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Tetracycline: General Adverse Effects

Mild gastrointestinal disturbances are common. A common and nearly unique feature of all tetracyclines is the formation of drug-melanin complexes, resulting in pigment deposition at various sites. Except for enamel defects and presumable disturbances of osteogenesis these deposits do not give rise to abnormalities of organ function. In view of tooth discoloration and enamel hypo-plasia, with a tendency to caries formation, tetracyclines should be avoided in children under 8 years of age and in women after the third month of pregnancy. The risk of photosensitivity reactions largely depends on the dose of the drug and the degree of exposure to sunlight. It may be increased in long-term treatment. Skin, nail, and other organ pigmentation often occur, even with low-dose long-term treatment. The syndrome of fatty liver degeneration is rarely encountered today, because risk factors such as pregnancy are respected, and formulations with lower doses are available. Adverse effects can occur with most tetracyclines if the dosage is not altered in patients with renal insufficiency.

Allergic reactions to tetracyclines are less than half as common as allergic reactions to penicillin. For this reason, tetracyclines are alternatives in patients with allergic reactions to other antibiotics. Exceptional observations of anaphylactic shock have been reported. In a few cases tetracyclines were assumed to be the cause of hypersensitivity myocarditis. Pneumonitis with eosinophilia has been described in association with tetracyclines. A serum sicknesslike syndrome was probably associated with minocycline in a 19-year-old man treated for acne. Allergic and toxic reactions may in some cases have been caused by degraded formulations or additives. Tumor-inducing effects have not been reported.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is common in patients treated with tetracyclines for louse-borne relapsing fever. Two forms of reaction are described at the start of tetracycline therapy: (a) fever, rigor, increased respiratory and heart rates, and occasional delirium and coma; (b) fever and disseminated intravascular coagulation. At about the time the temperature reaches its peak, spir-ochetes disappear from the peripheral blood. Meptazinol, a partial opioid antagonist, reduces the Jarisch-Herxheimer reaction in relapsing fever.

Bleeding with thrombocytopenia and signs of intravascular 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.

Comparisons of individual tetracyclines

The spectra of bacterial effectiveness of the various tetracyclines are fairly similar. However, metabolism and excretion vary. In general, preference is currently given to drugs that can be given in relatively low doses (not above 1.0 g/day).

Tetracycline (chlortetracycline) and oxytetracycline These tetracyclines are incompletely absorbed from the gastrointestinal tract. Plasma concentrations fall with half-lives of 6-12 hours. They are predominantly excreted by the kidney, extrarenal elimination amounting at most to 10-20%. They have a lower affinity for fat and membranes, which means that higher dosages to achieve therapeutic effectiveness. However, higher dosages can contribute to an increased risk of systemic toxic effects and, as absorption from oral administration is incomplete, also to an increased risk of gastrointestinal adverse reactions.

Demeclocycline (demethylchlortetracycline) Demeclocycline produces a significantly higher rate of phototoxic skin reactions than other tetracyclines, presumably owing to its long half-life (about 16 hours), resulting in therapeutic plasma concentrations lasting 24-48 hours, and an even longer-lasting accumulation of the drug in membranes and fatty tissues. Demeclocycline is eliminated about 20-40% by glomerular filtration. In patients with liver cirrhosis, cardiac failure, or impaired renal function, it should be used cautiously, because of its pronounced effect on electrolyte and fluid balance.

Doxycycline and minocycline

Doxycycline and minocycline are more lipophilic tetracyclines. They are well absorbed after oral administration. Their half-lives are 16-18 hours. Their higher affinity for fatty tissues improves their effectiveness and changes their adverse effects profile. Local gastrointestinal irritation and disturbance of the intestinal bacterial flora occur less often than with the more hydrophilic drugs, which have to be given in higher oral doses for sufficient absorption.

Nevertheless, their toxic effects are similar to those of other tetracyclines and arise from accumulation in fatty tissues. Accumulation in a third compartment and the resulting long half-life may contribute to an increased incidence of various toxic adverse effects during long-term treatment, even if lower daily doses are used. This seems also to be the case for pigmentation disorders and possibly for neurological disturbances.

Minocycline and doxycycline are predominantly eliminated by the liver and biliary tract (70-90%). Therefore, no change in dose is needed in patients with impaired renal function. However, it should be considered that hepatic elimination of doxycycline or minocycline might be accelerated by co-administration of agents that induce hepatic enzymes.

Methacycline

Methacycline is rarely used. It has similar efficacy to ampicillin in acute exacerbations of chronic bronchitis.

Chemically modified tetracyclines

As early as the 1960s it was recognized that tetracyclines might inhibit bone growth, supposedly by interference with calcium metabolism. It was not until collagenase was discovered in 1983 that intensive interest in the non-antimicrobial properties of tetracycline-based antibiotics developed. Most of the initial studies were done with doxycycline and minocycline, that is semi-synthetic tetracyclines with widespread medical and dental uses. However, in 1987, a non-antibacterial chemically modified tetracycline (CMT) that inhibited mammalian collagenase activity was described. At present, the CMTs (also known as COLs, from their having been introduced by CollaGenes Pharmaceuticals Inc, Newton, PA, USA) comprise a group of at least 10 analogues compounds (CMT-1 to CMT that differ in their specificity and potency in inhibiting MMP. Comparative pharmacokinetic data, obtained from animals, have recently been published, as has a bibliography covering more than 75 papers and abstracts related to the basic biological properties of these compounds. Chemically modified tetracyclines are more active in interfering with mammalian processes than the classical tetracyclines, which is the main justification for their use in non-infective problems. From a qualitative point of view, it might be reasonable to assume similar host-related adverse effects as the classical tetracyclines, while from a quantitative point of view, dosages, duration of therapy, etc., will influence the number of adverse effects. However, the risks might be quite high.

Hematologic

Sideroblastic anemia is characterized by the accumulation of iron in the mitochondria of erythroblasts. In a Phase I study in 35 patients with refractory tumors, eight taking CMT-3 developed anemia without leukopenia or thrombocytopenia. Three of these patients underwent bone-marrow examination and each had ringed side-roblasts. The authors referred to several cases of aplastic anemia, megaloblastic anemia, and hemolytic anemia in which members of the tetracycline family have been implicated. However, they stated that there has been no previous reports of sideroblastic anemia associated with any tetracycline derivative and that the molecular mechanisms by which CMT-3 might cause sideroblastic anemia are unclear.

Immunologic

Based on the strategy that inhibition of angiogenesis is of importance in anticancer therapy, CMT-3 (COL was used in a phase 1 study in 35 patients at the National Institutes of Health in the USA in patients with refractory metastatic cancer. The patients received a test dose of CMT-3, followed by pharmacokinetic testing during daily dosing for 7 days. After a few doses, three patients developed symptoms of drug-induced lupus, and the diagnoses were verified after a few days or weeks. CMT-3 was withdrawn and there was improvement.

Bacterial resistance

Prolonged treatment with the classical antibacterial tetracyclines results in bacterial resistance and/or opportunistic fungal infections. It has therefore been forecast, but not so far proven, that chemically modified tetracyclines without antibacterial activity may not cause microbial resistance. However, accepting that the major mechanism by which bacteria get rid of tetracyclines intracellularly is by increasing their efflux via P glycopro-tein, the chemically modified tetracyclines might also trigger that mechanism, thereby causing reduced sensitivity of the exposed bacterial population to all types of tetracyclines. Before this possibility has been ruled out, the new chemically modified tetracyclines should be introduced with great care.

Tetracycline: Side Effects

See also Individual agents

The tetracyclines are a closely related group of antibiotics with comparable pharmacological properties but different pharmacokinetic characteristics. They have both the advantages and disadvantages of broad-spectrum antibiotics. Tetracyclines are effective not only against bacteria and spirochetes, but also against some forms of Mycoplasma, Chlamydia, and Rickettsia, as well as protozoa. They affect multiplying microorganisms by inhibiting ribosomal protein synthesis. Their effect is therefore primarily bacteriostatic rather than bactericidal, depending on the kind of microorganism.

Most of the adverse effects of the tetracyclines depend on the concentration of the antibiotic in the affected organ. The more lipophilic drugs are more potent with regard to their bacteriostatic efficacy and hence usually require daily doses below 1 g.

Use in non-infective conditions

Tetracyclines have many effects on non-infective inflammatory processes. They have been tried, and claimed to be of some value, in the treatment of rheumatoid arthritis, periodontal disease, myocardial infections, gastric disorders, and experimentally in the treatment of cancers. In all of these disorders, the proposed mechanisms for effects are on the host rather than the microbial side.

Tetracyclines have many effects on cells involved in inflammatory reactions, including inhibition of neutrophilic functions, such as migration, phagocytosis, degranulation, and the production of free oxygen radical. Most of these effects are supposed to be due to chelation of divalent ions and can be partly reversed by the addition of calcium ions or zinc ions. Their ability to inhibit synthesis of mitochondrial proteins may be the background for their effects on lymphocytes, such as inhibition of lymphocyte proliferation in response to mitogens, inhibition of interferon gamma production, and inhibition of immunoglobulin production. Enzyme inactivation caused by tetracyclines has been studied in several models. Tetracyclines inhibited gingival collagenolytic activity in diabetic mice and in humans with periodontal disease. Subsequent studies showed that tetracyclines inactivated collagenases found in several places in the body. Most probably, the inhibitory effects of tetracyclines on collagenases are exerted through inactivation of metallo-proteases, rather than serine proteases. Tetracycline also has radical-scavenging properties, which may be partly related to the ulcer-healing effect observed in a rat model of gastric mucosal injury.

As is to be expected, modified cycline molecules devoid of antibacterial effects are as effective as non-modified molecules. New derivatives with refined anti-inflammatory and enzyme inhibitory (and reduced antimicrobial) effects are being studied in experimental laboratories.

Tetracyclines and metalloproteinases

A major target for non-infective indications of the tetracyclines is inhibition of metalloproteinases. The following is a brief summary of what is known about tetracyclines and metalloproteinases, followed by some comments about possible adverse effects.

The matrix metalloproteinases (MMPs) are a family of calcium- and/or zinc-dependent endopeptidases involved in degradation of extracellular matrix and tissue remodelling. At least 21 mammalian MMPs have been described. They participate in various biological processes, such as embryonic development, ovulation, angio-genesis, apoptosis, wound healing, and nerve growth.

Under normal conditions, the activity of MMPs is very low and is strongly regulated by natural tissue inhibitors (TIMPs). The TIMPS are a family of four structurally related proteins (TIMP-1, 2, 3, and, exerting dual control of the MMPs by inhibiting both their active forms and their activation. In addition, the proteolytic activity of MMPs is inhibited by non-specific protease inhibitors, such as alpha2-macroglobulin and alpha1-antiprotease.

In the presence of specific stimuli, exemplified by cytokines and growth factors, MMPs can be up-regulated. Chronic activation of MMPs, due to an imbalance between the activity of MMPs and TIMPs, can result in excessive degradation of the extracellular matrix and is believed to contribute to the pathogenesis of several diseases, such as rheumatoid arthritis, osteoarthritis, periodontal disease, emphysema, atherosclerosis, skin ulceration, and cancer.

The physiological and pathophysiological roles of MMPs and TIMPs have been extensively studied in knockout mice. For most of the MMPs and TIMPs there seem to be significant overlaps in functions, and a deficiency of one enzyme can be compensated for by the presence of others. Each MMP is encoded by a distinct gene, and about half of the human MMP genes so far discovered are on chromosome 11.

The mere fact that MMPs might be involved in the pathogenesis of several chronic disorders has made this field attractive to numerous pharmaceutical companies.

One major approach for controlling abnormal MMP activity has been the use of small molecular weight inhibitors, and several excellent reviews of the design of such inhibitors have been published.

Rheumatoid arthritis

In 1942, the Swedish doctor Nana Svartz introduced sul-fasalazine into therapy and suggested that it might be useful in rheumatoid arthritis because of its antibacterial activity. Since then, many antimicrobial agents have been tried in the treatment of rheumatoid arthritis, based on the assumption that the disease may be due to an infectious agent. Interest has focused on tetracyclines for the treatment of rheumatoid arthritis, reactive arthritis, and osteoarthritis and the state of the art has been reviewed. The theory that rheumatoid arthritis is due to an infectious agent has been refined to a statement that it may be a gene transfer disease in which some viruses act as vectors, thereby excluding a direct effect of antibacterial agents on the disease.

Two further perspectives on the use of tetracyclines in rheumatoid arthritis have been published. In addition to an effect on matrix metalloproteinases, the authors focused on a potential antiarthritic action of tetracyclines by their effects in the interaction between the generation of nitric oxide, matrix metalloproteinase release, and chondrocyte apoptosis. Both minocycline and doxycycline inhibit the production of nitric oxide from human cartilage and murine macrophages in concentrations that are achieved in vivo. The authors suggested that tetracyclines may have several potential chondroprotective effects: direct inhibition of matrix metalloproteinase activity and, by inhibition of nitric oxide production, further reduction of matrix metalloproteinase activity, reversal of reduced matrix synthesis, and reduced chondrocyte apoptosis.

In double-blind, placebo-controlled studies, minocycline relieved clinical symptoms and reduced some laboratory measures of disease activity in patients with rheumatoid arthritis. However, the progression of radiographic damage was not significantly reduced and minocycline caused several adverse effects. This led to investigations of the therapeutic effects of doxycycline in patients with rheumatoid arthritis. In 13 patients with moderate rheumatoid arthritis, low-dose doxycycline 20 mg bd reduced the urinary excretion of pyridinoline. Pyridinolines are collagen cross-links that are released from joints during cartilage and bone resorption and correlate with the severity of joint destruction. In a later study, doxycycline produced a significant reduction in the number of tender joints and significant improvements in disability and behavior in 12 patients with rheumatoid arthritis.

However, these studies were not placebo-controlled, and it was possible that the observed effects were due to factors other than doxycycline. Two double-blind, placebo-controlled trials have since been reported.

In a crossover study, 66 patients took 50 mg doxycycline or placebo twice a day for 12, 24, or 36 weeks. Patients’ assessments, swollen and tender joint counts, duration of morning stiffness, erythrocyte sedimentation rate, and the so-called modified disease activity score were used as measures of disease activity. Doxycycline had no significant effects on clinical and laboratory measures of disease activity, pyridinoline excretion, or progression of radiographic joint damage. Furthermore, there were adverse effects during treatment with doxycycline and not with placebo. The authors concluded that doxycycline 50 mg bd provided no therapeutic benefit in patients with rheumatoid arthritis.

In another study, a 16-week, randomized, double-blind, placebo-controlled trial, eligible subjects with active ser-opositive or erosive rheumatoid arthritis were randomly allocated to three treatment groups: doxycycline 200 mg intravenously, azithromycin 250 mg orally, or placebo. The primary end-points were changes between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline. The trial was stopped prematurely after 31 patients had been enrolled. Three subjects were withdrawn because of worsening arthritis. There were no significant differences across the groups in any of the three primary clinical end-points. The authors concluded that doxycycline did not reduce disease activity or collagen cross-link production.

Ten chemically modified tetracyclines (CMTs), minocycline, and doxycycline have been tested for their capacity to inhibit cartilage degradation in vitro. CMT-8 was the most active. The authors concluded that by carefully selecting a tetracycline-based MMP inhibitor and controlling dosages it should be possible to inhibit pathologically excessive MMP-8 and/or MMP-13 activity, especially that which causes bone erosion, without affecting the constitutive activity of MMP-1 needed for tissue remodelling and normal host function. They thought that of the CMTs, CMT-8 and to a lesser extent CMT-3 and CMT-7 were the most effective. However, the effects of these CMTs in a full-scale trial in rheumatoid arthritis have not been reported.

Reactive arthritis

It is well established that a number of microorganisms found in the gastrointestinal tract are associated with reactive arthritis and that most of these organisms might be susceptible to tetracyclines. Several investigations have shown clinical effects of tetracyclines in the treatment of reactive arthritis. In these cases, a more direct antibacterial effect of the triggering organism (if still present in the patient) might be the mechanism involved.

Osteoarthritis

Tetracyclines have been investigated in experimental osteoarthritis, because metalloproteases are involved in the breakdown of cartilage matrix seen in this condition. Doxycycline reduced the severity of knee osteoarthritis induced in dogs by ligamentous section and also reduced the degradation of type XI collagen exposed to extract of human arthritic cartilage.

Periodontal disease

Periodontal disease is caused by microorganisms, but host responses are in large part responsible for destruction of the periodontal support structures. In these patients, pathological activity of host-derived matrix metalloproteinases occurs in response to the bacterial infection in the periodontal tissues, causing destruction of collagen, the primary structural component of periodontal matrix. This in turn leads to gingival recession, pocket formation, and increased tooth mobility. The final outcome is loss of the tooth.

Tetracyclines inhibit collagenolytic activity in gingival tissue. Based on these findings, a large clinical development program was initiated to demonstrate the potential of a sub-antimicrobial dose of doxycycline to augment and maintain the beneficial effects afforded by conventional non-surgical periodontal therapy in adult periodontitis. A summary of these studies has been published. Several different dosage regimens and placebo were compared in patients who had had a variety of adjunctive non-surgical procedures. Of the various parameters studied, the following are worthy of mention: collagenase activity in gingival crevicular fluid and gingival specimens, so-called clinical attachment levels, probing pockets depths, bleeding on probing, and subtraction radiographic measurements of alveolar bone height.

Sub-antimicrobial doses of doxycycline reduced collagenase activity in both gingival crevicular fluid and gingival biopsies, augmented and maintained gains in clinical attachment levels and reductions in pockets depths, reduced bleeding on probing, and prevented loss of alveolar bone height. These clinical effects occurred in the absence of any significant effects on the subgingival microflora and without evidence of an increase in the incidence or severity of adverse reactions relative to the controls. The authors proposed that the main mechanism underlying these effects is inhibition of pathologically high matrix metalloproteinase activity in neutrophils (MMP and bone cells (MMP.

Acne

Over the years, various tetracyclines have been used in the treatment of acne. Their mechanism of action is not clear, but appears to be not purely antimicrobial, since they reduce chemotaxis of polymorphonuclear leukocytes, modify complement pathways, and inhibit the polymorphonuclear leukocyte chemotactic factor and lipase production in Propionibacterium acnes. They may also have a direct effect on sebum secretion, for example by modification of free fatty acids.

Adult respiratory distress syndrome

Adult respiratory distress syndrome (ARDS) has many causes, is associated with severe lung damage, and is characterized by pulmonary edema and hypoxemia. It has a high mortality. The current method of treatment is supportive and there is no specific therapy. This was the background to a thorough review of the anti-inflammatory properties of tetracyclines in the prevention of acute lung injury. The authors ended with an optimistic forecast, that targeting the proteases that cause ARDS with chemically modified tetracyclines may be useful in prevention and treatment. They ended by suggesting that strategies to prevent ARDS should focus on targets downstream from the initial inflammatory signals that provoke the cascade of events.

Glaucoma

Tetracyclines, especially demeclocycline, are among the most effective ocular hypotensive agents, according to studies in rabbits and cats. The biochemical mechanism of this effect is unknown. The prolonged effect and apparent lack of adverse ocular adverse effects suggest their possible usefulness for treating glaucoma in man.

Long-Term Effects

Drug resistance

Resistance to tetracyclines shows marked inter-regional variations and changes rapidly with time. The selection of resistant bacterial strains may be favored by widespread, often prophylactic, use in veterinary medicine and by long-term therapy for acne, periodontal disease, or symptomatic Borrelia infections. Many of the documented cases of resistance are of limited practical significance, since the tetracyclines are merely one of a number of therapeutic alternatives. The problem may be different when these drugs are the chemotherapeutic agents of first choice, that is in chronic Borrelia infections, especially arthritis due to Lyme disease and pulmonary or bubonic plague due to Yersinia pestis.

For infections with Chlamydia or Mycoplasma, effective alternative antibiotics are available. Increased rates of resistant strains of genital Mycoplasma may explain treatment failures.

A rather high resistance rate of 25-50% is reported for Hemophilus species, and this has to be taken into consideration if tetracyclines are given to patients with chronic pulmonary diseases or for the treatment of acute respiratory infections.

For infections with Neisseria gonorrhoea, tetracyclines are not indicated, owing to the higher prevalence of resistance, especially among penicillinase -producing strains. For these patients, better alternatives are usually available.

Second-Generation Effects

Teratogenicity

Teratogenic effects of tetracyclines have been demonstrated, as evidenced by increased rates of intrauterine death, congenital anomalies in general, and congenital cataracts in fetuses exposed to tetracyclines. However, it is often impossible to distinguish between the drug and an underlying unidentified viral infection as a cause of the observed abnormalities.

Of 38 151 pregnant women who had babies without any defects (controls), 214 (0.6%) had taken oral oxytetracycline; in contrast, of 22 865 pregnant women who had offspring with congenital abnormalities, 216 (0.9%) had taken oxytetracycline (OR = 1.7; 95% CI = 1.4). More women whose babies had congenital abnormalities had taken oxytetracycline in the second month of pregnancy:

• neural-tube defects (OR = 9.7; CI = 2;
• cleft palate (OR = 17; CI = 3;
• multiple congenital abnormalities (particularly the combination of neural-tube defects and cardiovascular malformations) (OR = 13; CI = 3.

The authors mentioned that their previous study had not shown a teratogenic potential of doxycycline, but concluded, far more prudently, that all tetracyclines are contraindicated during pregnancy.

Fetotoxicity

Discoloration of the first teeth is particularly likely if a tetracycline is given to the mother after the third month of pregnancy. Tetracyclines pass across the placenta and reach therapeutic concentrations in the fetal circulation.

Tooth discoloration is due to deposition of tetracyclines in the form of calcium complexes in the mineralizing zones of the teeth, and seems to be pathogenically related to the pigmentation of other organs. It occurs when tetracyclines are used during tooth formation. Tetracyclines pass through the placenta and are also found in high concentrations in the breast milk.

As mineralization of the deciduous teeth takes place from the fourth month of intrauterine life until 1 year after birth and continues for the permanent teeth up to the age of 7-8 years, pregnant women after the third month of pregnancy, nursing women, and children under the age of 8 years should not be treated with tetracyclines. Discoloration of the teeth after intrauterine exposure to tetracyclines was observed in up to 50% of children at risk and was especially high when tetracyclines were used during the last trimester. Besides its merely cosmetic aspect, tooth discoloration in children is associated with enamel defects and hypoplasia in severe cases. Adult-onset tooth discoloration coincident with minocycline administration occurred in four of 72 patients.

Susceptibility Factors

Age

Pregnant women after the third month of pregnancy, nursing women, and children under the age of 8 years should not be treated with tetracyclines, because of the risk of discoloration of the teeth. Besides its merely cosmetic aspect, tooth discoloration in children is associated with enamel defects and hypoplasia in severe cases.

Renal disease

Tetracyclines are removed by hemodialysis, but significantly less than creatinine or urea. Severe adverse effects of tetracyclines occur almost exclusively with doses over 1.0 g/day or in the treatment of pyelonephritis with concomitant renal insufficiency.

Drug Administration

Drug administration route

The intravenous formulation of tetracycline was instilled intrapleurally to produce chemical pleurodesis, with good effect, from the 1970s to the 1990s. The adverse effect most commonly seen with tetracycline was chest pain, which was often severe. In a comprehensive review of intrapleural therapy published in 1994 the incidence of chest pain was estimated at 14%, and fever occurred in 10% of patients. However, the intravenous form of tetracycline has been withdrawn by the manufacturer and so this agent is no longer available for pleurodesis.

Tetracycline: Drug-Drug Interactions

Antacids

Co-administration of tetracyclines with antacids or other drugs containing divalent or trivalent cations, such as calcium, magnesium, or iron, is contraindicated. Tetracyclines form complexes with such cations, which are very poorly or not at all absorbed.

To avoid this interaction, delay of 2-3 hours between the ingestion of tetracycline and the cation is recommended. Similarly, reduced systemic availability results from simultaneous intake of abundant quantities of milk or milk products.

Antidiarrheal drugs

Antidiarrheal drugs, such as kaolin-pectin and bismuth products, impair the absorption of tetracyclines by chelation (see the interaction with antacids in this post).

Coumarin anticoagulants

Although antibiotics can inhibit the production of vitamin K in the gut by intestinal bacteria, they do not thereby interfere with the actions of coumarin anticoagulation, since vitamin K that is produced by intestinal bacteria is of less importance than vitamin K that is obtained from dietary sources . Nevertheless, there have been sporadic reports that tetracyclines can enhance the effects of coumarin anticoagulants. The mechanism is not known, but evidence that tetracyclines can reduce the activity of prothrombin suggests an additive pharmacodynamic interaction.

Diuretics

The combination of tetracyclines with diuretics is particularly detrimental to renal function. Tetracyclines accumulate in patients with pre-existing renal insufficiency (for example elderly people, even if the serum creatinine is in the reference range) and can cause nausea and vomiting, which causes dehydration and worsens renal function. This is exacerbated by the effects of diuretics.

Iron

See antacids above.

Methoxyflurane

In patients taking oral or parenteral tetracyclines who undergo methoxyflurane anesthesia, renal insufficiency and oxalate crystal formation in renal tissue was attributed to an interaction between these drugs. Tetracyclines are therefore not recommended preoperatively.

Risperidone and/or sertraline

An interaction of tetracycline with risperidone and/or sertraline has been described.

A 15-year-old youth with Asperger’s syndrome, Tourette’s syndrome, and obsessive-compulsive disorder was stabilized on risperidone 1.5 mg bd and sertraline 100 mg od and had marked improvement in his social skills and tics, until he was given tetracycline 250 mg bd for acne. Within 2 weeks his tics were acutely exacerbated with pronounced neck jerking and guttural sounds. The sertraline was increased to 150 mg/day, but the tics did not resolve. The tetracycline was withdrawn after 1 month, and the tics improved within a few weeks.

The authors reviewed the major metabolic pathways of the three drugs used in this case. Tetracycline may have accelerated the hepatic metabolism of risperidone, but tetracycline has not been shown to induce CYP2D6, the major hepatic enzyme involved in the metabolism of risperidone. The authors claimed that it was more likely that tetracycline binds to risperidone or its active metabolite, making them inactive. They supported this suggestion by citing evidence that clozapine, which has similar pharmacology to risperidone, interacts with tetracycline in vitro.

They also commented on the possibility that the effect could have come from increased concentrations of sertraline, which can increase tics. Tetracycline may inhibit the hepatic enzymes that metabolize sertraline; however, adequate evidence is lacking. Another possibility is a protein binding interaction, because all three drugs are highly protein bound.

However, the observation that the tics were not worsened by an increase in sertraline dosage makes this possibility less likely. The mere fact that the withdrawal of tetracycline resulted in an improvement in the tics supports an interaction between tetracycline and risperidone.