What is the effect of anticholinergic agents on esophageal motility ?
J. Fournet (Grenoble)
The cholinergic regulation of esophageal motility, especially that of the lower esophageal sphincter (LES) has been the subject of several studies in animals and man. The results obtained have varied with the species, and the responses obtained with administration of anticholinergic agents of predominantly antimuscarinic action have varied correspondingly.
Effects of anticholinergics on the LES
The myogenic origin of the basal tonus of the LES is acknowledged, and appears to be exclusive in the opossum, the reference animal in experimental studies of the esophagus. In other animals, notably the dog and cat, a cholinergic component of this rest pressure of the LES has been demonstrated. In man, studies using modern recording techniques reveal a depressor action on the basal tonus of the LES.
In average therapeutic doses (6 µg/kg) atropine sulfate administered i.v. provokes a 42 p. cent fall in basal pressure of the LES over about an hour, and higher doses of 12 and 24µg/kg produce a fall of up to 75 p. cent . With the object of regularizing the absorption and variable pharmacodynamic effects from one subject to another, an optimal oral dose was sought by using for each healthy subject tested the unitary therapeutic dose (15 mg) immediately below that provoking classical side-effects. Under these conditions, propantheline, the anticholinergic effect of which in this dose predominates over the antinicotinic effect, exhibits a weak but, definite depression of rest LES pressure only at 120 min after injection : 18.01 ± 2.2 (X ± ESM) against 14.9 ± 2.9 (p < 0.05) .
The relaxation, which is the second essential property of the LES, is not affected by atropine or the synthetic derivatives of belladonna administered by the oral route during its activation by swallowing or esophageal distension. Indeed, relaxation is under the influence of putative, noncholinergic nonadrenergic neurotransmitter(s).
Effects of anticholinergic agents on peristaltic function
The intrinsic mechanisms of peristaltic function of the esophageal musculature depend essentially on the system of sequential rhombencephalic sequential programming. At the level of the striated muscle, which constitutes the upper fourth of the esophagus in certain species and in man, the neurotransmission deriving from this center is not under the influence of a cholinergic system of muscarinic nature.
Its activity is not modified by atropine derivatives. In the smooth muscle, forming approximately the lower 3/4 of the esophagus, muscular contraction depends in part on excitatory muscarinic transmission. Animal experiments reveal that atropine diminishes the amplitude of the contraction waves and the incidence of peristaltic sequences unleashed by swallowing, shortens the duration of the waves and lengthens their speed of propagation.
In man, atropine sulfate administered intravenously in doses of 6 and 12 µg/kg decreases the amplitude of the peristaltic contraction waves by about 50 p. cent for about one hour. The speed of propagation is slowed at the transition zone between the smooth and striated muscle. The incidence of primary complete peristaltic sequences provoked by swallowing is reduced to only 60 p. cent, compared with a rate of almost 100 p. cent after administration of isotonic saline ; this incidence is reduced to less than 10 p. cent with 24 µg/kg .
The oral administration of propantheline under the same conditions as those used for the study of LES : a) greatly diminishes the amplitude of the peristaltic waves in that part of the esophagus formed of smooth muscle, b) decreases the speed of propagation of the waves at the smooth-striated muscle transition zone, and c) significantly increases the number of nonperistaltic and repetitive waves. This derangement persists for about 120 min. Thus, by the oral route, the results obtained are manifestly analogous to those described with atropine sulfate given intravenously, but with lesser intensity and more prolonged duration .
In a dose of 15 mg, propantheline bromide has a depressor effect on the amplitude of esophageal contractions greater than that of nifedipine in a dose of 20 mg given orally. On the other hand, the depressor effect of nifedipine on the LES is greater .
In sum, the antimuscarinic anticholinergics produce a major change in peristaltic function (wave amplitude and propagation) and a more moderate effect on the LES. These drugs are logically contraindicated during gastroesophageal reflux because of their depressor action on the LES, but especially because of the decrease in the volume of esophageal clearance. The antisecretory salivary effect in these doses affects the plugging by bicarbonates, helping to diminish acid clearance of the esophagus. Thus, more acid may reflux into the esophagus and remain there longer.
The totality of modifications of esophageal motility described above is nonexistent or slight with pirenzepine, an anticholinergic virtually devoid of action on the smooth muscle and active on a subgroup of receptors poorly represented at this level .