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Antimetabolic drugs

Antimetabolic drugs. cyclophosphamide azathioprine 6-thioguanine mycophenolate mofetil methotrexate hydroxyurea. Common features. Inhibit DNA synthesis and transcription and RNA synthesis Inhibit cell proliferation Reduce cytokine synthesis Reduce expression of adhesion molecules

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Antimetabolic drugs

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  1. Antimetabolic drugs

  2. cyclophosphamide • azathioprine • 6-thioguanine • mycophenolate mofetil • methotrexate • hydroxyurea

  3. Common features • Inhibit DNA synthesis and transcription and RNA synthesis • Inhibit cell proliferation • Reduce cytokine synthesis • Reduce expression of adhesion molecules • Immunosuppress the host

  4. Approach to the patient • HIV status • Hepatitis, Tuberculosis • Malignant neoplasms

  5. Approach to the patient • Drug-drug interactions • Ability to give informed consent • Reliability of patient • Cost of therapy

  6. Other comorbid conditions • Alcoholism • Obesity • Diabetes • Pulmonary disease • Hepatic or renal insuffciency • Pregnancy, reproductive plans

  7. Pre-assessment of Patient • History and physical • PPD, chest X-ray • Hemogram, platelets • LFT’s, RFTs, • U/A • Pregnancy test

  8. Ongoing monitoring • Hemoglobin > 10 • WBC >2500 with neutrophiles >1500 • Platelets >80,000 • Modest elevations of ALT are acceptable if anticipated

  9. CYA

  10. Alkylating agents

  11. Genealogy of mustards • Sulfur mustard first synthesized in 1854 • Vesicant properties described 1887 • First use as weapon WWI • First observation description of hematopoietic effects (Krumbhaar) 1919 • First use as chemotherapy in mice (Goodman, Gilman and Dougherty) • First use in patient (above and Lindskog) 1942 • Medical work declassified 1946

  12. Nitrogen mustard

  13. Cyclophosphamide • Synthesized in 1958 • First clinical report 1962 • Original concept: tumor cells have elevated phosphatase and phosphoramidase activity. • Actual observation: Complex is cleaved by hepatic microsomal mixed-function oxidases, then distributed systemically

  14. Cytoxan as toxin • Impaired hematopoesis • Alopecia • Gastrointestinal toxicity • Sterility and testicular atrophy • Amenorrhea and ovarian fibrosis • Teratogenicity (dose related)

  15. Cytoxan as toxin • Cystitis, including hemorrhagic. • Bladder malignancies. • Impaired water excretion (distal tubular effect) • Other malignancies, especially hematologic.

  16. Dosing of cyclophosphamide • Dose: 2-3 mg/kg • Anticipate 2-3 months for clinical benefit in immunobullous disorders • Maintain hydration

  17. Cylophosphamide monitoring • Initially: Hemogram, platelets, ALT, BUN, Creatinine, U/A • Followup: Weekly Hemogram and platelets for 1 month, then monthly. Monthly U/A, BUN. Q3 month ALT. • Target Hemoglobin >10, WBC>4000, Platelets >100,000, no hematuria.

  18. Purine analogues (thiopurines)

  19. Azathioprine pharmacology • Adenine/hypoxanthine analogue • rapidly absorbed, wide distribution (no blood-brain distribution) • activated by xanthine oxidase to 6-mercaptopurine, then to thioinosinic acid • further hepatic metabolism by xanthine oxidase • ultimately renal excretion

  20. Azathioprine biological effects • false purine--inhibits DNA synthesis and translation • some “alkylating effect” from the imidazole group

  21. Azathioprine toxicity • Myelosuppression • Nonspecific GI toxicity • Various hypersensitivity phenomena (cholestasis, rashes) • Oncogenicity (hematologic--not solid tumors) • Teratogenicity potentially (not observed in transplant patients)

  22. Azathioprine monitoring • Initially: Hemogram, platelets, ALT, BUN, Creatinine. • Followup: Weekly Hemogram and platelets for 1 month, then monthly. Q3 month ALT, creatinine, BUN. • Target Hemoglobin >10, WBC>4000, Platelets >100,000.

  23. Azathioprine dosing • 1-3 mg/kg/day, depending on targeted disease • expect clinical improvement over months or even years.

  24. Thiopurine methyltransferase • Heterozygous deficiency in 10% of the population • Homozygous deficiency in 0.3% of the population

  25. 6-thioguanine • Clinical use since 1950’s • First report in psoriasis 1964 • Advocated by Herschel Zacheim since 1982

  26. 6-thioguanine pharmokinetics • Rapid, nearly compete GI absorption • Rapid hepatic clearance • minor renal role in clearance

  27. 6-thioguanine toxicity • Myelosuppression • Laboratory hepatotoxicity (no evidence of serious hepatotoxicity • Nonspecific GI upset (nausea, diarrhea)

  28. 6-thioguanine dosing • Initial dose is 40 mg/day. • Increase q 2 weeks by 20 mg/day until clinical response. • Maximum 160 mg/day (typical 80 mg/d) • When stable, maintenance at 1-3 X weekly can be maintained • Lab targets: WBC > 4000, Platelets > 125000, Hemoglobin > 11 • No dosage reduction with allopurinol

  29. 6-thioguanine monitoring • Baseline ALT, Hemogram with Platelets • Weekly Hemogram with Platelets during dose escalation, then q 2 weeks. • Monthly ALTduring dose escalation, then q 3 months • Target Hb >11, WBC > 4,000, Platelets > 125,000

  30. Mycophenolate mofetil (Cellcept)

  31. Mycophenolate mofetil • Fermentation product of P. stoloniferum. • First isolated 1913 • Mycophenolate mofetil = predrug-ester, ester hydrolyzed to to mycophenolic acid.

  32. Mycophenolate pharmokinetics • Lipid soluble. Rapidly absorbed • Chelates to divalent cations • Metabolized by gluconuryl transferase to glucuronide which is membrane impenetrable. (Inhibited by cyclosporin and tacrilimus) • Renal excretion. • Can be reactivated by epidermal and gut glucuronidase.

  33. Mycophenolic acid • Inhibits eukaryotic inosine monophosphate dehydrogenase • Blocks conversion of inosine-5-phosphate and xanthine-5-phosphate to guanosine-5-phosphate. • Net effect is decreased DNA synthesis and transcription. • Hypoxanthine/guanine phosphoribosyl pyrophosphatase (used purine salvage pathway) used by GI cells, neurons etc. • salvage pathway is relatively lacking in lymphocytes.

  34. Mycophenolate toxicity • G.I. disturbance, but not hepatotoxic • G.U. disturbances, but not nephrotoxic • Hematologic, reversible suppression • Infections suggested, but rate at least no worse than other immunosuppressives • Neurologic disturbances, nonspecific (rare ischemic neuritis and keratitis) • Probably not a carcinogen • Teratogenicity unknown

  35. Mycophenolate mofetil dosing • 500 mg po qid for 12 weeks • Increase by 250 mg/day monthly until clinical response • Maximum dose 4 gm/day (many published dose maximums presuppose cyclosporin administration)

  36. Mycophenolate mofetil monitoring • Baseline: Hemogram, ALT, BUN, UA, PPD (Pregnancy test) • Hemogram at weeks 1, 2, 3, 4, 6, 8, then monthly • 4-8 week follow-up

  37. Methotrexate biological effects • Inhibits dihydrofolate reductase which produces oxidized folate pool. • Blocks production of thymidylic acid, some purine synthesis, certain amino acid conversions and some neurotransmitter synthesis.

  38. Methotrexate biological effects • Inhibits psoriasis systemically, but not intralesionally • Inhibits s-adenyl methionine synthesis (proinflammatory molecule) • Promotes adenosine synthesis (anti-inflammatory molecule • Neither effect above is affected by folate

  39. Methotrexate toxicity • G.I., including mouth ulcers • Skin, including skin ulcers • Pneumonitis and interstitial lung disease(more common in RA) • Nephrotoxic in very high doses • Hematologic (macrocytosis) • Probably not carcinogenic • Teratogenic

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