Tetracyclines

 

Tetracyclines

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Salient features: Tetracyclines are a group of broad spectrum, bacteriostatic antibiotics having a nucleus of four cyclic rings. They are obtained either naturally or prepared semi-synthetically. The 1^st member of this group was Chlortetracycline derived from Streptomyces aureofaciens and it was introduced in 1948. Removal of chlorine atom from Chlortetracycline produced semi-synthetic Tetracycline introduced in 1952. They are acidic, amphoteric and hygroscopic compounds which in aqueous solution form salts with both acids and bases. They characteristically fluorescence when exposed to ultraviolet light. Tetracyclines form insoluble chelates with divalent and trivalent cations like Ca⁺², Mg⁺², Fe⁺³ and Al⁺³. Tetracyclines are stable as powder but their aqueous solutions are not stable, therefore for parentral injection, they are formulated in propylene glycol or polyvinyl pyrrolidine and stabilizers are added to enhance their stability. Physical and chemical properties of Tetracyclines permit them to be formulated as injections, capsules, powders, feed additives and ointments.

 

Mode of action: Tetracyclines inhibit bacterial protein synthesis and are primarily bacteriostatic. Tetracyclines enter gram negative bacteria by two transport mechanisms. The 1^st is passive diffusion through the hydrophilic channels formed by the porin proteins in outer cell membrane. The 2^nd mechanism involves an energy-dependent active transport system that pumps all Tetracyclines across the cytoplasmic membrane. Once they gain access to bacterial cell, they bind to 30S-ribosomal subunit and prevent binding/ access of amino-acyl tRNA to the acceptor (A) site on the mRNA-ribosome complex. This prevents addition of amino acids to the growing peptide chain resulting in inhibition of protein synthesis. Tetracyclines are more effective against multiplying micro-organisms. Effects of Tetracyclines are mostly reversible as the bacterial protein synthesis is restored when the drug is removed. Therefore a responsive host-defense system is essential for the removal of static bacteria. At high concentrations they also tend to impair protein synthesis in host cells by binding to eukaryotic 40S ribosomal subunit. However penetration of Tetracyclines in eukaryotic cells through cell membrane is poor due to lacking of specific carrier transport systems. Moreover the mammalian protein synthesis apparatus is less sensitive to Tetracyclines.

 

Classification: Tetracyclines are classified on the basis of their duration of action.

 

Classification of Tetracyclines
Category	Half life (t1/2)	Examples
Short-acting Tetracyclines	< 8 hours	Tetracycline, Oxytetracycline, Chlortetracycline
Intermediate-acting Tetracyclines	8-16 hours	Methacycline, Demeclocycline
Long-acting Tetracyclines	> 16 hours	Doxycycline, Minocycline

 

Pharmacokinetics: The oral absorption of Tetracyclines is variable with older drugs (e.g., Chlortetracycline) being less bioavailable and recent lipid soluble Tetracyclines (Minocycline and Doxycycline) being 100% bioavailable. Absorption of Tetracyclines from GIT is decreased in the presence of polyvalent cations (Ca⁺², Mg⁺², Fe⁺³ and Al⁺³) that are present in food, milk and milk products.  All Tetracyclines produce varying degree of tissue irritation on parentral administration. Therefore Procaine is added to Tetracycline solution for I/M administration in small animals (as their veins cannot be easily made prominent and furthermore their muscular mass is not larger enough to tolerate I/M injection) while in large animals Tetracyclines are commonly administered intravenously to avoid tissue irritation associated with I/M injection. Tetracyclines are widely distributed in most tissues including kidney, liver, lungs and bones. However with exception of lipid soluble members (Minocycline and Doxycycline), Tetracyclines do not penetrate the brain and CSF. They are also incorporated into forming bones, enamel and dentine of unerupted teeth possibly because of their binding action with Ca⁺². Tetracyclines cross the placental barrier and enter fetal circulation and amniotic fluid. With exception of lipid soluble Tetracyclines, the Tetracycline antibiotics are not metabolized to a significant extent in the body. Most Tetracyclines are excreted in the urine (60% excretion occurs via glomerular filtration pathway) and faeces (40% excretion occurs via biliary system).

 

Antimicrobial spectrum: Tetracyclines are broad spectrum antibiotics and they are active against a wide range of aerobic and anerobic gram positive and gram negative bacteria. They are also active against rickettisiae and spirocheates. When originally introduced, they affected practically all types of bacteria but recently strains of Pseudomonas, Proteus, Klebsiella, Salmonella, Staphylococcus and Corynebacterium have become resistant to them. They are ineffective against fungi and viruses.

 

Microbial resistance: Microbial resistance to Tetracyclines develops slowly in a graded manner and it can be acquired by three different mechanisms. The most important mechanism is decreased penetration of the drug into previously sensitive micro-organims. Enzymatic inactivation of Tetracyclines and production of proteins by micro-organisms (that protect ribosomes) are other mechanisms of bacterial resistance.

Clinical uses: Tetracyclines are broad spectrum antimicrobial agents and they can be used to treat a variety of pathological conditions that are mentioned below.

Ø  Bacterial diseases: Actinobacillosis (It is caused by Actinobacillus lignieresi and is also called “wooden tongue”), actinomycosis (also referred to as “lumpy jaw”, caused by Actinomyces bovis), mastitis, metritis,  pneumonia, tularemia (it is a disease of hares, ground squirrels, rabbits and rats, caused by Francisella tularensis and it is mechanically transmitted by flies or ticks), brucellosis, fowl cholera (Pasteurella multocida), nocardiasis (Nocardia asteroids) and psittacosis (also known as chlamydiosis, it affects parrots and virtually all cage birds and is caused by Chlamydia psittasi).

Ø  Rickettsial diseases: Anaplasmosis, Q fever (caused by Coxiella burnetti) and ehrlichiosis

Ø  Spirocheatosis: Canine leptospirosis, avian spirocheatosis (caused by Borrelia anserina) and lyme disease (a disease of humans and dogs that is caused by Borrelia burgdorferi).

Ø  Chlortetracycline is mainly used (in the form of feed additives) in food-producing animals as a growth promoter.

Ø  As Tetracyclines have high affinity for bones and get deposited in them, they are occasionally used as markers for the diagnosis of bone tumors.

Ø  Demeclocycline has a property to inhibit the effects of vasopressin/ADH (antidiuretic hormone) on renal tubules therefore it is occasionally used in conditions of excessive water retention.

 

Adverse effects: Tetracyclines have a relatively low toxicity at normal dosage levels. However a number of adverse effects have been associated with Tetracyclines.

1. Gastrointestinal upsets: All Tetracyclines produce GI irritation (manifested by diarrhea and abdominal pain) to varying degree in some patients particularly after oral administration. Superinfection by non-susceptible pathogens such as fungi, yeast and resistant bacteria is possible, which if occurs may lead to Candidiasis or enterocolitis. The oral administration of Tetracyclines may cause fatal diarrhea in horses and indigestion (due to deleterious effects on ruminal microbes) in ruminants.

2. Effects on bones and teeth:Tetracyclines are deposited in growing teeth and bones due to their chelating properties with Calcium. They form Tetracycline-Calcium-orthophosphate complex which inhibits calcification (hypoplastic dental enamel) and results in permanent discoloration (first yellowish then brownish) of teeth. The stained and hypoplastic teeth are more prone to various degenerations. High concentrations of Tetracyclines can interfere with Calcium deposition in bones and delay fracture healing. Given during pregnancy or in neonates, Tetracyclines may cause temporary suppression of odontogenesis and osteogenesis.

3. Hepatotoxicity: Tetracyclines (in excessive doses) can produce fatty liver infiltration leading to hepatotoxicity and jaundice.

4. Nephrotoxicity: Tetracyclines are potentially nephrotoxic, particularly in patients with pre-existing renal insufficiency.

5. Cardiovascular effects: The rapid I/V administration of Tetracyclines may result in hypotension, collapse and sudden death. This occurs due to rapid chelation of blood Calcium by the Tetracyclines. Pre-treatment with Calcium borogluconate and slow rate of I/V injection prevent these unwanted effects.

 

Contraindications: Tetracyclines are contraindicated in hepatic and renal insufficiency. They should not be administered to pregnant patients and infants (during osteogenesis and odontogenesis). The oral administration of Tetracyclines to ruminants and horses should be avoided due to risk of gastrointestinal upsets. Concurrent administration of Tetracyclines with milk and milk products should be avoided to prevent their wastage (as a result of their interaction with Calcium contained in milk and milk products).

 

Drug interactions: Antacids, Iron preparations, Saline purgatives (drugs that enhance intestinal motility), Kaolin (antidiarrheal), Pectin (antidiarrheal) and Sodium bicarbonate decrease the absorption of Tetracyclines from GI tract. Concurrent administration of nephrotoxic drugs (like Aminoglycosides and Loop diuretics) may hasten the renal damage. Tetracyclines may interfere with bactericidal activity of Penicillins, Cephalosporins and Aminoglycosides.