Chemotherapy

Chemotherapy Inhibitors of Cell Wall Synthesis Penicillins                Amide derivatives of 6-aminopenicillanic acid -Lactam antibiotic (blocks transpeptidation in periplasmic space) Also: ()’s murein hydrolases that degrade existing cell wall Used primarily for Gram  Extremely high CTI (especially for Gram) Adverse: few (even at high doses) PO, IV, IM Only crosses BBB in inflammation from meningitis -Lactamase resistance: Naficillin, Oxacillin, Cloxacillin, Methcillin Penicillin G: IM dose “depot” for 3 to 4 weeks Probenicid-sensitive urinary excretion Naficillin is the only one primarily cleared by biliary secretion Penicillin G & V: Gram+ Ampicillin & Amoxicillin: Broad spectrum (including Gram) Carbenicillin, Piperacillin & Ticarcillin: “Extended spectrum” (including Proteus, Pseudomonas and, for Piperacillin, Klebsiella) Benzyl Penicillin (Penicillin G) Benzathine Penicillin G Phenoxymethyl Penicillin (Penicillin V) Nafcillin Oxacillin Cloxacillin Ampicillin Amoxacillin Carbenicillin Indanyl Ticarcillin Mezlocillin Piperacillin Methcillin Mezocillin UTI Treatment  Penicillins  Cephalosporins  Sulfonamides  Nalidixic Acid  Nitrofurantoin Cephalosporins -Lactam antibiotic (acts in periplasmic space) Broader spectrum than the penicillins, but less useful IM, IV but poor oral absorption Not degraded by Penicillinase, but are Cephalosporinase sensitive (both are -Lactamases) Later generation   Gram activity (but  Gram activity),  Adverse effects,  Toxicity,  Cephalosporinase susceptibility  Only 3rd & 4th Generation penetrate CNS      1st Generation Cefadroxil Cephalothin Cephalexin Cefazolin 2nd Generation Cefoxitin Cefaclor Cefotaxime Cefuroxime 3rd Generation Ceftriaxone Ceftazidime Moxalactam Cefepime Cefotaxime 4th Generation Cefepine Other -Lactams  Monobactams are monocylic  Carbapenems are bicylic Monobactams Aztreonam Carbepenems Imipenam Meropenem (as opposed to bicyclic penicillins & cephalosporins)  effective against Gram (Serattia & Pseudomonas)  Imipenam is hydrolyzed by renal dipeptidases (co-administer Cilastatin to () the dipeptidase)  Meropenam is a newer, dipeptidase-resistant Carbapenem  Broad spectrum  -Lactamase resistance Clavulanic acid  Clavulanic Acid ()’s -Lactamases Other ICWS  Vancomycin  ()’s peptidoglycan synthesis  intracellular (rather than periplasmic)  not absorbed so PO administration for GI infection is essentially topical  Gram  “Red Man Syndrome” - histamine release with diffuse flushing  ()’s peptidogylcan synthesis  intracellular (rather than periplasmic)  Gram  only topical use (nephrotoxicity) Vancomycin Bacitracin Cycloserine  Bacitracin Membrane-Active Antibacterials  Cationic detergents that permeabilize the membrane  Gram most susceptible  No Systemic use (nephrotoxicity), only topical, joint or pleural infusion Polymixin B Colistmethate Inhibitors of Protein Synthesis Aminoglycosides      Irreversibly () ribosomes by binding the 30S Only IPS that are “universally bactericidal” Powerful agents, particularly against Gram IM, IV; enters CNS & Eye; Freely filtered Resistance (thus bactericidal) Streptomycin Kanamycin Neomycin Gentamicin Tobramycin Amikacin Netilmycin  Altered Uptake: cells have O2-dependent active uptake system; alteration  resistance (Strict Anaerobes & Facultative Anaerobes in anaerobic condition are resistant)  Altered Target: altered ribosome  Increased Metabolism: conjugates & removes aminoglycosides MOST IMPORTANT      Coadministration with Penicillin to stop resistance Adverse: ototoxicity & nephrotoxicity & rarely neuromuscular blockade Streptomycin: widespread resistance; used in life-threatening TB Kanamycin & Neomycin: topical Amikacin & Netilmycin: less resistance Page 1 of 7 11/7/2009 Milton Wolf Tetracyclines       Reversibly ()’s ribosomes by binding 30S (thus bacteriostatic) Broad spectrum particularly Mycoplasma, Chlamydia, Rickettsiae (Lyme Disease) Affinity for Ca++ & other divalent metals (plus Al+++) Good distribution (except CNS & Synovium) Renal & Hepatic clearance (exception - Doxycycline is entirely hepatic) Adverse: GI upset (irritant & superinfection), hepatotoxicity, renal toxicity, teeth & bone deposition, photosensitivity Tetracycline Chlortetracycline Oxytetracycline Doxycycline Minocycline Macrolides        Derivatives of Macrocylic Lactones Reversibly binds 50S subunit ()’s peptide bond formation Good distribution (except CNS) Resistance: plasmid-mediated methylation of rRNA on 50S or hydrolysis () some Cytochrome P450 isozymes (digoxin, terfenidine, anti-coagulant toxicity) Gram  Used in penicillin-resistant infections, plus Corynebacterium, Chlamydia, Mycoplasma, & Legionnaire’s  Adverse: GI upset, Hepatotoxicity - Cholestatic Jaundice(especially with Erythromycin Estolate), () certain CP450 enzymes: oral anticoagulants, oral digoxin, terfenidine  Newer Macrolides (Clarithromycin & Azithromycin): better PO. longer half life, active against MAC in AIDS Erythromycin base Erythromycin esters Clarithromycin Azithromycin Other Inhibitors of Protein Synthesis  Spectinomycin: bacteriostatic ()er of protein synthesis  Clindamycin: bacteriostatic ()er or protein synthesis  Chloramphenicol  binds 50S at same (or close) site as Erythromycin  pseudomembranous colitis from Clostridium difficile  broad spectrum bacteriostatic ()er of protein synthesis (binds 50S)  enters CNS (CNS levels = Serum levels)  extensive host metabolism  Resistance: plasmid-mediated acetylation by CAT (Cloramphenicol Acyl Transferase), also rarely diminished uptake  Adverse: aplastic anemia, Gray Baby Syndrome (since they lack the liver enzymes for glucuronidation)  ()’s Cytochrome P450  used in penicillin-resistant gonorrhea (but related to aminoglycosides) Spectinomycin Chloramphenicol Clindamycin Inhibitors of Nucleic Acid Synthesis & Other Synthetic Antibacterials Sulfonamides                 PABA analogs (bacteriostatic, blocks folate synthesis for purines) Broad Spectrum (common for uncomplicated UTIs) PO, Ophthalmic, Topical, rarely IV Enter CNS & cross Placenta Significant Host Metabolism Resistance: bacteria  levels of PABA (also  permeability or mutated dihydropteroate synthase enzyme) Adverse: allergic, Stevens-Johnson Syndrome (fever, malaise, erythema multiforma, mucosal ulceration), Hemolytic Anemia in G-6-P DH deficiency Silver Sulfadiazine (Silvadene): topical for burns Sodium Sulfacetamide: topical conjunctivitis Sulfasalazine: split by bacteria in GI to sulfonamide & amino salicylate (an antiinflammatory for IBD) Co-trimoxazole: TMP-SMX Dihydrofolate Reductase Inhibitor: blocks Dihydrofolate  Tetrahydrofolate PO Host also has Dihydrofolate Reductase (but low affinity) Adverse: Megaloblastic anemia, Leukopenia, Granulocytopenia Any labile cell can be a target Treat adverse effects with Folinic Acid already at Tetrahydrofolate level + bacteria don’t take it up Quinolone Nalidixic acid Fluorquinolones Ciprofloxacin (Cipro) Norfloxacin Ofloxcin Sulfisoxazole Sulfacytine Sulfamethoxazole Sulfasalazine (salicylazosulfapyridine) Sodium sulfacetamide Mafenide Silver sulfadiazine (Silvadene) Co-trimoxazole is a TMP-SMX Dihydrofolate Reductase Inhibitors Trimethoprim DNA Gyrase Inhibitors  DNA Gyrase aka Topoisomerase II  Nalidixic Acid: Gram, extensive host metabolism & urinary excretion  UTIs  Fluoroquinolones: Gram & , less metabolism and  more systemic use (Probenicidsensitive excretion)  Cipro Adverse:  Theophylline levels  toxicity  Resistance: not yet a problem (these are new drugs) Nitrofurantoin  Rapidly cleared only for UTIs (Gram or )  Mechanism: reactive oxygen species?  Resistance: all Pseudomonas and some Proteus Nitrofurantoin Milton Wolf Page 2 of 7 11/7/2009 Antimycobacterial Agents Tuberculosis Overview      Long dormant periods with acute symptomatic flare ups Intracellular Tx: 6-9 months (simple cases); up to 2 years (Tb meningitis or miliary) Combination Therapy due to rapid resistance 1st Line: more selective preferred unless resistant 1st Line Isoniazid Ethambutol Rifampin Pyrazinamide Streptomycin 2nd Line Cycloserine Ethionamide Para-aminosalicylic Acid Isoniazid (INH)        most frequently used ()’s synthesis of mycolic acid (growing cells only) - bactericidal Tx: multi-drug / Chemoprophylaxis: INH alone CNS level about 20% of serum level Liver metabolism: slow acetylator (3 hr) & fast acetylator (1.5 hr) Resistance: loss of catalase & peroxidase; widespread seldom used alone Adverse: hepatotoxicity (especially the elderly), neuropathy (reversed by Vitamin B 6, pyridoxine), optic neuritis Capreomycin Dapsone Ethambutol      Concentrated in RBCs (depot for continuous release) CNS level close to serum level Mechanism: unknown ()er of polyamine synthesis? Used in combination (high resistance) Adverse: optic neuritis (loss of red-green differentiation) Rifampin        ()’s RNA synthesis: binds DNA-dependent RNA Polymerase Also bactericidal for Gram & Gram cocci & Chlamydia CNS level about 40% of serum level Hepatic metabolism Resistance: permeability or binding site mutations (common combo therapy) Orange discoloration of tears, sweat, urine, saliva ()’s Cytochrome P450 Pyrazinamide     Bacteriostatic Hepatic metabolism Resistance common combo therapy Adverse: Gout (doesn’t respond to Probenicid), Hepatotoxicity Para-aminosalicylic Acid (PAS)  ()’s dihydropteroate synthetase of only tubercle bacilli  Adverse: GI symptoms, hypersensitivity (opposite of sulfonamides) Ethionamide  INH anolog  ()’s mycolic acid synthesis  Adverse: GI symptoms Cycloserine  ()’s alanine racemase  Adverse: CNS toxicity, psychosis Leprosy Dapsone     most commonly used hepatic metabolism / renal clearance effective against Mycobacterium leprae & Pneumocystis carinii Adverse: hemolytic anemia in G6P DH deficient people, methemoglobin Dapsone Rifampin Milton Wolf Page 3 of 7 11/7/2009 Anti-Fungals Amphotericin B        Broad spectrum Binds Ergosterol   Permeability (Fungicidal) Systemic via IV; PO is topical for GI Widespread, except CNS (requires intrathecal) Resistance:  uptake Adverse: fever, chills, nausea, headache, nephrotoxicity, hepatotoxicity, anemia (“amphoterrible”) Flucytosine coadministered to delay resistance (plus allows lower doses of Amp B) Polyenes Amphotericin B Nystatin Nystatin  Binds Ergosterol  Topical only (PO is topical for GI) Flucytosine               Fungistatic Cytosine analog (anti-metabolite) Target cell converts it to 5-Fluorouracil  ()’s DNA synthesis PO is absorbed, distributes to all tissues (including CNS) Renal clearance Adverse: not much Rapid resistance Antimetabolite Flucytosine Azoles () Fungal Cytochrome P450-dependent ergosterol synthesis (Fungistatic) No known resistance Clotrimazole: topical Miconazole: topical & IV; excreted in bile Ketoconazole: systemic (absorbed PO); excreted in bile Fluconazole: systemic (absorbed PO) & IV; excreted in urine Adverse: ()’s host CP450, liver enzymes Ketoconazole Adverse: rare hepatotoxicity,  serum levels of cyclosporine, terfenadine, Gynecomastia, Thrombophlebitis, Anaphylaxis  Fluconazole Adverse:  serum levels of phenytoin, cyclosporine  Miconazole Adverse: GI upset,  Warfarin & Coumarin activity Azoles Ketoconazole Miconazole Itraconazole Miconazole Clotrimazole Griseofulvin     ()’s nucleic acid synthesis or microtubule formation PO administration for topical infections Concentrated in keratin Ringworm & Athlete’s Foot Adverse: Headaches & GI upset Griseofulvin Anti-Parasitics Anti-Malarials Overview  Plasmodiium Life cycle: Anopheles mosquito  sporozoites to liver  tissue schizonts  RBCs  gametocytes  P. falciparum & P. malariae: one 4 week cycle; Tx w/ blood schizonticide  P. vivax & P. ovale: maintain dormant tissue schizonts in liver  mosquito Quinolines Chloroquine Mefloquine Primaquine Antifolates Pyrimethamine Fansidar Chloroquine        Blood Schizonticide Most commonly used agent Concentrated in RBCs (especially infected RBCs) Combined with Primaquine for P. vivax & P. ovale Prophylactic Tx for travelers Resistance widespread: pump out the drug Adverse: GI upset, headaches, retinopathy, myopathy, ototoxicity, hypotenstion, cardiac arrest Mefloquine  Blood Schizonticide  Prophylaxis or Chloroquine-resistant pts. Primaquine  Tissue Schizonticide (only one)  Combined with Chloroquine  Adverse: Hemolytic Anemia in G6PDH-deficient pts., GI upset, headaches, pruritus Pyrimethamine     Blood Schizonticide Dihydrofolate reductase inhibitor All species (especially for Chloroquine resistance) Fansidar: Pyremethamine + Sulfadoxine Page 4 of 7 11/7/2009 Milton Wolf Anti-Protozoals Metronidazole         Nitroimidazole Mechanism: reduced by protozoan  redox cycling  oxidative damage Indications: Trichomoniasis, Giardiasis, Amebiasis, some anaerobic bacteria PO absorbed + IV Enters CNS Renal clearance Adverse: nausea, headache, dry mouth Disulfiram-effect Metronidazole Pentamidine Trimethoprim-sulfamethoxazole Pyrimethamine-sulfonamide Diloxanide Furoate Pentamidine       Diamidine Mechanism: unkown (maybe ()’s protein, nucleic acid or phospholipid synthesis) Indications: Pneumocystitis (prophylaxis or Tx) IM or Aerosol (not absorbed PO) Does NOT enter CNS (but does cross placenta) Adverse: mast cell degranulation  hypotension, Pancreatic  cell toxicity  initial hypoglycemia, hepatotoxicity, nephrotoxicity Anti-Helminthics Mebendazole      Benzimidazole Mechanism: ()’s microtubule synthesis Indications: Pinworm, Hookworm, Ascariasis PO (but only 10% absorbed) limited to luminal infections Renal excretion Mebendazole Thiabendazole Praziquantel Pyrantel pamoate Thiabendazole     Mechanism: ()’s microtubule synthesis (may also () fumarate reductase) PO (rapidly absorbed) Liver metabolism / Renal excretion Adverse: GI upset, rare hepatotoxicity Praziquantel      Mechanism:  Ca++ permeability into helminth  contraction, paralysis  death Indications: Schistosomiasis & others PO (80% bioavailability) Liver metabolism / Renal excretion Adverse: GI upset, headache Pyrantel Pamoate     Mechanism: ()’s ACh release in helminth  depolarizing neuromuscular blockade Indications: Ascaris & Pinworms PO (poorly absorbed) limited to luminal infections Adverse: GI upset, headache, rash, fever Anti-Virals Inhibitors of Viral Uptake     Mechanism: ()’s viral absorption & uptake Indications: Influenza A (Tx & prophylaxis within 48 hrs) & Rubella PO Adverse: insomnia, nervousness, depression, drowsiness Nucleoside Analogs Ribavarin Vidarabine Acyclovir Ganciclovir Foscarnet Amantadine Inhibitors of Nucleic Acid Synthesis  Ribavarin  Nucleoside analog  Mechanism: Blocks GTP formation in DNA & RNA viruses  Indications: RSV, Influenza A & B  Aerosol  Purine Nucleoside analog  Mechanism: ()’s DNA synthesis via DNA Polymerase  Indications: Herpes, Varicella Zoster  Purine (Guanosine) Nucleoside analog  Mechanism: chain terminator & DNA polymerase inhibitor  Must be phosphorylated by thymidine kinase  Safest & most widely used ant-viral  Indications: Herpes (HSV1 > HSV2)  Resistance: Thymidine-deficient viruses  Vidarabine  Acyclovir Milton Wolf Page 5 of 7 11/7/2009  Ganciclovir  Purine (Guanosine) Nucleoside analog  Mechanism: ()’s DNA polymerase  Must be activated by thymidine kinase but the final phosphorylation is by cellular enzymes  Indications: CMV (some resistance)  Adverse: neutropenia, anemia, eosinophilia, headache  Foscarnet  also used in CMV HIV Treatment Reverse Transcriptase Inhibitors  Zidovudine (Azidothymidine, AZT)  Thymidine Nucleoside analog  Mechanism: ()’s Reverse Transcriptase  CNS level about 60% of serum level  Rapid glucuronide urine secretion  Indications: HIV  Adverse: bone marrow depression, headaches, insomnia (enhanced by acetaminophen & trimethoprin)  Purine Dideoxynucleoside Analog  Mechanism: ()’s Reverse Transcriptase  AZT-resistant strains  Adverse: peripheral neuropathy, pancreatitis (less toxic than AZT)  Often mixed with ddC & d4T as “cocktails” or sequentially Reverse Transcriptase Inhibitors Zidovudine (Azidothymidine, AZT) Didanosine (ddI) Stavudine (d4T)  Didanosine (ddI) Protease Inhibitors      ()’s HIV’s Aspartyl Protease Co-administration with the RTase Inhibitors Prevents resistance to the RTase Inhibitors Does not enter the CNS (like AZT) so AIDS Dementia is likely Promising results:  CD4 count &  viral load Protease Inhibitors Saquinavir Ritonavir Indinavir Cancer Chemotherapy Alkylating Agents Overview  CCNS  Mechanism: covalent modification of DNA  abnormal base pairing, blocked transcription or replication, loss of bases, etc.  Metabolism: Parent - inactive / Metabolite - active (except Mechlorethamine)  Resistance: Primarily by pumping out the drug by P-Glycoprotein (PGP); Also: DNA repair,  permeability,  trapping agents (eg. Thiols)  Adverse (any labile cell): Nausea & Vomiting (may be central and limited by Ondansetron, a serotonin antagonist), Alopecia, BM suppresion, Gonads, 2 Malignancy (unique to alkylating agents) Bis(chloroethyl)amines (Nitrogen Mustards) Cyclophosphamide Mechlorethamine Melphalan Nitrosoureas Carmustine Lomustine Alkylsulfonates Busulfan Platinum Complexes Cis-platin Hydrazine Procarbazine Nitrogen Mustards  Mechlorethamine: Half-life only a few minutes (metabolite inactive) injected into artery that feeds tumor (all others have active metabolites)  Adverse: caustic to skin & mucous membranes  Cyclophosphamide: Broad spectrum (including solid tumors) MOST USEFUL NITROGEN MUSTARD  Adverse: hemorrhagic cystitis MOPP Treatment for Hodgkin’s Disease 1. Mechlorethamine 2. Oncovin (Vincristine) 3. Procarbazine 4. Prednisone Nitrosoureas  Cross BBB  Brain Tumors Cis-Platin     Bifunctional: causes DNA crosslinking & ()’s DNA synthesis Binds via platinum atom Broad spectrum (including solid tumors) Adverse: Renal Toxicity (but not BM suppression) Procarbazine  Blocks DNA & RNA synthesis  Adverse: strongly Leukemogenic & Teratongenic Antimetabolites      CCS () DNA synthesis Used in combination with CCNS agents Adverse: bone marrow suppression Methotrexate  ()’s Dihydrofolate Reductase (DHFR)  Blocks Thymidine, Purines, Amino Acids (Indirect DNA Inhibition)  PO or Intrathecal  Resistance:  drug accumulation, changes in DHFR,  DHFR synthesis  Adverse: GI ulceration  PO  Activated to nucleotide by HGPRTase  Resistance:  HGPRTase activity or  levels of alkaline phosphatase Folic Acid Antagonists Methotrexate Purine Antagonists 6-Mercaptopurine 6-Thioguanine Pyrimidine Antagonists 5-Fluorouracil Cytarabine Gemcitabine  Purine Antagonists  5-Fluorouracil Milton Wolf Page 6 of 7 11/7/2009  Cytarabine  Activated to nucleotide by 5-FdUMP  ()’sThymidylate Synthase  Resistance:  5-FdUMP activity,  Thymidylate Synthase or alterations  Adverse: more toxic than the Purine Antagonists  Phosphorylated to active form  ()’s DNA Polymerases in S phase  Resistance:  uptake or  phosphorylation Plant Alkaloids     CCS Natural products IV Vinca Alkaloids  CCS (Metaphase Arrest)  Bind Tubulin  () Microtubule formation for Mitotic Spindle  Vinblastine: Testicular, Breast, Lymphomas  Vincristine: Leukemias, Lymphomas (HD & NHL), some solid tumors  Bile Excretion  Adverse: Neurotoxicity  Vincristine less like to suppress bone marrow than Vinblastine  CCS (late S to early G2)   DNA degradation (primarily via topoisomerase II inhibition - aka DNA Gyrase)  Small Cell Lung CA, Lymphomas, Acute Leukemias, Testicular  Urine Excretion  CCS (M phase)  Stabilizes Mitotic Microtubules  cells stuck in Metaphase  Breast, Ovary; Also: Lung, Head, Neck  Extensive Hepatic metabolism / Bile Excretion  Adverse: bone marrow suppression & neuropathy Vinca Alkaloids Vinblastine Vincristine Podophyllotoxins Etoposide (VP-16) Teniposide (VM-26) Other Paclitaxel (Taxol) Taxotere  Etoposide  Taxol  Resistance: removal by plasma membrane drug transporter Antibiotics        Natural products Mechanism: intercalate between DNA base pairs  ()’s DNA & RNA synthesis Also: strand breaks 2 to free radicals or topoisomerase II inhibition Only parenterally (particularly IV) Mitomycin - bladder infusion Resistance: active transport out of cells Adverse: bone marrow suppression, GI, alopecia Bleomycin  CCS (the only CCS antibiotic)  also chelates iron  generates free radicals  testicular CA (mixed with Vinblastine & Cis-platin)  adverse: irreversible pulmonary fibrosis  CCNS  intercalates between GC pairs  ()’s RNA synthesis, but not much DNA  CCNS  reduced to an alkylating agent  Unique in that it is particularly effective against solid tumors: cervix, stomach, pancreas, lung, bladder, colon  bladder infusion for papillomas  adverse: long-term BMS  CCNS  Dox: Broad Spectrum: solid, leukemias, lymphomas  Naun: Narrow Sprectrum: acute leukemias  Adverse: Cardiotoxicity Dactinomycin Daunorubicin Doxorubicin Bleomycin Mitomycin C  Dactinomycin  Mitomycin  Doxorubicin & Daunorubicin Hormones & Hormone Antagonists  More selective, less toxic treatment  Prednisone  Estrogens  ()’s lymphocyte proliferation  CLL, Lymphomas (HD & NHL)  Prostatic CA Hormones Prednisone Estrogens Diethylstilbestrol (DES) Modulation Of Hormone Release And Action Aminoglutethimide Leuprolide Acetate Tamoxifen Flutamide  Androgens  Aminoglutethimide  Leuprolide  ()’s Aromatase   estrogen levels  Breast CA  GnRH analog  ()’s LH & FSH release   androgen levels  Prostatic CA  Estrogen antagonist  Breast CA  Androgen antagonist  Breast CA  Tamoxifen  Flutamide Milton Wolf Page 7 of 7 11/7/2009