RHS Pharm Review (Chemo + Antimycobacterials + Anemia) PDF

Lecture #23 (Chemotherapy 1: Antimetabolites) Indications Primary = Disseminated + Not Amenable by Surgery Adjuvant = Micrometastases following Surgery + Radiation Neoadjuvant = Prior to Surgery to Shrink Cancer TXT Regimens given dose of drug destroys a constant fraction (1st order) = "lo...

Lecture #23 (Chemotherapy 1: Antimetabolites) Indications Primary = Disseminated + Not Amenable by Surgery Adjuvant = Micrometastases following Surgery + Radiation Neoadjuvant = Prior to Surgery to Shrink Cancer TXT Regimens given dose of drug destroys a constant fraction (1st order) = "log kill" ◦ 1 log kill -> reduced by 90% ◦ 2 log kill = 99% (3 log kill = 99.9%) Leukemia Diagnosis = 10^9 Leukemic cells ◦ Clinical Remission ‣ = 5-log kill = 99.999% w/ symptom improvement ‣ still 10^4 cells left (.0001% of 10^9) Bacterial Infections ◦ 3-log kill (not as difficult as tumor cell elimination) TXT Protocols Drug Combo Large Growth Fraction Rapidly Dividing Neoplasm Cell-Cycle Nonspecific Drugs cycling or resting in the G0 compartment cycling more sensitive ◦ S/M phases > G phases Clinically ◦ low growth fraction solid tumors ◦ high growth-fraction tumors Cell-Cycle Specific Drugs Clinically ◦ hematologic malignancies ◦ tumors w/ large growth fraction Drug Resistance Primary ◦ displayed on first exposure Acquired ◦ Single-Drug ‣ increased expression of 1+ genes ◦ Multi-Drug ‣ occurs after exposure to a single agent ‣ overexpression of membrane efflux pumps P-glycoprotein Drug Toxicity narrow therapeutic window compared to antimicrobial drugs ◦ often causes variable toxicity due to effect on normally rapidly dividing cells ‣ Buccal Mucosa + Marrow + GI Mucosa + Hair Cells Adverse Effects (Common) ◦ Severe Vomiting + Stomatitis + Marrow Suppression + Alopecia ◦ Tumor Lysis Syndrome (Emergency) ‣ via rapid cell death ‣ mainly seen in Leukemia or Lymphoma pxts ‣ Manifestations Hyperuricemia + Hyperkalemia + Hyperphosphatemia Hypocalcemia ◦ (due to precipitation of calcium phosphate). Uric acid + Calcium Phosphate crystals ◦ may precipitate in the kidney --> renal failure ‣ Management IV hydration w/ normal saline + Allopurinol or Rasburicase (allantoin) Prevention/Management of CINV 5-HT3 antagonist = Ondansetron NK-1 antagonist = Aprepitant Corticosteroid = Dexamethasone Adjunct therapy = Benzodiazepines ◦ Lorazepam or Alprazolam TXT-Induced Tumors Most CT drugs are mutagens (Especially Alkylating Agents) may arise 10 or more years after the original cancer was cured Antimetabolites Overview ◦ cycle-specific structural analogs of purines, pyrimidines or folate cofactors ◦ pathways related to nucleotide + nucleic acid synthesis ◦ most are prodrugs (undergo modification within the cell -> active) ◦ Maximal cytotoxic effects are in the S-phase Folate Analogs ◦ Methoxetrate (MTX) ‣ Inhibits dihydrofolate reductase -> deprives folate ‣ synthesis of dTMP + purine nucleotides decrease ‣ Metabolism undergoes conversion to a series of polyglutamates (MTX- PGs) ◦ via folylpolyglutamate synthase (FPGS) PGs ◦ strongly charged and cross cellular membranes poorly ‣ polyglutamation serves as a mechanism of ion trapping within cell ‣ Adverse Effects Common ◦ Stomatitis ◦ mucositis, ◦ myelosuppression ◦ alopecia ◦ nausea/vomiting Renal Damage (uncommon, high-dose) Hepatic Fibrosis/Cirrhosis Pneumonitis Neurological toxicity w/ IT administration ◦ Purine Analogs  ◦ Pyrimidine Analogs Leucovorin (N5-formyl-THF) Antidote to drugs that decrease levels of folic acid (MTX) ◦ rescues marrow provides the normal tissues with the reduced folate ◦ circumventing the inhibition of DHFR selectively rescues normal but not malignant cells ======================================================== ======================================================== Chemo L2 Antimetabolites FOLATE ANALOGS PURINE ANALOGS ◦ Thiopurines (6-MP + 6-TG) ‣ partially metabolized by the enzyme thiopurine methyltransferase (TPMT) weak TPMT activity -> severe toxicity (myelosuppression) ◦ higher risk in L phenotype (vs. H) ‣ 6-MERCAPTOPURINE (6-MP) Thiol analog of hypoxanthine MOA ◦ Converted to the nucleotide analog thio-IMP (TIMP) by salvage pathway enzyme HGPRT ‣ TIMP inhibits first step of de novo purine synthesis + blocks formation of AMP and GMP from IMP is methylated by TPMT to MeTIMP (inhibits DNPurS) is converted to thioguanine nucleotides (incorporated into DNA/RNA -> dysfunctional) AE = N/V/D + BM Suppression + Hepatotoxicity Drug Interactions ◦ metabolized to thiouric acid by xanthine oxidase ◦ Allopurinol (dose must be decreased to avoid  accumulation) ‣ 6-THIOGUANINE (6-TG) Thiol analog of guanine MOA ◦ 6-thioGMP (TGMP) via HGPRT ◦ TGMP ‣ inhibits purine synthesis/ conversion of IMP -> GMP ◦ 6-TG nucleotides (dysfunctional RNS/DNA) Clinically ◦ for acute nonlymphocytic leukemias Drug Interactions = Allopurinol does not potentiate 6-TG action ◦ same toxicities as 6-MP PYRIMIDINE ANALOGS ◦ 5-Fluorouracil ‣ MOA Converted to deoxyribonucleotide 5-FdUMP ◦ 5-FdUMP inhibits thymidylate synthase as ternary complex (enzyme/substrate/cofactor) --> Thymineless death ‣ cofactor = N5, N10-methylene-THF also converted to 5-FUTP + incorporated into RNA ‣ Metabolism dihydropyrimidine dehydrogenase (DPD) ◦ deficiency (5% of pxts) -> severe toxicity ‣ myelosuppression + neurotoxicity ‣ fatal/severe diarrhea ‣ Potentiation by Leucovorin increases cofactor levels (N5, N10-methylene-THF) Clinically ◦ 5-FU/leucovorin combo = colorectal cancer ‣ AE = N/V + Alopecia + BM Depression + Hand-Foot Syndrome H-F Syndrome = erythematous desquamation of palms/ soles ◦ extended infusions  ◦ Cytarabine (ARA-C) ‣ Analog of deoxycytidine. ‣ Phosphorylated to trisphosphate + Incorporated into DNA --> Inhibits DNA polymerase. ====== ANTITUMOR ANTIBIOTICS (Important Drugs) Bind to DNA via intercalation between bases: ◦ blocks synthesis/replication of new RNA/DNA + breaks strands ANTHRACYCLINES ◦ MOA (4 mechanisms) ‣ Inhibition of topoisomerase II ‣ Intercalation in DNA + blockade of synthesis + breakage. ‣ Binding to cell membranes -> alter fluidity + ion transport. ‣ Generation of free radicals (-> cardiac toxicity) ◦ AE = Myelosuppression + Cardiotoxicity ‣ Cardiotoxicity (dose-dependent) dilated cardiomyopathy associated with heart failure TXT = IV Dexrazoxane ◦ DOXORUBICIN (Widely Used) ◦ DAUNORUBICIN BLEOMYCIN ◦ Cell-cycle specific = G2 phase ◦ causes breakage of DNA by oxidative processes (as above) ◦ Mixture of glycopeptides ◦ MOA ‣ DNA-bleomycin-Fe2+ complex -> bleomycin-Fe3+ via oxidation ‣ free electrons react with O2 to form free radicals -> strands break ◦ AE ‣ pulmonary toxicity (pneumonitis, fibrosis) + dose-limiting ‣ very mild myelosuppression ====== ALKYLATING AGENTS cytotoxic effects via transfer of their alkyl groups  Alkylation of DNA -> Death ◦ single strand or both strands through cross-linking (more common) Cyclophosphamide (most used) AE ◦ Toxicities = BM + GIT (N/V) + gonads ◦ mutagenic + carcinogenic === Nitrogen mustards ◦ Mechlorethamine (unstable) ‣ Powerful vesicant given IV ‣ replaced by cyclophosphamide + melphalan (more stable) ‣ AE Severe (N/V + BM Depression) +Alopecia+Immunosuppression ◦ Cyclophosphamide (most used/esp in combo txt) ‣ Activated by CYP2B + Oral/IV + Broad Spectrum + Prodrug ‣ AE N/V + BM Depression + Alopecia + Sterility Hemorrhagic Cystitis (specific) via Acrolein metabolite ◦ prevented by adequate fluid intake ◦ parenteral administration of mesna (sulfhydryl to bind it) ◦ Ifosfamide ‣ Analog of cyclophosphamide + Infused IV ‣ Activated via hydroxylation by CYP3A4 (liver) ‣ Adequate hydration and mesna permit its use ‣ AE Greater platelet suppression, neurotoxicity, and urinary tract toxicity than cyclophosphamide High-dose = severe neurotoxicity (hallucinations/coma/ death) ◦ Melphalan ‣ AE = BM Suppression === Nitrosoureas (CARMUSTINE & LOMUSTINE) ◦ Very lipophilic + Cross the blood-brain barrier -> brain tumours ===  Other Alkylating Agents ◦ BUSULFAN ‣ AE = Pulmonary Fibrosis + Myelosuppression ◦ DACARBAZINE ‣ IV Prodrug + Methylating agent ‣ AE = N/V + Myelosuppression ◦ PROCARBAZINE ‣ Converted by liver P450 enzymes to alkylating metabolites ‣ AE NV + BM Depression + Mutagenic + Teratogenic Disulfiram-like reactions Weak MAO Inhibitor -> High BP if given w/ Sympathomimetic or Tyramine-containing foods === Platinum Coordination Complexes (CISPLATIN + CARBOPLATIN) ◦ Do not alkylate DNA (they covalently bind) ◦ Broad antineoplastic activity ◦ Foundational for these Cancers ‣ testicular/ovarian + head/neck + lung ‣ esophagus + bladder + colon ◦ MOA (IV) ‣ Inhibit DNA synthesis + cross-linking ◦ AE (Cisplatin) ‣ N/V + Ototoxicit + Peripheral neuropathy + Myelosuppression ‣ Nephrotoxicity (reduced by hydration and diuresis) TXT = Amifostine ◦ AE (Carboplatin) ‣ Dose-limiting toxicity is myelosuppression ‣ Less nausea + neuro/oto/nephro-toxicity than cisplatin ======================================================== MICROTUBULE INHIBITORS stabilizing (polymerization) or destabilizing (depolymerization) VINCA ALKALOIDS ◦ Natural alkaloids isolated from the Madagascar periwinkle plant ◦ MOA (Destabilizing) ‣ bind to β-tubulin and inhibit its ability to polymerize ‣ --> mitotic arrest in metaphase (division stops -> apoptosis)  ◦ VINCRISTINE (AE) ‣ Peripheral neuropathy (#1) + Alopecia + BM depression ◦ VINBLASTINE (AE) ‣ Myelosuppression (dose-limiting) (#1) ‣ Peripheral neuropathy + Alopecia TAXANES (PACLITAXEL) ◦ alkaloid derived from bark of Pacific ye ◦ MOA (Stabilizing) ‣ bind to the β-tubulin subunit + promote polymerization ‣ --> mitotic arrest in metaphase ◦ AE ‣ myelosuppression + peripheral neuropathy + alopecia ‣ Hypersensitivity (reduced via pre-medications) Dexamethasone + Dipenhydramine + H2 Blocker ======================================================== ======================================================== EPIPODOPHYLLOTOXINS (ETOPOSIDE) Semisynthetic derivative of podophyllotoxin (mandrake plant (may- apple)) MOA ◦ Inhibits topoisomerase II (DNA breaks) + Blocks cell in late S-G2 AE ◦ N/V + Alopecia + Myelosuppression ======= CAMPTOTHECINS (TOPOTECAN + IRINOTECAN) Camptotheca acuminata tree MOA ◦ Inhibits topoisomerase I (DNA breaks) AE ◦ Diarrhea + Myelosuppression ======= HORMONAL AGENTS ======= GLUCOCORTICOIDS (PREDNISONE) ◦ MOA ‣ lympholytic + suppress mitosis in lymphocytes ◦ Clinically  ‣ acute leukemia + malignant lymphomas ======= ESTROGEN INHIBITORS ◦ SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs) ‣ MOA agonists or antagonists (tissue-dependent) ‣ TAMOXIFEN MOA ◦ agonist (non-breast) + antagonist (breast) Metabolism ◦ CYP2D6 -> more potent SERM ‣ Avoid CYP2D6 Inhibitors Bupropion + Fluoxetine + Paroxetine Clinically ◦ Metastatic breast cancer (m/f) ◦ Adjuvant treatment of breast cancer (f) ◦ Preventive agent for breast cancer (f) AE ◦ N/V + Hot Flashes + Fluid Retention ◦ Vaginal Bleeding + Venous Thromboembolism ◦ Endometrial Cancer = ‣ RALOXIFENE MOA ◦ antiestrogen (uterus/breast) ◦ estrogenic (inhibit bone resorption) Clinically (postmenopausal women only) ◦ TXT + PV of osteoporosis ◦ Breast Cancer Prophylaxis for high-risk AE ◦ Hot Flashes + Leg Cramps + DVT ======= ◦ ESTROGEN-RECEPTOR ANTAGONISTS ‣ FULVESTRANT MOA ◦ inhibits receptor dimerization -> degradation ◦ Abolishes ER-mediated Transcription ◦ Zero Agonist Activity (No Shit Sherlock)  Clinically (postmenopausal women only) ◦ hormone receptor positive metastatic breast cancer w/ progression following antiestrogen use ======= ◦ AROMATASE (CYP19A1) INHIBITORS (AIs) ‣ aromatase function (androgen -> estrogen via aromatization) post-menopausal -> primary source of estrogens ‣ MOA low estrogen in post-menopausal -> reduces estrogen- mediated cancer ◦ for hormone receptor-positive (HRP) breast cancer) ‣ Clinically (postmenopausal women only) Adjuvant treatment for HRP Breast Cancer 1st line = metastatic HRP Breast Cancer Advanced Breast w/ Progression after Tamoxifen (SERM) Prevention of Breast in High-Risk (off-label) ‣ ANASTROZOLE + LETROZOLE Reversible + Competitive + Nonsteroidal ‣ EXEMESTANE Irreversible + Steroidal ======== ◦ ANDROGEN INHIBITORS (GOSERELIN + LEUPROLIDE) ‣ GONADOTROPIN-RELEASING HORMONE AGONISTS MOA ◦ Synthetic analogs of GnRH ◦ surge in LH and FSH -> transient increase in circulating gonadal steroids + inhibition of gonadotropin release ‣ if given continuously/depot ◦ Reversible suppression of ovarian/testicular steroidogenesis ‣ Testosterone levels fall to 10% in 1 month increases initially -> tumor flare/symptoms ◦ Flare TXT = Flutamide (symptom relief) Clinically ◦ Advanced prostate carcinoma +/- Flutamide ◦ Advanced breast cancer (Post-MP F) ◦ Mangement of Endometriosis === ‣ ANDROGEN RECEPTOR BLOCKERS MOA ◦ competitively inhibit binding of test + dihydrotest to androgen receptor Clinically ◦ metastatic prostate carcinoma management ‣ (combo w/ GnRH agonists) ◦ 2nd Gen (more potent) is replacing 1st Gen (less potent) First generation: ◦ Bicalutamide + Flutamide + Nilutamide Second generation: ◦ Enzalutamide + Apalutamide + Darolutamide === ‣ ANDROGEN SYNTHESIS INHIBITORS (ABIRATERONE) MOA ◦ Irreversible inhibitor of CYP17A1 -> very low testosterone Clinically ◦ given w/ a GnRH analog ◦ TXT Combo w/ Prednisone for metastatic: ‣ castration–resistant prostate cancer ‣ high–risk castration–sensitive prostate cancer AE (CYP17A1 inhibition) ◦ adrenocortical insufficiency + high BP + low K + fluid retention ‣ Reduced by co-administering prednisone ◦ hepatotoxicity + arrhythmia ======= RECEPTOR TYROSINE KINASE INHIBITORS/Monoclonal Abs Mutations that constitutively activate tyrosine kinases are implicated in malignancy ◦ Gefitinib ‣ Non-small cell lung + EGFR tyrosine kinase ◦ Erlotinib ‣ Non-small cell lung + pancreatic + EGFR tyrosine kinase ◦ Lapatinib  ‣ Breast cancer w/ HER2 overexpression (2nd line) ‣ EGFR + Her2 tyrosine kinases ◦ Imatinib ‣ Ph+ CML & Ph+ ALL ‣ Myelodysplastic/Myeloproliferative Diseases ‣ tyrosine kinase of Bcr-Abl ◦ Trastuzumab ‣ Breast cancer with HER2 overexpression (1st) ‣ Monoclonal antibody against Her2 ◦ Bevacizumab ‣ Metastatic colorectal cancer + Non-small cell lung ‣ Glioblastoma multiforme ‣ Renal cell carcinoma ‣ Monoclonal antibody against VEGF ======= CYCLIN DEPENDENT KINASE (CDK) INHIBITORS (PALBOCICLIB) CDKs modulate intracellular signaling during cell cycle ◦ CDK 4 + CDK 6 control progression from G0/G1 -> S ‣ initiation, growth and survival of many cancers taken orally Clinically (CDK 4/6 Inhibitors) ◦ Advanced HRP Breast Cancer (1st/Standard) ◦ HER2-negative advanced/metastatic breast cancer ◦ Combine With ‣ Aromatase inhibitor (initial endocrine therapy) = better outcome ‣ Fulvestrant (pxts w/ progression following endocrine therapy) AE ◦ BM Suppressed + Infections (Stomatitis) + Fatigue + N/D + Headache ======= PARP INHIBITORS (OLAPARIB) PARP repairs single-strand breaks via base excision MOA ◦ preventing cancer cells from repairing their DNA from chemo ‣ dsDNA breaks + Accumulate during replication ‣ NOTE Repair still Possible via Homologous Recombination via  BRCA1/BRCA2 genes (BRCA1/2 deficient -> apoptosis) Clinically ◦ homologous recombination-deficient (HRD) cancers (BRCA- deficient) ◦ Olaparib = HRD Ovarian + Breast + Prostate + Pancreatic ◦ oral drug AE ◦ AML + Myelodysplastic syndromes + Pneumonitis + DVT + Anemia ◦ N/V + loss of appetite + fatigue + myalgia/arthralgia ====== Miscellaneous Agents ASPARAGINASE ◦ some cancers require exogenous asparagine ◦ Asparaginase Hydrolysis Rxn in Serum ‣ Aspartagine + H2O -> Aspartate + NH3 ◦ MOA ‣ depriving cells of asparagine -> low proteins -> apoptosis ◦ AE ‣ Hypersensitivity + Low Clotting Factors + Liver Abnormalities ‣ Ammonia toxicity -> Pancreatitis + Seizures + Coma == HYDROXYUREA ◦ MOA ‣ Inhibits ribonucleotide reductase -> low dNTP -> No DNA ‣ Apoptosis during S phase + given orally == INTERFERONS (IFN-alpha) ◦ Clinically ‣ Hairy Cell Leukemia + CML ‣ Malignant Melanoma + Kaposi’s Sarcoma KEY CANCER DRUGS (SUMMARY TABLE ON LAST PAGE) ======================================================== ======================================================== ANTIMYCOBACTERIALS most = 6 months treatment ◦ CNS and bone disease require 12 months treatment ◦ dose is dictated by patient weight Individual case management with Direct Observed Therapy (DOT) TB Therapy Overview 1st Line (RIPE) ◦ Rifamycins + Isoniazid + Pyrazinamide + Ethambutol 2nd Line (SEAL) ◦ Streptomycin + Ethionamide + Amikacin + Levofloxacin 1st Line (RIPE) ◦ If Monotherapy --> Rapid Resistance ================================== Rifamycins (Rifampin/Rifampicin or Rifabutin (HIV)) ◦ MOA (Rifampin)  ‣ binds to subunit of bacterial DNA-dependent RNA polymerase --> inhibition of RNA synthesis ◦ MOR (Rifampin) ‣ point mutations in rpoB (gene for the subunit of RNA polymerase) --> Reduced binding to RNA polymerase ◦ Pharmacokinetics (Rifampin) ‣ CYP P450 inducer (Rifabutin is NOT) ‣ Well distributed (including CSF) ‣ Excetion: feces ◦ Antimicrobial Spectrum (Rifampin) ‣ MRSA + Gram (-/+) + Dividing/Non-dividing mycobacteria ‣ Intracellular/Extracellular Mycobacteria ◦ Clinically (SMALL P) (Rifampin) ‣ Serious staphylococcal infections (osteomyelitis, prosthetic joint infections and prosthetic valve endocarditis) ‣ MRSA (with vancomycin) ‣ Active TB infections ‣ Latent TB in isoniazid intolerant patients ‣ Leprosy (delays resistance to dapsone) ‣ Prophylaxis for meningitis + H.influenzae type B in exposed individuals ◦ Adverse Effects (Rifampin) ‣ Red-orange body fluids (urine, sweat and tears) common/harmless ‣ Hepatotoxicity (elevated LFTs) ‣ Safe for Pregnancy ‣ GI upset (anorexia, nausea, abdominal pain) ‣ Flu-like symptoms ‣ Rashes + Anemia + Thrombocytopenia (Occassional) ‣ Renal (rare) light-chain proteinuria nephritis acute tubular necrosis ◦ Properties (Rifabutin) ‣ for HIV patients for less induction of CYP ‣ substitute to those intolerant to rifampin ‣ Not Confirmed Safe for Pregnancy ============================ Isoniazid (INH) Overview ◦ Synthetic analog of pyridoxine + Most potent anti-TB drug Antimicrobial Spectrum ◦ Bactericidal against actively dividing mycobacteria ◦ Bacteriostatic against slowly dividing mycobacteria ◦ Bactericidal against both intracellular and extracellular mycobacteria MOA ◦ inhibits synthesis of mycolic acids --> disruption of cell wall MOR ◦ High level of resistance via deletion of KatG ◦ Low level resistance via overexpression of inhA + mxts of KasA Mycolic Acid Synthesis + MOA (Diagram) MOR Pharmacokinetics  ◦ CYP P450 inhibitor ◦ Metabolized by the liver N-acetyltransferase via acetylation (genetically determined) ‣ fast acetylators = Asian + Native Americans ◦ Diffuses readily in body fluids, tissues and caseous material ◦ No therapeutic consequence when appropriate doses are administered daily ‣ subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption Adverse Effects ◦ Hepatotoxicity (INH-induced hepatitis) (most common) ◦ Neurotoxicity ‣ peripheral neuropathy, restlessness, muscle twitching, seizures, memory loss & insomnia ‣ more likely to be seen among slow acetylators ◦ Treated w/ Pyridoxine (Vitamin B6) ◦ GI upset (anorexia, nausea, abdominal pain) ◦ Drowsiness ◦ Lupus-like Syndrome (Rare) ◦ Hemolysis (G6PD deficient pxts) NOTE ◦ Safe for Pregnancy ================================= Pyrazinamide Overview ◦ Relative of nicotinamide ◦ Part of combination therapy for active infections ◦ If used alone, resistance rapidly emerge Antimicrobial Spectrum ◦ Bacteriostatic against slowly dividing > actively dividing mycobacteria MOA  ◦ must be enzymatically hydrolysed by mycobacterial pyrazinamidase (encoded by pncA) to active pyrazinoic acid MOR ◦ impaired uptake of pyrazinamide or mutations in pncA Pharmacokinetics ◦ Works best in acidic pH Acute Gouty Arthritis ◦ Hepatotoxicity ◦ Rare ‣ Myalgia ‣ GI irritation ‣ maculopapular rash ‣ porphyria ‣ photosensitivity ◦ NOTE ‣ Only given in pregnancy if benefits outweigh the risks ================================== Ethambutol Overview ◦ combination therapy for active infections ◦ If used alone, resistance rapidly emerge ◦ Least potent against MTB Antimicrobial Spectrum ◦ Bacteriostatic agent which provides synergy with other drugs MOA ◦ inhibits arabinosyltransferases (encoded by emb gene)  ‣ --> decreased carbohydrate (arabinogalactan) polymerization of cell wall MOR ◦ mutations (usually overexpression) in the emb gene Pharmacokinetics ◦ Oral ◦ Distributed in most tissues ◦ Excreted mainly in the urine and a small fraction in the feces ◦ Dose adjustment may be needed in patients with renal insufficiency Adverse Effects ◦ Visual disturbances (dose dependent) ‣ (Most Common + Reversible) More Common ◦ decreased visual acuity ◦ red-green color blindness More Serious ◦ optic neuritis ◦ retinal damage ◦ Rare ‣ Headache ‣ confusion ‣ peripheral neuritis ‣ hyperuricemia ◦ NOTE ‣ Safe in pregnancy ‣ NOT given in children too young to permit assessment of visual acuity/color blindness Visual Acuity + Color Discrimination Testing ◦ Baseline and monthly testing with particular attention to patients on higher doses or with renal impairment ‣ ISHIHARA TEST for color discrimination ‣ SNELLEN CHART for visual acuity ================================== 2nd Line Drugs (SEAL)  Streptomycin + Ethionamide + Amikacin + Levofloxacin Uses ◦ resistance to 1st-line or failure of clinical response ◦ serious treatment-limiting adverse drug reactions ================================== Streptomycin Aminoglycoside Bactericidal against dividing mycobacteria MOA ◦ inhibits protein synthesis by binding at 30s mycobacterial ribosome Clinically ◦ combinations for the treatment of life-threatening TB ‣ TB meningitis ‣ miliary dissemination ‣ severe organ TB ◦ Given parenterally Adverse Effects ◦ Toxicities are dose-related and can be reduced by limiting therapy to no more than 6 months ◦ Increasing frequency of resistance limits the use of this drug ◦ Ototoxicity (vertigo and hearing loss) (Common + Permanent) ◦ Nephrotoxicity ‣ decreased urine output + elevated BUN & creatinine NOTE ◦ Teratogenic ================================== Ethionamide related to isoniazid (NO cross-resistance with Isoniazid) Resistance can develop rapidly if used alone MOA ◦ blocks mycolic acid synthesis ◦ Given orally Adverse Effects ◦ gastric irritation  ◦ neurotoxicity (alleviated by pyridoxine supplementation) ◦ hepatotoxicity ================================== Amikacin Aminoglycoside like streptomycin MOA ◦ inhibits protein synthesis by binding at 30s mycobacterial ribosome ◦ Given parenterally Clinically ◦ streptomycin-resistant or multidrug-resistant mycobacterial strains ‣ Most multidrug-resistant strains still remain SUSCEPTIBLE to this drug ‣ Prevalence of amikacin-resistant strains are low ( succinyl coA Deficiency ◦ usually caused by malabsorption so parenteral therapy is usually necessary ◦ NB patients with normal absorption can use oral form ◦ Vit B12 formulations = Hydroxocobalamin + Cyanocobalamin Folate Deficiency risk ◦ elderly + pregnant women + alcoholic abuse ◦ persons with chronic hemolytic anemia pregnancy – can lead to neural tube defects (so its supplemented) Clinical Manifestations ◦ anemia ◦ NO neurological signs or symptoms Drugs that can impair folate metabolism and cause deficiency Trimethoprim + Methotrexate + Pyrimethamine + Phenytoin Therapy ◦ Folic acid supplementation should NEVER be initiated in isolation in a person with macrocytic, megaloblastic anemia until serum methylmalonate assay is available ◦ should be given orally → 1-4 months or hematological recovery ◦ Prophylactic folic acid supplementation should be given to patients who are at a high risk for developing deficiency. Hydroxyurea (SCD) Prophylaxis against painful crises & reduces hospitalizations Induces the production of fetal hemoglobin. Increases endothelial production of NO Decrease expression of neutrophil adhesion molecules AE ◦ Hematologic (Leukopenia + Megaloblastic changes) ◦ Maculopapular skin rash ◦ Painful leg ulcers ======================================================== QUICK CANCER SUMMARY