Tetracyclines and Antacids

Abstract/Summary

The serum levels, and as a consequence the therapeutic effectiveness, of the tetracychne antibiotics can be markedly reduced or even abolished by the concurrent use of antacids containing aluminium, bismuth, calcium or magnesium. Other antacids such as sodium bicarbonate which raise the gastric pH may also reduce the bioavatlabihty of some tetracychne preparations.

Clinical evidence

Aluminium-containing antacids

A study on five patients and six normal subjects given 500 mg chlortetracychne orally every 6 h showed that if they were given two tablespoonfuls of aluminium hydroxide gel (Amphojel) at the same time, within 48 h the serum chlortetracychne levels had fallen 80-90% One patient had a recurrence of her urinary tract infection which only subsided when the antacid was withdrawn. This was confirmed in another study.

Other studies in man showed that 30 ml aluminium hydroxide reduced oxytetracylme serum levels by more than 50%, 20 ml caused a 75% reduction in demeclocychne serum levels, 15 ml caused a 100% reduction in serum doxycychne levels, and 30 ml magnesium-aluminium hy droxide (Maalox) caused a 90% reduction m tetracyhne serum levels.

Calcium, magnesium or bismuth-contmmng antacids

Bismuth salicylate markedly reduces the absorption of tetra¬cychne and a 50% reduction in serum doxycychne levels can occur. Bismuth carbonate interacts with the tetracyclines in vitro. Magnesium sulphate certainly interacts with tetracychne, but in the clinical study on record the amount of magnesium was much higher than would nor¬mally be found in the usual dose of antacid. Magnesium oxide interacted in an in vitro study. There seem to be no direct clinical studies with calcium-containing antacids but a clinically important interaction seems an almost certainty, based on an in vitro study with calcium carbonate, studies of calcium in milk (see synopsis on 'Tetracyclines + Milk and Dairy products') and as dicakium phosphate, and as an excipient in tetracychne capsules.

Sodium-containmg antacids

A study m eight subjects showed that when given a 250 mg capsule of tetracychne hydrochlonde with 2 g sodium bicarbonate, the mean absorption of the tetracychne was reduced 50%. If however the tetracychne was dissolved before ad¬ministration, the absorption was unaffected by the sodium bicarbonate.

Another study stated that 2 g sodium bicarbonate had an insignificant effect on tetracychne absorption.

Mechanism

Work in the mid-1950s demonstrated that the tetracyclines bind with aluminium, bismuth, calcium, magnesium and other metallic ions to form compounds (chelates) which are much less soluble and therefore much less readily absorbed by the gut. In addition it has been shown that the solubility of the tetracyhnes is a hundred times greater at pH 1-3 than at pH 5-6, so that an antacid which raises the gastric pH above about 4 for 20-30 mm could prevent up to 50% of the tetracychne from being fully dissolved in the stomach. Once the undissolved drug is emptied out of the stomach, the pH in the duodenum (5-6) and in the rest of the gut are unfavourable for full dissolution, so that a good proportion of the tetracychne may never dissolve and so it remains unavailable for absorption. This may also explain why sodium bicarbonate interacts with tetracychne A third reason for the reduced absorption may be because the tetracyclines are adsorbed onto the antacid.

Importance and management

Extremely well-documented, long and well-established interactions. Their clinical importance depends on how much the serum tetracychne levels are lowered, but with normal antacid dosages the reductions cited above (50-100%) are so large that many organisms will not be exposed to minimum inhibitory concentrations (MIC). As a general rule none of the aluminium, bismuth, calcium or magnesium containing antacids, or others such as sodium bicarbonate which can markedly alter gastric pH, should be given at the same time as the tetracychne antibiotics. If they must be used, separate the dosages as much as possible to prevent their admixture in the gut Sodium bicarbonate and other antacids which only affect the extent of absorption by altering gastric pH will only interact with tetracychne preparations which are not already dissolved before ingestion (e g those in capsule form) Patients should be warned about taking any over-the-counter antacids and indigestion preparations.

Instead of using antacids to minimize the gastric irritant effects of the tetracydines it is usually recommended that tetracyclines are taken before food, however it is not entirely clear how much this affects their absorption. One study demonstrated that food reduced the absorption of demeclocydine, whereas another claimed that it did not.