Tetracycline with iron

The complexing of tetracyclines with calcium poses a problem in paediatric medicine. Discoloration of teeth results from the formation of a coloured complex with the calcium in the teeth the deposition of drug in the hones of growing hahies can lead to problems in bone formation. Table 10.4 reveals that there is no correlation between the binding capacity of a tetracycline with iron and that with calcium, suggesting different modes of complexation. The in vitro data are simpler to interpret the semm levels are the... 

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, and ascorbic acid. Any additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors. 

The administration of tetracycline with food can ameliorate its irritative effects, bnt food can adversely affect the drug s absorption. In contrast, the absorption of doxycycline is only slightly affected by the presence of food, including dairy prodncts. Becanse all tetracyclines can form complexes with divalent cations, the absorption of any tetracycline is markedly decreased when administered with iron-containing tonics or antacids containing calcium, magnesium, or aluminum. Sodium bicarbonate also adversely affects tetracycline absorption. 

The presence of food in the stomach, especially if it is fatty, delays gastric emptying and the absorption of certain dmgs the plasma concentration of ampicillin and rifampicin may be much reduced if they are taken on a full stomach. More specifically, calcium, e.g. in milk, interferes with absorption of tetracyclines and iron (by chelation). 

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 (75,174,175). 

Drug interactions The bioavailability of tetracyclines is significantly deaeased when administered with antacids containing aluminum, calcium, or magnesium, with iron-containing products, or with food. Food or dairy products do not affect the bioavailability of doxycycline or minocycyline. 

Ettner, N. Hillen, W. Ellestad, G.A. Enhanced Site-Specific Cleavage of the Tetracycline Repressor by Tetracycline Complexed with Iron, J. Am. Chem. Soc. 115, 2546-2548 (1993). 

Concomitant use of tetracycline with antacids containing aluminum, calcium, or magnesium decreases absorption of oxytetracycline (because of chelation) concomitant use with food, milk or other dairy products, oral iron products, or sodium bicarbonate also impairs oral absorption. 

Fig. I.l A drug chelation interaction. Tetracycline forms a less-soluble chelate with iron if the two drugs are allowed to mix within the gut This reduces the absorption and depresses the serum levels and the antibacterial effects (after Neuvonen PJ, BMJ (1970) 4, 532, with permission). The same interaction can occur with other ions such as Al, Ca, Mg, Bi and Zi . ...

Only tetracycline, oxytetracycline, methacycline, minocycline and doxy-cycline have been shown to interact with iron, but it seems reasonable to expect that the other tetracyclines will behave in a similar way. 

An active substance, although initially released from its dosage form (and dissolved), may become unavailable for absorption due to reactimis with other medicines or food components [4]. An example is the formation of insoluble complexes of tetracycline with calcium or aluminium ions from antacids or milk products. Interaction (chelation or binding) with iron ions leads to a reduced absorption for a variety of active substances such as doxycycline, penicillamine, methyldopa and ciprofloxacin. The absorption of active substances showing pH-dependent dissolution behaviour may be influenced by medicines that influence the gastric pH, such as H2-antagonists, proton pump inhibitors and antacids. Antimycotic active substances such as ketoconazole or itraconazole dissolve better in acidic fluids. Therefore their bioavailability may be increased by the concomitant use of an acidic drink like cola, whereas the concomitant use of antacids or proton pump inhibitors is likely to reduce the bioavailability. Concomitant use of milk may increase the dissolution of acidic active substances, whereas fats from food may increase the bioavailability of lipophilic active substances like albendazole and griseofulvin. 

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

The absorption of oral iron is decreased when tlie agent is administered with antacids, tetracyclines, penicillamine, and the fluoroquinolones. When iron is administered with levothyroxine, there may be a decrease in tlie effectiveness of levothyroxine When administered orally, iron deceases the absoqition of lev-odopa. Ascorbic acid increases tlie absoqition of oral iron. Iron dextran administered concurrently with chloramphenicol increases serum iron levels. 

Do not take antacids, tetracyclines, penicillamine, or fluoroquinolones at the same time or 2 hours before or after taking iron without first checking with the primaiy health care provider. 

The following drugp have a decreased pharmacologic effect when administered with an antacid corticosteroids, digoxin, chlorpromazine, oral iron products, isoniazid, phenothiazines, ranitidine, phenytoin, valproic acid, and the tetracyclines. 

Adverse effects with the tetracyclines include gastrointestinal upset drug interactions with dairy products, antacids, and iron and phototoxicity. Minocycline can also cause vestibular complications (headache and dizziness) and skin discoloration that is not typical with tetracycline and doxycycline.16... 

There are problems as well in the absorption of certain drugs in the presence of specific food components. L-Dopa absorption may be inhibited in the presence of certain amino acids formed from the digestion of proteins [43], The absorption of tetracycline is reduced by calcium salts present in dairy foods and by several other cations, including magnesium and aluminum [115-117], which are often present in antacid preparations. In addition, iron and zinc have been shown to reduce tetracycline absorption [118], Figure 17 illustrates several of these interactions. These cations react with tetracycline to form a water-in-soluble and nonabsorbable complex. Obviously, these offending materials should not be co-administered with tetracycline antibiotics. 

Take drugs that have a direct irritant effect on the esophageal mucosa with plenty of liquid if they cannot be avoided (bisphosphonates, tetracyclines, quinidine, potassium chloride, iron salts, aspirin, nonsteroidal antiinflammatory drugs). 

We have already met several of the important concepts in this topic, so now it is time to round them up and bring out the major principles. In the first place drug molecules clearly might interact with food molecules in the lumen of the gut. Perhaps the best-known example of this is the interaction between the tetracyclines and dietary calcium and iron. The binding, which occurs between them, produces a chelate, which is not particularly lipid-soluble, and therefore the overall absorption of tetracycline may be reduced to the point where plasma levels do not achieve effective antibiotic concentrations. The commonest dietary constituent to produce this binding is milk with its high calcium content. Tetracycline ingestion should be separated from food as far as possible. 

Drugs may bind to other drugs in the gut. We have already met the iron/calcium interaction with tetracyclines, which reduces the absorption of the antibiotic. 

The absorption of tetracyclines is markedly reduced by aluminium and magnesium containing antacids. Tetracyclines may chelate other ions, in particular iron salts, with resultant poor absorption of both drugs. This interaction can be avoided by giving iron salts either 3 hours before or 2 hours after the tetracycline. 

Adverse effects consist mainly of gastrointestinal intolerance such as nausea, epigastric pain and diarrhea and, especially in the elderly constipation with continued therapy. All ferrous salts may cause a black coloration of the faeces. Children are particularly susceptible to potentially lethal iron intoxications. Oral iron preparations should not be administered concurrently with tetracyclines as mutual interference with absorption will occur. 

These antibiotics are partially absorbed from the stomach and upper gastrointestinal tract. Food impairs absorption of all tetracyclines except doxycycline and minocycline. Absorption of doxycycline and minocy-cbne is improved with food. Since the tetracyclines form insoluble chelates with calcium (such as are found in many antacids), magnesium, and other metal ions, their simultaneous administration with milk (calcium), magnesium hydroxide, aluminum hydroxide, or iron will interfere with absorption. Because some of the tetracyclines are not completely absorbed, any drug remaining in the intestine may inhibit sensitive intestinal microorganisms and alter the normal intestinal flora. 

The absorption of tetracycline administered orally is variable and depend upon the type of tetracycline used. The tetracycline form insoluble complexes i.e. chelation with calcium, magnesium, milk and antacids reduce their absorption. Administration of iron also interferes with the absorption of tetracycline. Doxycycline is rapidly and virtually completely absorbed after oral administration and its absorption is not affected by presence of food or milk. 

Tetracyclines, as broad-spectrum antibiotics, are the drugs of choice in treating Mycoplasma pneumoniae infections. Most tetracyclines are absorbed to various degrees (30 to 100%) from the gastrointestinal tract, primarily from the stomach and upper small intestine. The absorption of tetracyclines is hindered by milk and milk products, by numerous antacids such as aluminum hydroxide, sodium bicarbonate, and calcium carbonate, and by iron preparations such as ferrous sulfate. Therefore, these and similar substances should not be administered orally together with tetracycline (Figure 3.4). 

TETRACYCLINES IRON-ORAL 1.1 iron levels when iron given orally 2.1 plasma concentrations of these drugs, with risk of therapeutic failure 1. 1 absorption 2. Iron chelates with tetracyclines and l their absorption 1. Separate doses as much as possible - monitor FBC closely 2. Separate doses of other drugs as much as possible and monitor their effect... 

Antibiotics. Long-term administration of antibiotics could lead to vitamin B6 deficiency, If symptoms of peripheral neuropathy develop (numbness and tingling of the extremities), administer vitamin B6. Sulfasalazine can decrease the absorption of folic acid, and trimethoprim can cause folate deficiency, hence the need to administer folic acid if there is evidence of deficiency. Rifampicin can cause disturbances in vitamin D metabolism and lead to osteomalacia. The absorption of tetracyclines can be reduced by calcium, magnesium, iron and zinc, while this antibiotic could also decrease the absorption of these minerals. This effect is probably least with minocycline and is not confirmed with doxycycline. Doses of minerals and antibiotic should be separated by at least 2 hours. The absorption of quinolones is reduced by cationic and anionic supplements. 

Interactions. Iron chelates in the gut with tetracyclines, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, norfloxacin and ofloxacin it also forms stable complexes with thyroxine, captopril and biphosphonates. These interactions can be clinically important. Ingestion should be separated by 3 hours. 

Tetracyclines and Metals. Tetracyclines can combine with metal ions, such as calcium, magnesium, aluminum, and iron, in the GI tract to form complexes that are poorly absorbed. Thus, the simultaneous administration of certain drugs (e.g., antacids, iron preparations, products containing calcium salts) by patients on tetracycline therapy could result in a significant decrease in the amount of antibiotic absorbed. When two drugs are recognized as having a potential to interact, there is sometimes a tendency to believe that one of them should be discontinued. In the case of the tetracycline antacid interactions, problems can be... 

Neuvonen P, Mattila M, Gothoni G, Hackman R. Interference of iron and milk with absorption of tetracycline. Scand J Clin Lab Invest 1971 27(Suppl 116) 76. 

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 (54). 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. 

Doxycycline can cause nausea, vomiting, and diarrhea. The bioavailability of doxycycline is reduced if coadministered with multivalent ions such as iron or magnesium. However, unlike tetracycline, it can be administered with food and dairy products. In addition, patients taking tetracyclines may experience photosensitivity, especially if they are fair skinned. Patients taking tetracyclines should avoid prolonged exposure to sunlight. 

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