Medical Pharmacology Chapter 33:  General Principles: Chemotherapy

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General Principles of Chemotherapy

Many of the same basic principles apply to antimicrobial, antiparasitic and anticancer chemotherapy.

 

Selective Toxicity:

Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 723.

 

Chemotherapeutic Drug Targets

Targets for Antimicrobial/Antiviral Drugs

  • Bacterial Cell Wall Synthesis Inhibitors

  • Agents that Increase Cell Membrane Permeability

  • Protein Synthesis Inhibitors: interfere with 30S or 50S bacterial ribosome function

 

  • Drugs that Bind to the 30S bacterial ribosomal subunit, leading to cell death

  • Agents that interfere with nucleic acid synthesis

  • Antimetabolites

  • Inhibitors of Viral Replication

 

Bacterial cell wall synthesis inhibitors:

  •  Penicillins

  •  Cephalosporins

  •  Cycloserine

  •  Vancomycin (Vancocin)

  •  Bacitracin

  •  Miconazole (Monistat)(imidazole antifungal)

  •  Ketoconazole (Nizoral)(imidazole antifungal)

  •  Clotrimazole (Mycelex)(imidazole antifungal)

Agents that increase cell membrane permeability

  • Polymixins (detergent)

  • Colistimethate (detergent)

  • Nystatin (Mycostatin)(polyene antifungal)

  • Amphotericin B (Fungizone, Amphotec)(polyene antifungal)

 

Protein synthesis inhibitors: interfere with 30S or 50S bacterial ribosome function.

Bacteriostatic

  • Chloramphenicol (Chloromycetin)

  • Tetracyclines

  • Erythromycin estolate (Ilosone)

  • Clindamycin (Cleocin)

Drugs that bind to the 30S bacterial ribosomal subunit, leading to cell death.

Bacteriocidal

  •   Aminoglycosides (e.g.gentamicin (Garamycin), tobramycin (Nebcin))

 

Agents that interfere with nucleic acid synthesis

  • Rifamycins (rifampin (Rimactane)): inhibits DNA-dependent RNA polymerase

  • Quinolones: inhibit gyrase

Antimetabolites

  • Sulfonamides

  • Trimethoprim (generic)

 

Some Nucleic Acid Analogs (Antivirals): inhibitors of viral replication

  • Zidovudine (Retrovir, AZT, azidothymidine)

  • Ganciclovir (DHPG, Cytovene)

  • Vidarabine (Vira-A)

  • Acyclovir (Zovirax)

Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1029-1030

 

Disease caused by bacteria and the the role of the host response in outcome of chemotherapeutic intervention

 

Importance of Host Response

Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1994, p. 592.

Disease Manifestations of Bacterial Disease

Toxin Elaboration

  • Clinicial manifestation of some bacterial infections are primarily due to toxin elaboration.

    • For example:  Botulinum toxin: C. botulinum, Tetanus toxins: C. tetani, Diptheria toxin causes the disease due to infection with C. diphtheriae

  • Some specific aspects of bacterial disease are caused by elaborated toxins.

    • Enterotoxins cause the diarrhea associated with E. coli, Salmonella, Shigella, Staphylococcus and V. cholerae.

    • Toxins involved in Toxic shock syndrome caused by Staphylococci, steptococci, P. aeruginosa and Bordatella: include: Toxic shock syndrome toxin (TSST), erythrogenic toxin, exotoxin A and pertussis toxin.

    •  Staphylococcal enterotoxins, TSST-1 and streptococcal exotoxins have been classified as superantigens which are capable of inducing certain T cell proliferation without processing of the protein toxin by antigen-presenting cells. 

      • This process involves, in part, the elaboration of IL-1 and TNF-alpha which may cause many clinical features seen in staphylococcal toxic shock syndrome, scarlet fever, streptococcal toxic shock syndrome.

Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 855.

 

  • Endotoxins (lipid A portion of gram-negative LPS) may cause many clinical presentations seen in gram-negative bacterial sepsis: Toxins involve include: IL-1 and TNF-alpha--

    • Clinical presentations include:fever, intravascular coagulation, shock, and muscle proteolysis. 

Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 855.

Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1994, p. 592.

Pharmacokinetic barriers that reduce the effectiveness of treatment

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Mechanisms for chemotherapeutic drugs resistance

How Bacteria Acquire Resistance

Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1031.

Microbial Resistance and Specific Drugs

Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.

Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.

Clinical indications and rationale for the use of multiple drugs at the same time (combination chemotherapy)

Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 862.

 Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 862.

 

Rationale for chemoprophylaxis

Chemoprophylaxis

Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1049-1050

 
 
 

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