Tetracyclines

Tetracyclines have a broad range of antimicrobial activity and differences between the individual members are in general small.

Mode of action. Tetracyclines interfere with protein synthesis by binding to bacterial ribosomes and their selective action is due to higher uptake by bacterial than by human cells. They are bacteriostatic.

Pharmacokinetics. Most tetracyclines are only partially absorbed from the alimentary tract, enough remaining in the intestine to alter the flora and cause diarrhoea. They are distributed throughout the body and cross the placenta. Tetracyclines in general are excreted mainly unchanged in the urine and should be avoided when renal function is severely impaired. Exceptionally, doxycycline and minocycline are eliminated by nonrenal routes and are preferred for patients with impaired renal function.

Uses. Tetracyclines are active against nearly all Gram-positive and Gram-negative pathogenic bacteria, but increasing bacterial resistance and low innate activity limit their clinical use. They remain drugs of first choice for infection with chlamydiae (psittacosis, trachoma, pelvic inflammatory disease, lymphogranuloma venereum), mycoplasma (pneumonia), rickettsiae (Q fever, typhus), Vibrio cholerae (cholera) and borreliae (Lyme disease, relapsing fever) (for use in acne, see p. 313). Their most common other uses are as second line therapy of minor skin and soft tissue infections especially in (3-lactam allergic patients; surprisingly, many MRS A strains currently remain susceptible to tetracyclines in the UK.

An unexpected use for a tetracycline is in the treatment of chronic hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) when water restriction has failed. Demeclocycline produces a state of unresponsiveness to ADH, probably by inhibiting the formation and action of cyclic AMP in the renal tubule. It is effective and convenient to use in SIADH because this action is both dose-dependent and reversible.

Adverse reactions. Heartburn, nausea and vomiting due to gastric irritation are common, and attempts to reduce this with milk or antacids impair absorption of tetracyclines (see below). Loose bowel movements occur, due to alteration of the bowel flora, and this sometimes develops into diarrhoea and opportunistic infection (antibiotic associated or pseudomembranous colitis) may supervene. Disorders of epithelial surfaces, perhaps due partly to vitamin B complex deficiency and partly due to mild opportunistic infection with yeasts and moulds, lead to sore mouth and throat, black hairy tongue, dysphagia and perianal soreness. Vitamin B preparations may prevent or arrest alimentary tract symptoms.

Tetracyclines are selectively taken up in the teeth and growing bones of the fetus and of children, due to their chelating properties with calcium phosphate. This causes hypoplasia of dental enamel with pitting, cusp malformation, yellow or brown pigmentation and increased susceptibility to caries. After the fourteenth week of pregnancy and in the first few months of life even short courses can be damaging. Prevention of discolouration of the permanent front teeth requires that tetracyclines be avoided from the last 2 months of pregnancy to 4 years, and of other teeth to 8 years of age (or 12 years if the third molars are valued). Prolonged tetracycline therapy can also stain the fingernails at all ages.

The effects on the bones after they are formed in the fetus are of less clinical importance because pigmentation has no cosmetic disadvantage and a short exposure to tetracycline is unlikely significantly to delay growth.

Since tetracyclines act by inhibiting bacterial protein synthesis, the same effect occurring in man causes blood urea to rise (the antianabolic effect). The increased nitrogen load can be clinically important in renal failure and in the elderly.

Tetracyclines induce photosensitisation and other rashes. Liver and pancreatic damage can occur, especially in pregnancy and with renal disease, when the drugs have been given i.v. Rarely tetracyclines cause benign intracranial hypertension, dizziness and other neurological reactions.

Interactions. Dairy products reduce absorption to a degree but antacids and iron preparations do so much more, by chelation to calcium, aluminium and iron.

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