Methotrexate Chapter 13

shevyatiwari's version from 2015-09-26 06:11


Question Answer
Methotrexate is a competitive inhibitor of DHPTF. DHFR
Mtx is dissimilar to folic acidF. Differs in only 2 sites
Mtx is only given PO or IMF. Can also be given IV, SC, intrathecal
Absorption of Mtx is slowF. Rapidly absorbed. Triphasic reduction. Ist phase 45mins - distribution throughout body. Nb DOES NOT XBBB
Oral administration takes longer to peak levels than IMT
Absorption is predictable at a dose of 20mgF. It is incomplete and variable after 15mg
Food does not affect the absorption of MtxT in Adults. F in children - in kids milk based meals decrease bioavailability
Non absorbable abs such as neomycin reduce MtxT
Mtx penetrates the BBBF - hence use of intrathecal MTX for chemo
Mtx has a biphasic reductionF. Triphasic. Phase one -45 minutes MTX widely distributed to tissues. Phase 2 -renal excretion 2-4hrs (weak acid) phase 3 -terminal halflife 10-27hrs- slow release of MTX from tissues primarily bound to dihydrofolate reductase
Mtx is a strong baseF. Weak organic acid
Salicylates, probenecid, sulphonamides can cause low levels of MtxF, increased as are also weak acids and cause decreased excretion of MTX and displacement from plasma proteins - therefore increased toxicity
Mtx is 99% protein boundF. 50%
Mtx enters cells by passive diffusionF. Active transport
Mtx is metabolised in the kidneyF. Intracellularly, inc. in the liver to pollyglutamated forms
Mtx has active metabolitesT. Metabolised intracellularly to polyglutamated forms- toxic metabolites which may be very persistent in various tissues
Folic acid binds to DHFR with less affinity than MtxT. Folic acid competes with MTX to bind to DHFR - thereby decreases the adverse effects of MTX by increasing tetrahydrofolate production
Mtx inhibits cell division at all stages of the cell cycleF. Specific for S phase ( DNA synthesis ) - as all anti-metabolites
Mtx can be bypassed by leucovorinT
Mtx can be bypassed by thymidineT. Folinic acid- leucovorin calcium and thymidine can be used to reverse acute haemtox secondary to MTX
The mechanism of action in psoriasis is the suppression of hyper proliferation of keratinocytesF. Blocks proliferation of T -lymphocytes and blocks migration (chemotaxis) of activated T cells in certain tissues. Effect on lymphoid cells 1000x greater than effect on human keratinocytes
Mtx suppresses primary, secondary antibody responses as well as delayed type hypersensitivityF. Does not affect delayed hypersensitivity. Inhibits DNA synthesis in immunologically competent cells
The anti-inflammatory effects of Mtx are due to inhibition of DHFRF. Due to increased adenosine (an anti-inflammatory) through a complex interaction with AICAR transformylase and ecto 5'nucleotidase
Retinoids and mtx can interactT. Increased hepatotoxicity
Dapsone interacts with MtxT. Increased risk of haematological toxicity
Trimethoprim inhibits DHPTF. DHFR
Tetracyclines interact with MtxT. Displace Mtx from Plasma proteins -> increased Mtx
There are no dermatological FDA indications for MtxF. Psoriasis, Sezary
The only absolute C/I: hypersensitivity and pregnancyF. Also lactation
Mtx is cat XT
Latent TB is an absolute C/I to MtxF. Relative
A male must not conceive for 6 months post MtxF. 3 months and a female for one month post cessation of MTX! Important reproductive side effects as MTX = potent teratogen and abortifacient but has less long term mutagenic and carcinogenic potential than alkylating agents. Men also get reversible oligospermia
Immunodeficiency is a C/I to MtxT, relative
Pulmonary toxicity is dose dependentF. Not always- Acute pneumonitis - rare and Idiosyncratic- can occur with extremely small doses and be fatal if not stopped - Josephine. Pulmonary fibrosis however is dose dependent and more common with RA pts.
Routine CXR's in 2 yearly intervals are rccommendedF.
Pulmonary toxicity is more common in RA patients than psoriasis patientsT
Macrocytosis without anaemia is common in dermatology patients on MtxT
Low albumin is a common RF for Mtx induced pancytopeniaF. Less common
TMP/SMX and NSAID use are common RF for Mtx pancytopeniaTMP/SMX and Dapsone all increase risk of Haem tox as all inhibit folate metabolic pathway. NSAIDS and Salycilates - cause decreased excretion of MTX and displacement from plasma proteins so increase levels of MTX and toxicity
Mild renal disease is a RF for Mtx pancytopeniaT
Lymphoma is increased in psoriasis patients on MtxF, no evidence
Nausea and anorexia are more common S/E than D/V/ulcerative stomatitisT
Miscarriage rates are high with MtxT. Cat X Wolverton and not for lactation. Cat D in Aus.
Men can have oligospermia due to MtxT
The mechanism of renal failure in Mtx is unknownF. Precipitation of Mtx in renal tubules. Not seen with low dose therapies in psoriasis. Renal impairment - rare
MTX can cause phototoxicityT

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