1 / 29

Tetracyclines

Tetracyclines. Basic and Clinical Pharmacology Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol & Toxicol (UON). Notes available at: bvm2010@gmail.com. Description. Broad spectrum antibiotic Produced by Streptomyces genus of Actinobacteria Bacteriostatic (binds to 30S ribosomal subunit)

ajaxe
Download Presentation

Tetracyclines

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Tetracyclines Basic and Clinical Pharmacology Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol & Toxicol (UON). Notes available at: bvm2010@gmail.com

  2. Description • Broad spectrum antibiotic • Produced by Streptomyces genus of Actinobacteria • Bacteriostatic (binds to 30S ribosomal subunit) • Could also bind to 50S subunit • Causes cytoplasmic membrane alterations with Incr. efflux of intracellular bacterial components

  3. Indications • Broad spectrum antibiotics: active against gram +ve and gram –ve bacteria. • Drugs of choice in: Chlamydophilosis; Ehrlichiosis; Coxiellosis;Rickettsiosis and for some Mycobacterial and Mycoplasmal infections

  4. Pharmacodynamics • Reversible binding to 30S subunit • Also binds to some extent to 50S subunit • Alterations of cytoplasmic membrane inducing leakage of nucleotides from the bacterial cell

  5. Mechanism of Action • Diffusion through porin bacterial channels • Reversible binding • Inhibition of binding of tRNA to the mRNA ribosome complex • Interference with protein synthesis

  6. Pharmacokinetics • Bioavailability: less than 40% I.M; 100% I.V; 60-80% Oral. • Food and /milk reduces GI absorption by 50% or more • Upto 67% plasma protein bound • Not metabolised • Concentrated by the liver in bile &Eliminated in urine and feaces in biologically active form.

  7. Pharmacokinetics (Cont.) • LD50=808mg/kg (orally in mice) • Doxycycline is excreted in feaces

  8. Bacterial resistance • Energy dependent efflux • Ribosomal protection • Chemical modification and enzymatic catalysis

  9. Drug interactions • Absorption is decr. By antacids; iron containing prep. • Synergism with tylosin in pasteurella Rx • Comb. With polymixins incr. their efficacy. • Doxycycline is synergistic with rifampicin or streptomycin in brucellosis Rx • Doxy. Is synergistic with.pyrimethamine in toxoplasmosis Rx.

  10. Toxicity and adverse effects • Relatively safe drugs • Toxicity is attributed to their irritant nature; • Disturbances of intestinal flora • Ability to bind calcium (cardiovascular effects, deposition in teeth and bone); • Their toxic effects on liver and kidney cells.

  11. Antineoplastic drugs • Drugs used in cancer chemotherapy • Goal (remission/palliation) • Challenges: Increased toxicity (myelosuppression and git injury). • Mostly affected: rapidly dividing cells e.g. bone marrow; intestines; testis; skin • Also apoptosis; peripheral neuropathy

  12. Cancerous cells: the target site! • Biological similarity with normal ells • Neoplastic cells are dividing more rapidly: Quantitative differences

  13. Cell cycle kinetics • Important aspect since many antineoplastics target rapidly dividing cells: cell cycle specificity-:G1; S; G2; M; G0 Phase. • The question of incr. vulnerability to bone marrow and git cells due to their rapid division arises. • Cells in G0: resistant to chemotherapy!

  14. Drug resistance, a chemotherapeutic challenge! • Incr. efflux • Enzymatic catalysis • Rapid DNA repair • Decr. Binding to target sites in the tumor cells.

  15. Alkylating agents • CCNS agents • Substituting an alkyl group for a reactive hydrogen atom in the DNA leading to cross linking of the DNA molecule • Include nitrogen mustards and nitrosoureas • Dose limiting toxicity: bone marrow suppression • Are carcinogenic and mutagenic

  16. Nitrogen mustards • Cyclophosphamide: well distributed following oral & I.V adm. • Metabolism • Toxicity (diarrhoea; vomiting; cysitis); myelosuppression • Cystitis minimized by diuresis and Mesna((sodium-2-mercapto-ethane sulfonate),

  17. Nitrogen mustards • Others are: Ifosfamide; chlorambucil and melphalan

  18. Nitrosoureas • Carmustine and lomustine • Highly lipophilic • Indicated in brain tumors • Toxic to the CNS, liver and kidneys

  19. B). Antimetabolites • Folic acid analogues (methotrexate) and pyrimidine analoques (5-fluoro uracil & Cytosine arabinoside ) • Methotrxate is a CCS, active against the S phase • Inhibits dihydrofolate reductase and thymidylate synthase enzymes for purine and pyrimidine synthesis

  20. Methotrexate • Hence interferes with folic acid synthesis in cancerous and normal cells • Calls for leucovorin (folate co enzyme) adm. • Well distributed to all tissues except CNS

  21. PyrimidineAnaloques • 5-fluorouracil, a, CCS, targeting the S phase • Inhibits thymidylate synthase activity, thereby inhibiting DNA synthesis. • Variable git absorption-adm.i.v • Shows enhanced CNS toxicity in cats: hence contraind. • Dose limiting toxicity: Bone marrow and git toxicity

  22. C). Mitotic Inhibitors • Vinca alkaloids (vincristine and vinblastine,) CCS at the M phase. • Well distributed except in the CNS. Adm I.V. • Metabolism and excretion • Vinblastine is less tolerated in small animals • Indicated in transmissible venereal tumors (TVT)

  23. D). Antibiotics • CCNS agents, inhibiting DNA and RNA synthesis • Include the anthracyclines (doxorubicin, mitoxantrone), dactinomycin and bleomycin. • Adm. I.V. • Dose limiting toxicity is myelosuppression

  24. E). Enzymes • Asparaginase (L-asparagine amidohydrolase) : inhibits protein synthesis • G1 phase specific • Toxicity includes induction of an anaphylactic reaction, pancreatitis and hepatotoxicity

  25. F). Platinum Co-ordination Complexes • Cis-platinum: inhibits DNA synthesis • Dse limiting toxicity: nephrotoxicity • Use of diuretics • Contraindications: in cats due fatal pulmonary vasculitis • Carboplatin is better tolerated than Cis-platinum

  26. G). Corticosteroids • Incorporated in cancer chemotherapy protocols: are cytotoxic • CCNS • Metabolized in the liver and excreted in urine • Dose limiting toxicity: immunosuppression & git toxicity.

  27. H). Miscellaneous Agents • i).Hydroxyurea • S phase specific • Excreted unchanged in urine • Dose limiting toxicity: bone marrow depression

  28. ii). Procarbazine • CCNS (a potent carcinogen and teratogen) • Well absorbed following oral adm. • Leads to DNA damage via incr. generation of reactive free radicals • A MAOI: hence containdicated in patients taking tricyclics; sympathomometic amines and tyramine cont. foods • Dose limiting toxicity: myelosuppression

  29. Brainy quote • Thomas Carlyle Quote: Permanence, perseverance and persistence in spite of all obstacles, discouragement, and impossibilities: It is this, that in all things distinguishes the strong soul from the weak” (Thomas carlyle-1795-1881, Scottish Historian and essayist, Leading figure in the Victorian Era)

More Related