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Tetracycline: Organs and Systems

Cardiovascular

Cardiovascular reactions to tetracyclines have often been associated with other symptoms of hypersensitivity, such as urticaria, angioedema, bronchial obstruction, and arterial hypotension. Such reactions occurred in patients who had tolerated tetracyclines previously and were therefore considered as anaphylactic.

Respiratory

There have been a few cases of acute bronchial obstruction after the administration of a tetracycline.

Pneumonitis with eosinophilia has also been described.

When pleural tetracycline instillation is used to produce local inflammation for pleurodesis in spontaneous pneumothorax, there are no severe short-term or long-term adverse effects.

Nervous system

Tetracyclines rarely cause benign intracranial hypertension. This syndrome has primarily involved children, although it has also been observed in adults. Re-exposure can result in recurrence. As a rule, the symptoms develop within days or occasionally several months after the start of therapy, in one case only after 18 months of tetracycline therapy for acne. The syndrome includes headache, nausea and vomiting, dizziness, tinnitus, papilledema, and visual disturbances caused by scotoma or optic nerve damage. Intracranial pressure can be raised up to three-fold. Distinct intracer-ebral lesions are not visible on CT scan or angiography and the ventricular spaces are not enlarged. With the exception of raised intracranial pressure, all findings, including the cell count and protein concentration of the cerebrospinal fluid, are normal. After withdrawal, symptoms resolve over a period of hours to days or occasionally weeks. Increased use of long-term therapy with tetracyclines for acne may contribute to a higher prevalence of this syndrome.

Early studies showed that curare blockade was increased by tetracyclines. This effect can be antagonized by calcium ions. There was a short-term increase in muscular weakness in patients with myasthenia gravis after intravenous tetracycline. The mechanism may be a calcium-antagonizing effect of magnesium ions present in the tetracycline solvent, as the

symptoms could be provoked by similar amounts of magnesium alone. The formation of calcium complexes with non-protein-bound tetracycline, thus lowering the serum concentration of free calcium, may also be involved.

Sensory systems

Acute transitory myopia was described as an effect of tetracycline therapy, probably due to changes in refractive power.

Endocrine

Hormone production in patients with "black thyroid," who had taken a tetracycline for prolonged periods, was normal.

Metabolism

Tetracyclines can increase blood urea nitrogen or serum urea concentrations without a corresponding increase in serum creatinine (that is without accompanying renal damage). The mechanism is an excess nitrogen load of metabolic origin accompanied by negative nitrogen balance. This effect is termed "anti-anabolic", but is in fact the result of inhibition of protein synthesis, which affects not only microorganisms but to some degree mammalian cells also. Sodium and water depletion, due to the diuretic effect of some tetracyclines, can further enhance uremia.

Tetracyclines have been associated with hypoglycemia. Insulin doses may have to be reduced.

Hematologic

Hematological changes with tetracyclines are extremely rare. However, in individual cases, hemolytic anemia, neutropenia or slight leukopenia, thrombocytopenia, and even aplastic anemia have all been described. In the light of the fact that such blood changes are often reported without a clear description of their cause, the relation to the drug often remains doubtful, especially if reactions are listed in tabular form and information on specific details or concomitant drug therapy is lacking.

Bleeding with thrombocytopenia and signs of intra-vascular coagulation in patients treated for louse-borne relapsing fever may be due to a Jarisch-Herxheimer reaction mediated by the release of endotoxins from disintegrating spirochetes.

Mouth and teeth

The long-term esthetic results of treating severely stained teeth due to tetracyclines by endodontics and internal bleaching have been assessed in 20 patients and found to be excellent. A therapeutic strategy may be bleaching after the preparation for porcelain laminate veneers or night-guard vital bleaching.

Stomatitis, other signs of irritation of the oropharynx, and a rash in and around the orifices have been described in patients taking tetracyclines. This may partly be considered as mucous membrane manifestations of allergic or toxic origin. Secondary infections by pathogenic organisms, such as C. albicans, viruses, or bacteria, should always be considered.

Gastrointestinal

Nausea, vomiting, and epigastric burning are the most common adverse effects of tetracyclines. This is also true for the lower-dose formulations. The symptoms are usually mild and seldom necessitate withdrawal. Nausea occurs in 8-15% of patients.

Esophageal damage

Esophageal ulcers have been described in association with oral doxycycline or tetracycline. Acute onset of substernal burning pain and dysphagia was noted within hours of taking the drug. Remaining parts of the ingested capsule were identified by esophagoscopy.

Thirty centers for pharmacovigilance in France have reported 81 cases of esophageal damage after treatment with tetracyclines collected between 1985 and 1992. There were 64 ulcers, eight cases of dysphagia, and nine of esophagitis. Most (96%) of the cases were caused by doxycycline and 73% of the patients were female, mean age 29 years. Prescriptions were for dermatological (54%), urogenital (23%), and ENT diseases. In one patient, a 71-year-old man, an esophagobronchial fistulation required esophagectomy. In 92% the drugs were not taken correctly, that is at bedtime or without a sufficient quantity of fluid. Treatment with sucralfate 1 g tds did not change the outcome of tetracycline-induced esophageal ulcers.

In three studies of more than 600 children with chest pain, none had tetracycline-induced esophagitis as a cause of their pain.

Patients should not lie down immediately after taking a tetracycline capsule and the formulation should be swallowed with generous quantities of water.

Liver

A clinical syndrome, often with fatal outcome, has been recognized as a complication of high doses of tetracycline. It is characterized by nausea, vomiting, and spiking fever. Jaundice, acidosis, and uremia are also often present, while hematemesis and melena are only occasionally observed. Some patients die because of refractory hypotension. The histopathological findings are those of diffuse fatty liver degeneration. Although the syndrome was primarily described in pregnant women, it is not restricted to them. Impaired renal function, and thus reduced renal elimination of tetracyclines, as well as serious infections, increases the risk of this complication. Since the introduction of lower doses of tetracycline (under 1 g/day), the syndrome of fatty liver degeneration with severe hepatic insufficiency has become rare. However, a few reports have described liver reactions in previously healthy individuals with no pre-existing conditions and given usual oral doses of tetracyclines. Liver enzymes and renal function should be monitored, especially in patients at risk.

A personally experienced case of likely tetracycline-induced liver injury after low-dose tetracycline has been reported. The patient took oral doxycycline 200 mg/ day for 8 days and had markedly altered liver function. The liver enzyme activities normalized only 109 days after withdrawal. The authors also reviewed all reports of liver damage to Swedish Adverse Drug Reactions Advisory

Committee (SADRAC) in the period 1965-95. There were 23 liver reactions with a suspected causal relation to oral low-dose tetracycline derivatives. A causal relation was considered likely in three cases and possible in eight, giving an incidence of roughly one in 18 million defined daily doses. There were no deaths from these liver reactions, and liver enzyme activities normalized in all cases without any serious clinical consequences. The authors remarked that the frequency of liver reactions resulting from tetracyclines may be somewhat higher, as previous studies in Sweden suggest that only 20-50% of severe adverse reactions are reported to SADRAC.

Pancreas

Pancreatitis is a common feature of the clinical syndrome of fatty liver due to tetracyclines, although it has also been observed without overt liver disease in a patient after two separate exposures.

Urinary tract

Tetracyclines not uncommonly cause a raised serum urea concentration due to impaired protein synthesis rather than renal damage, However, renal insufficiency can occur, and patients with pre-existing renal insufficiency are particularly likely to develop raised blood urea nitrogen, serum phosphate, and serum sulfate concentrations during treatment with most tetracyclines. These changes may be associated with acidosis and even symptoms of uremia. Renal dysfunction can be missed if diuresis alone is monitored, since non-oliguric renal insufficiency has been reported. Interstitial nephritis is extremely rare.

Uremia, which may at least in part be due to a reduction in renal function, has been observed in patients with liver cirrhosis, cardiac failure, or interstitial nephritis, which is extremely rare.

Most observations suggest that a determining factor for the risk of renal insufficiency is a relative overdose of the drug in patients with pre-existing renal damage, particularly in those who are already dehydrated (for example due to diuretic therapy). The half-life of tetracyclines is prolonged several-fold in patients with renal dysfunction. With normal renal function, 20-70% of an intravenous dose of tetracycline is eliminated by glo-merular filtration. Maintenance therapy must be adjusted to the degree of renal impairment.

Acquired Lignac-De Toni-Fanconi syndrome, with polyuria, polydipsia, glycosuria, aminoaciduria, hyper-phosphaturia, and hypercalciuria, was described in a number of patients treated with outdated tetracycline formulations. The degeneration products responsible for the toxic action are probably epitetracycline, anhydro-4-epitetracycline, and anhydrotetracycline, as similar renal damage was produced in rats with anhydro-4-epite-tracycline.

A few observations of a nephrogenic diabetes insipidus-like syndrome with demeclocycline (demethylchlortetra-cycline hydrochloride) and resistance to exogenous vasopressin suggested impairment of renal concentrating function by tubular damage. Demeclocycline has therefore been proposed for the treatment of inappropriate secretion of antidiuretic hormone.

Acute interstitial nephritis leading to acute renal insufficiency has been reported after a single repeated dose of tetracycline.

Skin

Pronounced responsiveness of the skin and nails to light is a complication of systemic therapy with tetracyclines. In general, the pathogenesis of skin reactions promoted by sunlight exposure is mediated by phototoxicity, as suggested by the high occurrence rate (up to 9 out of 10 patients), depending on sun exposure and drug dosage. Experimental studies identified a wavelength close to 320 nm within the ultraviolet spectrum as the most potent area for the induction of phototoxic reactions. It has been described with various tetracyclines and presumably occurs with all of them. The skin changes resemble those of minor to severe sunburn, with erythema, edema, papules, blisters, and urticaria. In some circumstances they resemble cutaneous porphyria and have therefore been described as "porphyria-like cutaneous changes".

Pigmentation due to tetracyclines occurs, but the exact frequency is not known. It has been observed with newer and lower-dose formulations as well as with older drugs, and presumably occurs with all tetracyclines. In contrast to phototoxic reactions, pigmentation can appear without light exposure and without inflammation. Pigment deposits were observed in light-exposed and non-exposed skin, the conjunctivae, the oral mucosa, the tongue, and internal organs, such as the thyroid and heart valve endothe-lium. The pigment is presumed to be a drug-melanin-calcium complex and depends on the che-lating properties of the tetracycline molecule. Although pigmentation usually tends to persist after withdrawal, it does not provoke any symptoms or organ dysfunction, except for cosmetic problems. A number of cases occurred in patients treated for acne, and may possibly have been due to more common use of long-term treatments, although there is no evidence that the risk is increased in these patients.

Allergic skin and mucous membrane reactions occur with a very low incidence of 0.3%, which is about 10-fold lower than the incidence of such reactions in patients treated with other antibiotics. A generalized rash can occur during tetracycline treatment. Various forms have been described, including generalized urticaria, maculopapular rash, erythema exudativum, multiforme-like eruptions, and rare cases of Stevens-Johnson syndrome. Even acute generalized exanthematous pustulosis has been described. Fixed drug eruptions due to systemic administration are rare, as is a serum sickness-like syndrome. Allergic contact dermatitis induced by local application of a tetracycline is an exception.

Antimicrobial drugs, especially co-trimoxazole, ampicillin, and tetracyclines, can cause fixed drug eruptions.

Nails

Pronounced photosensitivity of the skin and nails is a complication of systemic therapy with tetracyclines. Onycholysis is associated with nail discoloration.

Dystrophy is usually preceded by photosensitivity reactions of the skin. Depending on the degree and area of light exposure, onycholysis may also affect the toe nails. In contrast to idiopathic onycholysis, it not only affects women.

Musculoskeletal

Deposition of tetracyclines in bone tissue has been demonstrated in animals and man. However, whereas osseous tissue in adult patients treated with tetracycline has shown deposits only in areas of repair or remodelling, children's bones contain extensive areas of deposition. Tetracycline deposition in bone has been reported to have an effect on longitudinal bone growth. In experimental tissue cultures, osteogenesis was impaired by tetracyclines in concentrations similar to serum concentrations that are associated with a therapeutic effect (that is 1 µg/ml). The deposition of tetracyclines in human bone begins in utero as early as in the first trimester of pregnancy. With regular tissue turnover, the deposits disappear.

Infection risk

Monilial infections of the vulva and vagina in temporal association with tetracycline use can occur, even without other predisposing factors such as diabetes, pregnancy, immunodeficiency, and therapy with oral contraceptives and glucocorticoids. They also occur in patients treated with other antibiotics. C. albicans is not always the cause of vaginitis. The same is true for balanitis in men. If symptoms persist or change in patients with urethritis or adnexitis, this may be due to treatment failure, because of resistance of the causative pathogen.

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