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 Immunosuppress the host

Approach to the patient

• HIV status • Hepatitis, Tuberculosis • Malignant neoplasms

Approach to the patient

• • • •

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

Other comorbid conditions

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

Pre-assessment of Patient

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

Ongoing monitoring

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

CYA

Alkylating agents

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

Nitrogen mustard

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

Cytoxan as toxin

• • • • • •

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

Cytoxan as toxin

• • •

Cystitis, including hemorrhagic.

Bladder malignancies.

Impaired water excretion (distal tubular effect)

•

Other malignancies, especially hematologic.

Dosing of cyclophosphamide

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

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.

Purine analogues

(thiopurines)

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

Azathioprine biological effects

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

Azathioprine toxicity

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

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.

Azathioprine dosing

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

Thiopurine methyltransferase

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

6-thioguanine

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

6-thioguanine pharmokinetics

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

6-thioguanine toxicity

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

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

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

Mycophenolate mofetil

(Cellcept)

Mycophenolate mofetil

•

Fermentation product of P. stoloniferum.

•

First isolated 1913

•

Mycophenolate mofetil = predrug-ester, ester hydrolyzed to to mycophenolic acid.

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.

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.

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

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)

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

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.

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

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

Methotrexate pharmacology

• • • • Rapid absorption 90% renal excretion, 10% hepatic with minimal enterohepatic circulation.

No significant CNS penetration Binding to DHF-reductase is pH dependent.

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.

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.

Methotrexate monitoring

• • • Baseline:Hemogram 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.

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

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?

Hydroxyurea

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

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

Hydroxyurea pharmacology

• • • • Rapid absorption within 2 hours Wide distribution Renal excretion.

Complete excretion with 24 hours

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

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 < 3 gms, leukocytes>5000, Platelets>150,000

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

Annual costs (1993)

Goekerman (outpt) PUVA Outpt UVB Methotrexate (no biopsy) Etretinate (=acetretin?) Hydroxyurea Cyclosporin 3920 2605 1966 1381 1995 1131 6648