After reading this article we will discuss about:- 1. Chemistry of Tetracyclines 2. Classification of Tetracyclines 3. Antibacterial Spectrum 4. Bacterial Resistance 5. Mechanism of Action 6. Administration 7. Pharmacokinetics 8. Side Effects 9. Precautions 10. Therapeutic Indications 11. Dosage Regimens.
Chemistry of Tetracyclines:
As the name suggests, chemically tetracyclines have four partially unsaturated cyclohexane rings and are the close congeners of polycyclic napthacenecarboxamide.
By little substitution in the basic ring structure at different positions, we get different compounds as given below:
Classification of Tetracyclines:
(a) On the basis of sources:
(b) On the basis of duration of action:
(i) Short acting tetracyclines: Chlortetracycline, oxytetracycline and tetracycline.
(ii) Intermediate acting tetracyclines: Demeclocyline and methacycline.
(iii) Long acting tetracyclines: Doxycycline and minocycline.
Antibacterial Spectrum:
Tetracyclines are broad spectrum antibiotics and are highly effective against gram- positive but less against gram-negative bacteria. Most susceptible bacteria beta haemolytic streptococci, non-haemolytic streptococci, clostridia, Brucella, Hemophilus and Klebsiella.
Moderately Sensitive Bacteria:
Corynebacterium, Escherichia coli, Pasteurella, Salmonella and Bacillus anthracis.
Relatively Resistant Bacteria:
Proteus, Pseudomonas, Aerobacter aero-genes, Shigella, Streptococcus faecalis and staphylococci. In addition to the bacterial microorganisms, these are also effective against mycoplasma, spirochetes, actinomycetes, rickettsiae and certain large viruses of psittacosis group in animals and lymphogranuloma venereum group in humans.
In high concentrations, these are also effective against some of the protozoans particularly anaplasma. However, these are not effective against yeasts, moulds and other fungi and thus tetracyclines also known as antibiotics with “blanket activity”. Presence of pus, blood, serum or bacterial debris do not influence the antibacterial activity of tetracyclines to a considerable extent.
Bacterial Resistance:
Resistance to tetracyclines develops slowly in a graded manner. Nearly complete cross- resistance is seen amongst different members of tetracyclines except minocycline which may not show cross resistance with others in the group.
It generally develops due to impaired uptake of antibiotic into bacteria due to formation of a barrier to prevent penetration of the antibiotic into the cell or the bacteria acquire the capacity to pump it out or the resistance may be plasmid mediated.
In addition, other proposed mechanisms are:
(i) Decreased accumulation of tetracycline as a result of either decreased antibiotic influx or acquisition of an energy dependent efflux pathway;
(ii) Decreased access of tetracycline to the ribosome because of the presence of ribosome protection proteins; and
(iii) Enzymatic inactivation of tetracyclines.
Mechanism of Action:
Tetracyclines are primarily bacteriostatic but in high concentrations may be bactericidal, too. Through passive diffusion, tetracyclines gain access in outer cell membrane and by energy- dependent active transport in the inner cytoplasmic membrane.
Once the tetracyclines gain access to the bacterial cell, these specifically bind to the 30S bacterial ribosomal subunit in the susceptible bacteria and prevent the access of aminoacyl tRNA to the acceptor site on the mRNA ribosome complex and thus the peptide chain fails to grow and thereby inhibit protein synthesis.
In addition, they have the property to chelate the polyvalent cations like Ca2+ and Mg2+ which are essential for various enzymatic activities of the bacteria.
In mammalian host cells, the carrier-involved in active transport system is absent and the protein synthesing apparatus is less sensitive to tetracyclines, therefore, adverse effects of tetracyclines on host cells are minimal, however, these possess selective toxicity for the microbes.
Administration:
Tetracyclines can be administered by oral, parenteral, topical or intra-mammary routes, though in human beings, oral is the intended route. But in herbivores, oral route is not indicated as these inhibit the normal bacterial fermentation of plant fibres.
All the tetracyclines can be administered by intravenous (IV) or intramuscular (IM) routes in animals except chlortetracycline which can not be administered by IM route as it is quite irritant and painful and results in irregular and incomplete absorption. However, care must be taken not to give too fast IV injection, avoid perivascular leakage otherwise it induces local irritation, thrombophlebitis, necrosis etc.
Local application of tetracyclines in ophthalamic ointments or buffered aqueous solutions for conjunctival membranes in human beings and animals is also useful. However, in veterinary medicine, intramammary infusion of tetracycline antibiotics for the treatment of mastitis in cows, buffaloes and goats is extensively employed.
Pharmacokinetics:
Absorption:
All tetracyclines are adequately but incompletely and irregularly absorbed from the gastrointestinal tract. Most of the absorption takes place from the stomach and upper part of the small intestine and is greater in fasting state. Absorption is impaired by milk and milk products, administration of aluminium hydroxide gel, sodium bicarbonate, calcium and magnesium salts and iron preparations.
Following a single oral dose of chlortetracycline, oxy-tetracycline or tetracycline in carnivores, peak plasma concentrations are achieved in 2-4 hours and high concentrations persist for 6 hours or longer. Thus, for tetracyclines, 6 hour dosing interval is recommended.
After intramuscular injection of tetracycline and oxy-tetracyline, peak plasma concentrations are attained within 1 hour and sufficient blood concentrations are maintained for up to about 12 hours. Similarly, after IV injection, maximum blood levels are achieved immediately and detectable levels persist for up to 12 hours after a single dose.
Distribution:
From the blood, tetracyclines diffuses throughout the body and are found in highest concentrations in the kidneys, liver, spleen and lungs. These are also deposited at the ossification sites.
Tetracyclines are able to cross the placental barrier and foetal blood concentration is half of that of the maternal blood. Diffusion of tetracyclines into cerebrospinal fluid (CSF) is difficult and CSF concentration of chlortetracycline is about 1/4th of that in plasma.
Tetracyclines are removed from the blood by liver, where they are concentrated and then excreted by way of bile into the intestine from where they are partially reabsorbed i.e. these undergo enterohepatic circulation. Tetracyclines are secreted in high concentrations in milk equal to or higher than those in the blood and combined IV and local administration has been recommended in cases of acute mastitis.
Metabolism:
Metabolism of tetracyclines is limited. Mostly the parent compound is excreted in urine and faeces. Bile secretion may be 30 times to that of blood and enterohepatic recirculation results in prolonged maintenance of therapeutic concentrations.
Excretion:
Tetracyclines are mainly excreted through kidneys and in milk, though faecal elimination is also there. Due to enterohepatic recirculation, blood concentrations of tetracyclines remain high for prolonged period, therefore, an appropriate withdrawal period should be established for different species of animals.
Side Effects:
Though tetracyclines are relatively nontoxic, yet produce some adverse effects.
Suprainfection:
Gastrointestinal disturbances are due to suprainfection by drug resistant bacteria, fungi, yeasts etc. These also suppress bacterial fermentation in herbivores, resulting in anorexia and diarrhoea as alter the normal flora or microorganisms in the digestive tract and sometimes even resulting in acute tympany.
Irritation:
Following oral administration, chlortetracycline is slightly more irritant than other tetracyclines and may result in nausea, vomition and diarrohea in pigs, dogs and cats. Intramuscular injections of tetracyclines are painful especially chlortetracycline is extremely irritant and painful.
Thus, this route should be avoided. In human beings and monogastrics, particularly dogs and cats, tetracyclines may cause irritation in stomach and result in abdominal pain, nausea, vomition and sometimes even oesophageal ulcers.
Effect on Teeth and Bones:
Tetracyclines have the property to chelate calcium and result in the formation of tetracycline- calcium orthophosphate complex which gets deposited in the developing teeth and bones and results in yellow or brown discoloration and ill formed teeth and depression of bone growth. Therefore, therapeutic use of tetracyclines is contraindicated during pregnancy and in early childhood.
Effect on Cardiovascular System:
Rapid IV injection of tetracycline produces hypotension and sudden collapse. Acute depression of cardiovascular function appears to be related to the ability of tetracycline to chelate ionised calcium. This effect can be avoided by slow infusion of the drug or by pre-treatment with IV calcium gluconate.
Photo toxicity:
Phototoxic dermatitis may be observed in some individuals particularly with demeclocycline and doxycycline, but this reaction is rare in animals.
Hepato and Nephrotoxicity:
Tetracyclines, if taken for prolonged periods, may result in fatty infiltration and jaundice and also precipitate acute hepatic necrosis. Tetracyclines also enhance the renal failure. A reversible Fancony syndrome like condition is produced by outdated tetracyclines due to proximal tubular damage caused by degraded products. The syndrome is characterised by polyuria, polydipsia, glycosuria, aminoaciduria, nausea and vomition.
Hypersensitivity:
Not common with tetracyclines, however, skin reactions including urticaria, eruptions, exfoliative dermatitis, anaphylaxis, burning of eyes, brown or black coating of tongue (for human beings), glositis and angioedema may also be observed. Cross sensitization among various tertracylines is extremely common.
Precautions:
(i) Tetracyclines, particularly chlortetracyclines should not be administered via intramuscular route.
(ii) Tetracyclines should not be used during pregnancy, lactation and in children.
(iii) Tetracyclines should be used with utmost care in patients with hepatic and renal damage.
(iv) Tetracyclines should not be administered with milk and in patients receiving antacids and also immediately after intake of food.
Therapeutic Indications:
Tetracyclines are broad spectrum antibiotics and may be used for the treatment of mixed infections causing bronchopneumonia, enteritis, urinary tract infections, metritis, mastitis, prostatitis, and pyodermatitis.
Specific disease conditions like anaplasmosis, pasteurellosis, actinomycosis, actinobacillosis, leptospirosis, nocardiosis, heart worm disease, canine ehrlichiosis, cutaneous streptothriocosis, bovine hoof disease, brucellosis, East coast fever, porcine balantidiosis and psittacosis/ornithosis, blue comb disease of turkeys and chronic respiratory disease. In addition, tetracyclines are also employed as feed additive for promoting growth.
Dosage Regimens:
Local Infections:
1. 440 mg of all tetracyclines HCl/quarter for bovine mastitis;
2. 1mg/g of ointment for conjunctivitis;
3. 5mg/ml of tetracycline in buffered solution for eye infections.
4. 1 or 2 tablets of 0.5 gram for intrauterine infections of cows and buffaloes and 1/2 to 1 tablet for ewes.