Tetracyclines

Classification and Mechanism of Action

Based on their source of derivation, the drugs are divided into two main groups:

1. Natural (biosynthetic): tetracycline, oxytetracycline.
2. Semisynthetic: methacycline, doxycycline.

The primary site of action for tetracyclines is the bacterial ribosomal complex. The drug binds to the 30S subunit and blocks the aminoacyl-tRNA acceptor site (A-site) on the messenger RNA. As a result, aminoacyl-tRNA cannot bind to the complex, no new amino acids are added, and the elongation of the polypeptide chain is halted. This leads to the complete cessation of protein synthesis.

The action is bacteriostatic in nature. The high selectivity of these drugs is explained by the fact that bacteria take up the antibiotic via a specialized energy-dependent transport system (gram-negative microbes also utilize passive diffusion through porin proteins). Mammalian cells lack this active transport mechanism, which ensures low toxicity to the host organism.

Spectrum of Activity and Clinical Application

Tetracyclines are broad-spectrum antibiotics. Due to their high lipophilicity, they penetrate cells exceptionally well, making them indispensable for infections caused by intracellular pathogens.

• First-line drugs: brucellosis (in combination with gentamicin or rifampin) and rickettsial infections (epidemic typhus, Q fever).
• Intracellular and atypical infections: respiratory tract infections, trachoma, psittacosis, and urogenital chlamydiosis (Chlamydia); atypical pneumonia (Mycoplasma); legionellosis.
• Highly dangerous and zoonotic infections: plague, tularemia, cholera.
• Borreliosis: Lyme disease, relapsing fever.
• Intestinal and abdominal infections: shigellosis, amebiasis, peritonitis, and cholecystitis (caused by E. coli), as well as eradication of Helicobacter pylori in peptic ulcer disease.
• Additionally, they are used for tropical malaria prophylaxis and in treatment regimens for syphilis, Haemophilus influenzae, and Klebsiella infections.

Pharmacokinetics and the "Chelate Rule"

Because these drugs are highly lipophilic, they are well absorbed in the gastrointestinal tract, cross biological barriers, and accumulate in tissues.

Based on their half-life, they are categorized into:

• Short-acting (6–8 hours): tetracycline, oxytetracycline (require administration 4 times daily).
• Long-acting (12–24 hours): methacycline, doxycycline (administered 1–2 times daily).

A crucial chemical property of this group is their ability to form insoluble chelate complexes with divalent and trivalent ions (calcium, magnesium, iron, zinc, aluminum). If a tablet is swallowed with milk (a calcium source), an antacid (magnesium, aluminum), or an iron supplement, the antibiotic binds to these ions and fails to be absorbed into the bloodstream. Therefore, tetracyclines are prescribed strictly on an empty stomach.

The exception is doxycycline. Unlike the others, it is excreted primarily via feces in an inactive form rather than through the kidneys. This allows it to be safely prescribed to patients with renal failure and minimizes damage to the normal intestinal microflora.

Side Effects and Contraindications

Specific adverse reactions of tetracyclines are directly related to their chemical properties:

• Bone and tooth damage: due to their affinity for calcium, the drugs are deposited (sequestered) in bone tissue. This causes skeletal development abnormalities, enamel damage, and permanent yellow or gray-brown tooth discoloration.
• Photosensitization: the molecules absorb ultraviolet light, which sharply increases skin sensitivity to sunlight and can lead to severe sunburns.
• Hepatotoxicity: direct toxic effects on the liver.
• Local irritation: nausea, vomiting, flatulence, diarrhea upon oral administration; thrombophlebitis upon intravenous administration.
• Dysbiosis: development of superinfections (candidiasis, pseudomembranous enterocolitis).
• Allergic reactions: ranging from urticaria to anaphylactic shock.

Due to their impact on skeletal development, tetracyclines are strictly contraindicated in pregnant women and children under 8 years of age.

Administration Forms and the Problem of Resistance

The choice of pharmaceutical formulation depends on the severity and localization of the infection:

• Oral (capsules, tablets): the standard route for most diseases.
• Parenteral (intravenous, intramuscular, intracavitary): soluble salts are used for severe purulent-septic processes.
• Topical (ointments): skin ointment is used for acne and skin infections, while eye ointment is used for bacterial blepharitis, keratitis, and iridocyclitis.

Due to widespread medical use, many bacteria (staphylococci, enterococci, pneumococci) have developed cross-resistance to tetracyclines. The main microbial defense mechanism is plasmid-mediated active efflux (pumping the antibiotic out of the cell). Less frequently, bacteria synthesize specific proteins that protect the ribosome or enzymes that degrade the drug molecule.