Tetracyclins & glycylcyclins
- 1. TETRACYCLINES & GLYCYLCYCLINES Dr. J.N. Chaturvedi Assoc. Prof. (Desig.), Pharmacology S.S. Medical College, Rewa (M.P.)
- 2. Tetracyclines & Glycylcyclines- Structure & Agents ◦ Tetracyclines are derivatives of basic four ring structure shown above. Available agents: ◦ Tetracycline. ◦ Doxycycline. ◦ Minocycline. ◦ Demeclocycline. ◦ Glycylcyclines- Tetracycline congeners with substituents that confer broad spectrum activity & activity against tetracycline resistant bacteria: ◦ Tigecycline.
- 3. Tetracyclines & Glycylcyclines- Mechanism of Action Enters by passive diffusion across cell wall of gr +ve bacteria or via porin channels in the outer membrane of gr-ve bacteria Entry across cytoplasmic membrane by active transporters. Binds to 30s ribosomal subunits Prevents access of aminoacyl tRNA to A-site on mRNA polysome complex. ◦ Inhibition of protein synthesis ◦ Premature termination of polypeptide chain synthesis.
- 4. Tetracyclines & Glycylcyclines- Antimicrobial Spectrum ◦ Tetracyclines are bacteriostatic against a wide range of bacterial & protozoa. ◦ Intrinsically more active against gr+ve bacteria as compare to gr-ve. Gram positive Gram negative & other Protozoa • Streptococci (pyogenes & pneumoniae). • Staphylococci (MSSA & MRSA) • Bacillus anthracis • Listeria monocytogenes • H. Influenzae, • H. ducreyi • Burkholderia pseudomallei • Brucella spp. • Vibrio spp. • C.jejuni • H. pylori • Yersenia spp. • Enterococci, Enterobacteriaceae, Acinetobacter, B. fragilis (Tigecycline) • Rickettsia • C. Burnetii • M.pneumoniae • Chlamydia • Legionella spp. • Ureaplasma • Atypical mycobacterium • Spirochetes: Borrelia, Treponema • Plasmodium
- 5. Tetracyclines & Glycylcyclines- Mechanism of Resistance 1. Decreased accumulation either due to increased efflux or decreased entry. 2. Production of ribosomal protection protein. 3. Enzymatic inactivation.
- 6. Tetracyclines & Glycylcyclines- Pharmacokinetics ◦ Absorption: ◦ Oral absorption is incomplete for tetracycline & demeclocycline. ◦ Doxycycline & Minocycline are well absorbed orally. ◦ Tigecycline is available only for parenteral use. ◦ Concomitant administration of divalent/trivalent cations (Ca++, Mg++, Al+++, Zn++ etc.) impairs absorption. ◦ Tmax= 2-4 hrs. ◦ Distribution: ◦ Widely distributed (incl. prostate, RE system of liver & spleen, bone marrow, dentine and enamel of unerupted teeth) ◦ Can cross BBB, placenta & breast milk. ◦ aVd= 7-10 L/kg.
- 7. Tetracyclines & Glycylcyclines- Pharmacokinetics ◦ Metabolism: ◦ Hepatic metabolism (minocycline & tigecycline) ◦ Excretion: ◦ All tetracyclines are excreted (metabolites/ unchanged) primarily in urine except doxycycline (excreted in bile). T1/2 (tetracycline)= 6-12 hrs T1/2 (doxy-, demeclo-, minocycline)= 16hrs
- 8. Tetracyclines & Glycylcyclines- Therapeutic Uses ◦ General Points: ◦ First line therapy for infections caused by rickettsia, mycoplasma & chlamydia. ◦ Doxycycline is most important member of tetracyclines. ◦ Tigecycline is reserved drug for MRSA/ VRSA/ VRE. Agent Oral Dose Parenteral dose Adults Pediatric (children >8years of age) Adult Pediatric (children >8years of age) Tetracycline 1-2g/d in 2-4 divided doses 25-50mg/kg/d in four divided doses - - Doxycycline 100 mg q12-24h 2.2mg/kg q12h f/b 2.2mg/kg in q12-24h 100 mg q12-24h 2.2mg/kg q12h f/b 2.2mg/kg in q12-24h Minocycline 200 mg f/b 100 mg q12h 4mg/kg f/b 2mg/kg q12h 200 mg f/b 100 mg q12h 4mg/kg f/b 2mg/kg q12h Tigecycline - - 100 mg loading f/b 50mg q12h. Dose is reduced in case of hepatic dysfunction -
- 9. Tetracyclines & Glycylcyclines- Therapeutic Uses 1. Respiratory Tract Infection ◦ Doxycycline for community acquired pneumonia in non-hospitalized patients. ◦ Tigecycline as single agent for community acquired pneumonia requiring hospitalization. 2. Skin and Soft tissue infection ◦ Doxycycline & minocycline for cutaneous MRSA infection. ◦ Low dose tetracycline (250 mg q12h) for acne. ◦ Tigecycline for complicated skin & soft tissue infection. 3. Intra-abdominal infection ◦ Tigecycline for VRE
- 10. Tetracyclines & Glycylcyclines- Therapeutic Uses 4. Sexually transmitted diseases. ◦ Uncomplicated chlamydia urethritis/cervicitis/rectal ulcer: 7 day course of doxycycline. ◦ Acute epididymitis (C. trachomatis or N. gonorrhoeae): single i.m inj ceftriaxone 250mg + 10 day course of doxycycline. ◦ Lymphogranuloma venerum (C. trachomatis): 21 day course of doxycycline. ◦ Non-pregnant, penicillin allergic pri., sec. or latent syphilis: Doxycycline for 02 weeks 5. Rickettsial infections. ◦ Rocky mountain spotted fever ◦ Recrudescent epidemic typhus (Brill’s disease) ◦ Murine typhus ◦ Scrub typhus ◦ Rickettsial pox. ◦ Q fever. 6. Anthrax ◦ Doxycycline for prevention & treatment. Doxycycline
- 11. Tetracyclines & Glycylcyclines- Therapeutic Uses 7. Other Infections: a) Brucellosis ◦ Doxycycline + Rifampicin/streptomycin b) Tularemia ◦ Doxycycline is used alternative to streptomycin. c) Actinomycosis ◦ Doxycycline is used alternative to PnG. d) Nocardiosis ◦ Minocycline is used alternative to TMP-SMX/sulfonamides
- 12. Tetracyclines & Glycylcyclines- Therapeutic Uses 7. Other Infections: e) Yaws ◦ Doxycycline alternative to Azithromycin. f) Leptospirosis ◦ Milder forms g) Relapsing fever h) Lyme disease i) H.pylori infection ◦ Tetracycline in triple or quadruple drug regimen for H.pylori eradication.
- 13. Tetracyclines & Glycylcyclines- Adverse Effects 1. Gastrointestinal ◦ GI irritation is most common. ◦ Epigastric burning, abdominal discomfort, esophagitis & esophageal ulceration. ◦ Superinfection with yeasts (candida spp.) 2. Photosensitivity ◦ Tetracyclines>> glycylcyclines. ◦ With or without nail pigmentation & onycholysis. 3. Hepatic ◦ Pts. With renal failure receiving daily >2g of oxytetracycline parenterally.
- 14. Tetracyclines & Glycylcyclines- Adverse Effects 4. Renal ◦ Nephrogenic DI with demeclocycline ◦ Fanconi syndrome with outdated tetracycline. 5. Dental ◦ Permanent brown discolouration of teeth. More common if given to infant-5 year of age. Treatment of pregnant patients also leads to brown discolouration in their children. 6. Other ◦ Depresses bone growth. ◦ Thrombophlebitis. ◦ Increased ICP (pseudotumor cerebri) in infants. ◦ Vestibular toxicity with minocycline. ◦ Hypersensitivity reactions.