Antimetabolic drugs

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Antimetabolic drugs
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• cyclophosphamide
• azathioprine
• 6-thioguanine
• mycophenolate mofetil
• methotrexate
• hydroxyurea

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Common features

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

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Approach to the patient

• HIV status
• Hepatitis, Tuberculosis
• Malignant neoplasms

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Approach to the patient

• Drug-drug interactions
• Ability to give informed consent
• Reliability of patient
• Cost of therapy

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Other comorbid conditions

• Alcoholism
• Obesity
• Diabetes
• Pulmonary disease
• Hepatic or renal insuffciency
• Pregnancy, reproductive plans

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Pre-assessment of Patient

• History and physical
• PPD, chest X-ray
• Hemogram, platelets
• LFTs, RFTs,
• U/A
• Pregnancy test

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Ongoing monitoring

• Hemoglobin gt 10
• WBC gt2500 with neutrophiles gt1500
• Platelets gt80,000
• Modest elevations of ALT are acceptable if
  anticipated

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CYA
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Alkylating agents
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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

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Nitrogen mustard
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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

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Cytoxan as toxin

• Impaired hematopoesis
• Alopecia
• Gastrointestinal toxicity
• Sterility and testicular atrophy
• Amenorrhea and ovarian fibrosis
• Teratogenicity (dose related)

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Cytoxan as toxin

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

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Dosing of cyclophosphamide

• Dose 2-3 mg/kg
• Anticipate 2-3 months for clinical benefit in
  immunobullous disorders
• Maintain hydration

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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 gt10, WBCgt4000, Platelets
  gt100,000, no hematuria.

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Purine analogues

• (thiopurines)

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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

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Azathioprine biological effects

• false purine--inhibits DNA synthesis and
  translation
• some alkylating effect from the imidazole group

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Azathioprine toxicity

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

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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 gt10, WBCgt4000, Platelets
  gt100,000.

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Azathioprine dosing

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

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Thiopurine methyltransferase

• Heterozygous deficiency in 10 of the population
• Homozygous deficiency in 0.3 of the population

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6-thioguanine

• Clinical use since 1950s
• First report in psoriasis 1964
• Advocated by Herschel Zacheim since 1982

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6-thioguanine pharmokinetics

• Rapid, nearly compete GI absorption
• Rapid hepatic clearance
• minor renal role in clearance

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6-thioguanine toxicity

• Myelosuppression
• Laboratory hepatotoxicity (no evidence of serious
  hepatotoxicity
• Nonspecific GI upset (nausea, diarrhea)

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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 gt 4000, Platelets gt 125000,
  Hemoglobin gt 11
• No dosage reduction with allopurinol

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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 gt11, WBC gt 4,000, Platelets gt 125,000

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Mycophenolate mofetil

• (Cellcept)

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Mycophenolate mofetil

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

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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.

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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.

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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

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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)

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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

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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.

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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

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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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Methotrexate pharmacology

• Rapid absorption
• 90 renal excretion, 10 hepatic with minimal
  enterohepatic circulation.
• No significant CNS penetration
• Binding to DHF-reductase is pH dependent.

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Methotrexate hepatotoxicity

• The more intermittent the dosing, the better.
• Risk is cumulative(?), maximal cumulative dose
  estimated to be 7.5 grams
• Diabetes and obesity may be comorbid risk
  factors. Alcoholism definitely is.

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Methotrexate dosing

• Start at 10 mg/week, single dose (test dose of
  2.5-5 mg).
• Increase by 2.5 mg/week/month until response.
• Maximum dose 30 mg/week
• Coadminister Folate 1 mg daily.
• May be used as combination with mycophenolate
  mofetil or cyclosporine, allowing 50 dose
  reduction of each.

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Methotrexate monitoring

• BaselineHemogram and platelets, ALT, BUN,
  Creatinine.
• Follow-up CBC, Platelets weekly for month, then q
  month.
• ALT, BUN, Creatinine q 2 months.
• Repeat blood work one week after dosage increase.

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Methotrexate and liver biopsies

• With risk factors 2-4 months into therapy, then
  1, 3, 4 grams cumulative.
• Without risk factors 1.5, 3, 4.5 grams cumulative

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How about some coffee talk

• Adenosine potent anti-inflammatory mediator
• Caffeine is a potent inhibitor of adenosine
  receptors.
• What happens when coffee drinkers take
  methotrexate?

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Hydroxyurea

• First synthesis 1860
• First use in cancer 1960
• First use in psoriasis 1969

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Hydroxurea mechanism of action

• Binds to and inhibits ribonucleotide reductase,
  M2 component of dimer (Fe-containing polypeptide)
• inhibits DNA nucleotide synthesis.
• May also inhibit DNA polymerase

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Hydroxyurea pharmacology

• Rapid absorption within 2 hours
• Wide distribution
• Renal excretion.
• Complete excretion with 24 hours

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Hydroxyurea toxicity

• Cytopenia
• Reversible drug-induced enzyme-identified
  hepatitis (disputed by others?)
• Teratogenicity
• Skin rashes--fixed drug eruption, poikiloderma
  (dm-like), hyperpigmentation, leg ulcers.
• GI symptoms--nausea, dyspepsia

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Hydroxyurea dosing

• Start 500 mg bid, maximum dose 1 gm bid.
• May increase by 500 mg/ day monthly, but increase
  monitoring frequency to weekly when doing so.
• Maximum 2 grams/ day
• Take with food.
• Lab targets Hemoglobin drop lt 3 gms,
  leukocytesgt5000, Plateletsgt150,000

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Hydroxyurea monitoring

• Baseline Hemogram, ALT, BUN, Urinalysis, PPD
• Lab q week for one month, then q 2 for month,
  then q month.
• Follow up a 1-2 months

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Annual costs (1993)