESP (mmHg)
30-
20 -
10"
I" -vv
![[Myocardial effects of the calcium antagonists nifedipine, nisoldipine and isradipine in coronary heart disease].](/assets/img/hold.png)
