The first tetracycline, chlortetracycline (Fig. 1), was described in 1948 as a product isolated from Streptomyces aureofaciens. Oxytetracycline and tetracyline itself (so-called because it lacks both the chlorine of chlortetracycline and the hydroxyl of oxytetracycline) quickly followed. This class of antibiotics include: Doxycycline, Chlortetracycline, Clomocycline, Demeclocycline, Lymecycline, Meclocycline, Metacycline, Minocycline, Oxytetracycline, Penimepicycline, Rolitetracycline, Tetracycline.
All can be administered orally except for rolitetracycline.
Figure 1. chemical structure of chlortetracycline
Tetracyclines have a broad spectrum, displaying good activity against most Gram-positive and Gram-negative bacteria (excluding Proteus spp. and Pseudomonas aeruginosa), rickettsiae, chlamydiae, mycoplasmas, and spirochaetes. They share similar antibacterial activity but are distinguished by their pharmacokinetic profile. Doxycycline and minocycline are the most widely used and are almost completely absorbed when given orally. They do not aggravate renal failure so that can be used in renally impaired patients; they also exhibit marginally better antibacterial activity and sufficiently long serum half-lives to allow them to be given only once or twice daily.
Susceptible bacteria concentrate tetracyclines by active transport. In the cell they interfere with the binding of aminoacyl tRNA to the A site on the ribosome. Like chloramphenicol, the tetracyclines are predominantly bacteriostatic. The mechanism of the most common form of resistance is mediated by the production of a new protein which prevents uptake of the drug. There is almost complete cross-resistance between tetracyclines, although minocycline may retain activity against some tetracycline-resistant strains.
Classification of Tetracyclines
Historically, tetracyclines are considered First generation if they are obtained by biosynthesis such as: Tetracycline, Chlortetecycline, Oxytetracycline, Demeclocycline. Second generation if they are derivatives of semi-synthesis such as: Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Rolitetracycline. Third generation if they are obtained from total synthesis such as: Tigecycline. However, some researchers consider Tigecycline to be distinct from other tetracyclines drugs and are considered as a new family of antibacterials called Glycylcyclines.
Figure 2. Structures of tetracyclines and their pharmacological action.
The therapeutic use of tetracyclines has declined over the years with the increase of resistance, particularly among enterobacteria and streptococci. They are still widely used for the treatment of respiratory infections, particularly chronic bronchitis and mycoplasma pneumonia. They are the drugs of choice for rickettsial and chlamydial infections of all types but newer macrolides may take their place.
Tetracyclines are active against malaria parasites and some other protozoa. Doxycycline is sometimes used for antimalarial prophylaxis and in combination with quinine in the treatment of Plasmodium falciparum infections.
The pharmacokinetic profile of tetracyclines has recently been reviewed .
Table 1. Pharmacokinetics of tetracyclines.
For most agents absorption is in the range 2560%. Serum concentrations rise slowly after oral administration with absorption occurring in the stomach, duodenum and small intestine. Cmax (mg/ml) depends on dose, but is generally in the range 15 mg/ml. tmax is in the range 24 hrs except for demeclocycline whose Cmax is delayed until 46 hrs. Tetracyclines form insoluble complexes with divalent and trivalent cations like calcium, magnesium, iron and aluminium, which markedly reduces absorption . Protein, fat and carbohydrate meals reduce the absorption of tetracycline by about 50% .
The volume of distribution (Vd) of tetracyclines is in the order of 1.31.7 l/kg or a total volume of distribution of 100130 l. Protein binding is variable.
Unchanged tetracyclines are excreted by renal and bilary routes. Renal elimination (ClR) is related to glomerular filtration for most agents, with the exception of chlortetracycline [4-5]. With the exception of rolitetracycline, the amount of drug excreted in the urine is <50%. More than 40% is found in the faeces after biliary elimination and for most drugs enterohepatic circulation . Biliary concentrations can exceed blood by a factor of 5 .
None of these agents undergoes metabolism with the exception of tetracycline, 5% of which is excreted as the metabolite D-epitetracycline.
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