Tetracycline: An introduction, classification, mechanism, structure, uses with its effects.

Tetracycline

Structure-of-tetracycline

The meaning of tetracycline is that Tetra- four, cycl- hydrocarbon ring, and ine- derivation. These are chemically octahydronapthacene ring derivatives which are bacteriostatic and board spectrum antibiotics that kill certain infections that causing microorganisms and used to treat a wide variety of infections. It was firstly obtained from the fermentation of the streptomyces spp.

It is a large family of antibiotics was discovered in the form of chlortetracycline and oxytetracycline (the first members of the tetracycline group) as natural products. Streptomyces aureofaciens and S. rimosus are the source of chlortetracycline and oxytetracycline, respectively.  

Another tetracycline was renowned later, as naturally occurring molecules from Streptomyces species of microorganisms or a derived from semi-synthetic way, for example-methacycline, doxycycline, and minocycline.

History-

“Benjamin minge Duggar” was the head of the soil engineering department in the year of 1940, who identified tetracycline as a therapeutic substance that produced from soil microorganisms.

Structure-of-streptomyces-spp.
streptomyces spp

At the early phase, tetracyclines ware first originated from the fermentation product of golden-colored soil bacterium that named streptomyces aureofacians. All tetracyclines are slightly bitter solids which are slightly water-soluble, but their hydrochlorides are more soluble.  Aqueous solutions are unstable.  All have practically the same antimicrobial activity (with minor differences).  The subsequently developed members have high lipid solubility, greater potency, and some other differences.

Molecular formula-C22H24N2 O8
Molecular weight– 444.4 g/mol
IUPAC Name-(4S,4aS,5aS,6S,12aR)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide

Classification of tetracycline-

Short-acting (Half-life is 6-8 hours)- Tetracycline, chlortetracycline, Oxytetracycline
Intermediate-acting (Half-time is ~12 hours)- Demeclocycline, Metacycline
Long-acting (Half-time is 16hours or more)- Doxycycline, Minocycline, Meclocycline

You may read- antimicrobial agents.

Mechanism-

These are specific inhibitors of bacterial protein synthesis.They bind to the 30S ribosomal subunit and prevent the binding of aminoacyl tRNA to the mRNA-ribosome complex, which initiates protein synthesis. There is two main binding sites fir the tRNA molecule, the peptidyl(p-site) binds the tRNA bearing the peptide chain, the acceptor amino site (A-site).

Mechanism-of-tetracycline
Source-internet

Tetracycline reversibly binds to the 30s subunit at the site-A to prevent attachment of the aminoacyl tRNA, terminating the translation process. The bacterial ribosome is a 70s particle made up of 30s subunit and 50s subunits. The subunit combines with the 30s subunit-mRNA complex to form a ribosome then binds tRNA and catalyzes the building of the protein chain.

Antibacterial spectrum-

Tetracyclines are bacteriostatic antibiotics that effective against in a wide variety of organisms, which including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. They are commonly used in the treatment of acne and Chlamydia infections.

When tetracyclines are originally introduced, they inhibited practically all types of pathogenic microorganisms except fungi and viruses, so these are named as ‘broad-spectrum antibiotic’. However, promiscuous and often indiscriminate use has gradually narrowed the field of their usefulness.

The resistance-

Tetracyclines are the most commonly encountered naturally occurring resistance to an efflux pump that expels drug out of the cell and preventing intracellular accumulation.

Resistance-of-tetracycline
Source-internet

Other mechanisms of bacterial resistance to tetracyclines include enzymatic inactivation of the drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome.

 Resistance to one tetracycline does not confer universal resistance to all tetracyclines, and the development of cross-resistance may be dependent on the mechanism of resistance.

Pharmacokinetics-

 Absorption

Tetracyclines are adequately absorbed after oral ingestion. Administration with dairy products or other substances that contain divalent and trivalent cations (for example, magnesium, calcium, and aluminum antacids, or iron supplements) decreases absorption, particularly for tetracycline, due to the formation of nonabsorbable chelates. Both the derivative of tetracycline like-doxycycline and minocycline are available as oral and intravenous preparations.

 Distribution

The tetracyclines are well concentrated on the bile, liver, kidney, gingival fluid, and skin. Moreover, they bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have high calcium content. Penetration into most body fluids is adequate.

Only minocycline and doxycycline achieve therapeutic levels in the cerebrospinal fluid (CSF). Minocycline also achieves high concentrations in saliva and tears, rendering it useful in eradicating the meningococcal carrier state. All tetracyclines cross the placental barrier and concentrate on fetal bones and dentition.

Elimination

Tetracyclines are primarily eliminated unchanged from the urine, and minocycline undergoes hepatic metabolism and it eliminated to a lesser extent via the kidney. Doxycycline is preferred in patients with renal dysfunction, as it is primarily eliminated via the bile into the feces.

Administration

Tetracyclines are most commonly administered in the dosage form of an oral capsule. The dosage form of a capsule should be taken half hour before food and two hours after food.  Liquid oral preparations for pediatric use are banned in India. The intramuscular route does not recommend tetracyclines because they are painful and absorption from the injection site is poor. The slow intravenous injection may be given in severe cases but is rarely required now.

A variety of topical preparations (ointment, cream, etc.) are available, but should not be used, because there is a high risk of sensitization. However, the ocular application is not contraindicated.

SAR of tetracycline-

SAR-of-tetracycline

-Substitution on nitrogen via alkylation reduces proportionately to the size of the alkyl group.

-C2 and C3 keto-enol are essential for activity.

-The dimethylamino group at the 4-position must have the A orientation: 4-epitetracyclines is very much less active than natural isomers.

The removal of the 4-dimehylamino group reduces activity.

-Substitution with -OH/polar group at C-5, produce water-soluble derivatives which can be administered orally only.

Example– methacycline

-=CH2 substitution at R3 increases the antimicrobial action of drug molecules.

-A cis-A/B-ring fusion with a beta-hydroxy group at C-12a is apparently also essential. Ester of the C-12a hydroxyl group is inactive, with the exception if the formyl ester, which readily hydrolyzes in aqueous solution.

-Alkylation at C-11a leads to loss of activity of drug molecules.

-Substitution at C-7. With electron-withdrawing groups like- chloro and nitro, and strongly electron-donating groups enhance activity.

-D-ring must be aromatic, changes into the ring system lead to decreases or abolished the biological action of drugs.

-Polar substituents like-hydroxyl groups, at C-5 and C-6 decrease lipid versus water solubility of the tetracycline.

The position is, however, considerably more sensitive than the 5-position to this effect. Substitution via OH at C-6 increases lipophilicity and more stable to acids.

Example– Doxycycline

-Under the alkaline condition, OH at C-6 changes into oxygen anion and then attacks the C-11 (ketone group) lead to intramolecular nuclear reaction, by electron transfer, C ring rupture to generate inactive iso-tetracycline lactone.

-Linear fused four aromatic rings are necessary for biological action or vice versa.

Chlortetracycline

It was isolated by Duggar in 1948 from S. aureofaciens. It reversibly binds to the 30S subunit at the A-site to prevent attachment of the aminoacyl tRNA, leading to terminate the translation process. Also known as aureomycin hydrochloride.

Structure of chlortetracycline-
Structure-of-chlortetracycline
Physical properties of chlortetracycline-

It is yellow in color and odorless crystalline powder.

Soluble 1 in 75 on water and 1 in 560 of alcohol, in the solution of alkali hydroxides and carbonates.

It is insoluble in acetone, in chloroform, dioxin, and ether.

the pH of a 1% solution in water is between 2.3 to 3.3.

It should be store in an airtight container and protected from light.

Uses of chlortetracycline

-Used in the treatment of infections of the respiratory tract, sinuses, middle ear, intestine, and eye infections.

-Used in skin infection.

Doxycycline

Doxycycline is an antibiotic in the tetracycline group that available for antibacterial therapy. Doxycycline is α-6-deoxy-5-oxytetracycline and also Vibramycin is first reported by Stephens in 1958. It reversibly binds to the 30S subunit at the A-site to prevent attachment of the aminoacyl tRNA, terminating the translation process.

Structure of doxycycline-
Structure-of-doxycycline
Physical properties of doxycycline-

It is a yellow crystal powder.

It is very slightly soluble in alcohol, practically insoluble in chloroform and ether, freely soluble in dilute acid, and in alkali hydroxide containers.

the pH of 1% suspension in water is between 5.0 to 6.5.

It should store in an airtight container and protect from light.

Uses of doxycycline-

-Used in the treatment of infections caused by gram-positive and gram-negative bacteria like- in the respiratory tract, eye infections, and UTIs.

-Used in cancer recurrence.

-Used in the treatment of infections like- syphilis, oral herpes simplex, acne, and malaria.

-Used in amoebiasis.

Minocycline

These are specific inhibitors of bacterial protein synthesis. These are bind with the 30S ribosomal subunit and prevent the binding of aminoacyl tRNA to the mRNA-ribosome complex, which initiates protein synthesis.

Structure of minocycline-
Structure-of-minocycline
Physical properties of minocycline-

It is a yellow crystalline powder.

It is sparingly soluble in water, slightly soluble in alcohol, practically insoluble in chloroform and ether, and soluble in solution of alkali hydroxides and carbonates.

the pH of the solution in water containing 1% is between 3.5 to 4.5.

It should be stored in an airtight container and protect from light.

Uses of minocycline-

-Used in the treatment of infections caused by gram-positive and gram-negative bacteria like- in the respiratory tract, eye infections, and UTIs.

-Used in syphilis, sinusitis, oral herpes simplex, and acne.

-Used in leprosy infection.

-Used in the treatment of prophylaxis or anthrax.

Oxytetracycline

It inhibits protein synthesis by binding to the 30S subunit of ribosomes and preventing aminoacyl tRNA from binding.

Structure of oxytetracycline-
Structure-of-oxytertacycline
Physical properties of oxytetracycline-

It is in pale yellow to tan, odorless crystalline powder, that darkens on exposure to strong sunlight.

Soluble 1 in 4150 of water, sparingly soluble in alcohol, practically insoluble in chloroform, freely soluble in 3N hydrochloric acid, and in alkaline solutions.

The pH of a 1% suspension in water is between 4.5 to 7.0.

It loses potency in the solution of pH below 2 and is rapidly destroyed by the alkali hydroxide solution.

It should be stored in an airtight container and protect from light.

You may read- Beta lactam antibiotics.

Precautions-

-Tetracyclines should not be used during pregnancy, lactation, and children.

-They should be avoided in patients on diuretics: blood urea may rise in such patients.

-They should be used cautiously in renal or hepatic insufficiency.

-Preparations should never be used beyond their expiry date.

-Do not mix injectable tetracyclines with penicillin—inactivation occurs.

-Do not inject tetracyclines intrathecally.

Adverse effects-

-Gastric discomfort

-Deposition of the drug in bones and teeth

-Liver failure

-Vertigo

-Avoid in pregnancy

-Effects on calcified tissue

-Hepatotoxicity

-Phototoxicity

-Vestibular dysfunction

-Pseudotumor cerebri

-Contradictions

Tigecycline

Tigecycline is the first member in the new class of synthetic tetracycline analogs (glycylcyclines) which is active against most bacteria that have developed resistance to the classical tetracyclines. Thus, they have the broadest spectrum of activity. Tigecycline is a derivative of minocycline and was introduced in 2005.

Antibacterial spectrum-

Tigecycline is active against most gram-positive and gram-negative cocci and anaerobes, including tetracycline-resistant strains of Strep. pyogenes, Strep. pneumoniae, Staph. aureus, MRSA, VRSA, Enterococcus faecalis, and VRE, most Enterobacteriaceae, Acinetobacter, as well as tetracycline sensitive organisms like Rickettsia, Chlamydia, Mycoplasma, Legionella, etc. However, Pseudomonas and Proteus are inherently nonresponsive to tigecycline.

Resistance of tigecycline-

Tigecycline acts in the same manner as tetracyclines. The lack of cross-resistance between the two groups is mainly because the tetracycline efflux pumps acquired by many resistant bacteria have low affinity for tigecycline and are unable to pump it out. In other resistant bacteria, the ribosomal protection protein against tetracycline is less active in protecting the ribosomal binding site from tigecycline. Thus, the two most important mechanisms of tetracycline resistance do not operate against tigecycline.

Pharmaco-kinetics of tigecycline-

Tigecycline is poorly absorbed from g.i.t, so, the only route of administration is by slow I.V. infusion. It is widely distributed in tissues; the volume of distribution is large with >7 L/kg. Consequently, the concentration of plasma is low. It is eliminated mainly from the bile, so the dose adjustment is not needed in renal insufficiency.  The duration of action is long, and elimination t½ is 37–67 hours.

Dose– 100 mg loading dose, followed by 50 mg 12 hourly by intravenous infusion over 30–60 min, for 5–14 days.

Structure of tigecycline-
Structure-of-tigecycline
Uses of tigecycline-

-used in many infections, it is approved only for the treatment of serious and hospitalized patients of community-acquired pneumonia, complicated skin and skin structure infections (but not diabetic foot), complicated intraabdominal infections caused by enterococci, anaerobes, and Enterobacteriaceae.

-It is not recommended for hospital-acquired/ ventilator-associated chest infections, because in a comparative trial, all-cause mortality was higher in the tigecycline group than in the comparator group receiving other antibiotics.

-It is also not suitable for urinary tract infection, because only low concentrations are attained in the urine.

 The clinical efficacy of tigecycline in other infective conditions is still to be established.

The adverse effect of tigecycline-

-The most common side effect is nausea and occasionally vomiting.

-Others are epigastric distress, diarrhea, skin reactions, photosensitivity, and injection site complications.

-Superinfections and other adverse effects of tetracyclines can occur with tigecycline as well.

-It is not recommended for children and during pregnancy. Few cases of pancreatitis are reported.


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