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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)

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Tetracyclines

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  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)

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