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.
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.
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.
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.
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.
·
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.
·
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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