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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Anti-Infectives

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Tetracyclines - Antimicrobials

Tetracyclines are generally considered to be “broad spec-trum” antibiotics owing to their efficacy against a wide range of micro-organisms.

Tetracyclines

Tetracyclines are generally considered to be “broad spec-trum” antibiotics owing to their efficacy against a wide range of micro-organisms. They are close congeners of polycyclic naphthacenecarboxamide.

Examples

Chlortetracycline and oxytetracycline are obtained from Streptomyces aureofaciens and S. rimosus respectively.Demeclocycline is the product of a mutant strain of S.aurofaciens, while tetracycline, methacycline, doxycycline,and minocycline are all semisynthetic derivatives. 

Uses

The tetracyclines have a wide range of antimicrobial activity against aerobic and anaerobic gram-positive and gram-negative bacteria, as well as several microorganisms which are generally resistant to antibiotics, such as Rickettsia, Coxiella burnetti,Mycoplasma pneumoniae, Chlamydia, Legionella, atypicalmycobacteria, and Plasmodium species.

Toxicokinetics

Most of the tetracyclines are absorbed from the GI tract. The percentage of an oral dose that is absorbed is lowest for chlor-tetracycline (30%), followed by oxytetracycline, demeclocy-cline (95%), and highest for minocycline (100%). Absorption is adversely affected by concurrent ingestion of milk and milk products, iron salts, and several types of antacids.

Following absorption, tetracyclines are distributed widely in tissues and secretions. There is a tendency to accumulate in the reticuloendothelial cells of liver, spleen, and bone marrow, and in bone, dentine, and enamel (of unerupted teeth).* They cross the placenta and enter the foetal circulation and amniotic fluid.

The primary route of excretion is the kidney, though a small quantity is excreted by way of bile into the intestines from where part of it enters the enterohepatic cycle. Doxycycline is not eliminated via the same pathways as other tetracyclines, and does not accumulate significantly in patients with renal failure, making it the safest of the group.

Mode of Action

Tetracyclines are bacteriostatic agents and act by inhibiting protein synthesis, the 30s ribosomal subunit, binding to amino-acyl transfer RNA, and binding to the 50s ribosomal unit.

Adverse and Clinical (Toxic) Features

·            Acute overdose of tetracyclines is generally not attended with serious toxicity. Gastro-intestinal distress is common, manifested by nausea, vomiting, epigastric pain, and occasionally diarrhoea. Rarely, there is devel-opment of oesophagitis, oesophageal ulcers, and even pancreatitis.

·            Pancreatitis, characterised by moderate to severe epigas-tric pain with elevated serum amylase and lipase levels, has been reported with minocycline therapy.

·            Hepatic damage results from large doses, and is char-acterised by jaundice, azotaemia, acidosis, and shock. Autoimmune hepatitis and fulminant hepatic failure, requiring liver transplantation, have been associated with long-term minocycline therapy.

·            Renal toxicity has also been reported. Ingestion of outdated or degraded tetracycline can result in the devel-opment of a variant of Fanconi syndrome characterised by vomiting, polydipsia, polyuria, proteinuria, acidosis, glycosuria, and aminoaciduria.

·            Patients administered tetracyclines (especially doxy-cycline and demeclocycline) should avoid exposure to sunlight, or else photosensitivity reactions may occur in the skin, as also onycholysis and pigmentation of nails. Skin hyperpigmentation consisting of either focal blue-grey pigmentation at sites of prior cutaneous inflam-mation or normal skin of the legs, or diffuse dark-grey discolouration of sun-exposed areas has been reported.

·            Tetracyclines should not be administered to pregnant women and also to children under the age of 8 years. Hepatotoxicity, pancreatitis, and renal failure may occur in pregnant women following inges-tion of tetracyclines during pregnancy. Maternal ingestion of tetracyclines during pregnancy, particularly during the first trimester, may cause various congenital defects, including cardiovascular defects, oral clefts, polydactyly, hypospadias, limb hypoplasias and inguinal hernias.

·            Intravenous administration of tetracyclines can result in severe thrombophlebitis.

·              Long-term therapy with tetracyclines is associated with leukocytosis, atypical lymphocytes, toxic granulation of granulocytes and thrombocytopenic purpura.

·            Administration of tetracyclines to infants and elderly patients can cause increased intracranial pressure (pseu­dotumour cerebri).

·            Hypersensitivity reactions including skin rash, angi-oedema and anaphylaxis have been reported in sensitive individuals. 

·            Minocycline sometimes produces vestibular toxicity manifested by vertigo, ataxia, nausea, and vomiting. A lupus-like syndrome, consisting of fevers, fatigue, and diffuse arthralgias, has also been reported during long-term minocycline therapy for treatment of acne.

·            Demeclocycline has been reported to cause nephrogenic diabetes insipidus.

Treatment

·      Withdrawal of the drug and institution of supportive measures.

·      Renal and hepatic monitoring steps should be instituted when prolonged use of large doses of tetracyclines has occurred.

·      Severe toxicity is unlikely after ingestion. Gastrointestinal decontamination is generally not required. Antacids may be useful in treating gastric irritation.


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