Doxycycline-induced espohageal ulceration in the U.S. military service

Military Medicine, Apr 2000 by Morris, Todd J

The mechanism by which doxycycline induces esophageal injury is not clear, but it is likely to be direct injury secondary to prolonged contact between the medication and the esophageal mucosa.10,16 This involves a combination of drug-specific factors, including the pH of doxycycline in solution, the intrinsic caustic nature of the drug, the dissolution rate, the drug dose, and the dose form.17 In addition, the specific manner in which the drug is administered and individual patient conditions may contribute to injury.

Doxycyline forms an acidic solution when dissolved in water with a pH of 2.5 9 to 3.0. 18 However, acid injury alone is unlikely to be responsible for the formation of esophageal ulcers. The normal esophagus is regularly exposed to fluid with pH

Doxycycline causes direct tissue injury when in contact with esophageal mucosa. O'Meara reported a case of doxycyclineinduced esophageal ulceration. At the base of the ulcer was an exudate the same color as the capsule, suggesting that the capsule had lodged and dissolved at that point and that direct contact of the capsule, or the drug as the capsule dissolved, was responsible for the injury.20 This finding was confirmed in an animal model. Six different tetracycline preparations, including doxycycline capsules and tablets, were tested for their local ulcerogenic effect in the esophagus of cats. The medications were suspended on a string at approximately the mid esophagus. After 3 days, the animals treated with doxycycline capsules all had esophageal mucosa erosion and full-thickness esophageal inflammation at the site of the medication. Doxycycline in tablet form caused less injury, and lymecycline capsules and barium control capsules caused no injury.10

Because doxycycline appears to have a directly caustic effect on esophageal mucosa, the dissolution rate of the capsule may play an important role in injury causation. Medications can lodge in the esophagus and as they dissolve expose the mucosa to a very high local drug concentration. A rapid dissolution rate, 10 minutes or less, is a feature of most drugs associated with esophageal injury and could be a critical factor in the development of this problem.21 Doxycycline dissolves in artificial saliva within 10 minutes. Furthermore, as capsules age they dissolve significantly faster than new capsules. New capsules dissolve in water in 15 minutes and in dilute acid in 9.8 minutes. Capsules more than 1 year old dissolve in water in 5 minutes and in a dilute hydrochloric acid (pH = 3.5) environment in 3.95 minutes.22

In a study of the esophageal transit time of different pills and capsules, Hey et a1.23 reported that capsules, especially light capsules (

Drug administration practices may also affect the development of medication-induced esophageal injury. Drug consumption immediately before sleep may contribute to esophageal injury, as was seen in one of our patients. Esophageal peristalsis during sleep is infrequent,24 and saliva production from the parotid, submandibular, and submaxillary glands essentially ceases.25 In a detailed study of esophageal acid clearance, saliva production was an important factor in neutralizing acidic contents within the esophagus as well as in aiding acid clearance with each swallow.26 Sleeping individuals may be unaware of early symptoms and fail to respond. This extends the time of contact between the medication and the esophageal mucosa and may predispose to more severe injury.11