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Information about Methotrexate

Published on February 19, 2014

Author: daulatramdhaked



MOA, pharmacokinetics, adverse effects, monitering, indications

INTRODUCTION Methotrexate is a Antimetabolite agent with antiinflammatory properties and possibly immunosuppressive effect. In 1971 US FDA approve methotrexate for use in Psoriasis & for Rheumatoid arthritis in 1980. 

STRUCTURE:  Methotrexate (4-amino-N methyl pteroylglutamic acid)is a potant competitive antagonist (inhibitor)of enzyme dihydrofolate reductase(DHFR). It is structurally similar to folic acid , the natural substrate for this enzyme .  Mtx. Differing from folic acid in only two areas:-

monoheptaglutamate Pteroyl OH N H NH2 (Amino group) FOLIC ACID CH3 (Methyl group) METHOTREXATE

   Methotrexate can be administrated orally ; intravenously , intramuscularly, or subcutaneously.It is rapidly absorbed through the G.I.T tract, although peak level occur more slowly (1 hr after ingestion)through this route than other two routes. The drug is well distributed throughout the body except in the brain, penetrating the blood brain barrier poorly (used intrathecal in some chemotherapy regimens). Once absorbed , the level of Mtx. in plasma has triphasic reduction (distribution , renal excretion , termination)

(A) DNA Synthesis Effects: Inhibits DNA synthesis by competitively and irreversibly inhibiting enzyme, dihydrofolate reductase (DHFR) which converts dihydrofolate to tetrahydrofolate essential for DNA synthesis.

(B) Anti-inflamatory Effects: Methotrexate increases local concentration of adenosine, antiinflammatory mediator,by blocking AICART enzyme . It decreases the concentration of S-adenyl methionine (SAM, proinflammatory mediator) by blocking methionine synthetase.

T-Cell Effects (C)

Indication :FDA-approved indication  •  Psoriasis including non- responsive or disabling plaque psoriasis of more than 20% BSA, psoriatic arthritis, pustular psoriasis, psoriatic erythroderma. Sezary syndrome.

Off-lable use : Reiter's disease (For cutaneous and rheumatologic manifestations).  Dermatomyositis (useful predominantly for muscle involvement).  Sarcoidosis  Mycoses stage). (with systemic involvement) fungoides (Patch and plaque  Pemphigus vulgaris.

   Pityriasis rubra pilaris (higher or double doses as compared to psoriasis). Crusted scabies. Vasculitis (as a steroid sparing agent) Dermatitis  Atopic dermatitis  Other dermatosis Sarcoidosis, keloides, lymphomatoid papulosis, keratoacanthomas, cutaneous crohn’s d’s.

Contraindication:Absolute C/I : Pregnancy  Lactation

Relative C/I: Unreliable patient – including excessive alcohol intake.  Decrease renal function test(dose must be reduced).  Diabetes mellitus or obesity.  Severe hematologic abnormalities.  Man or woman contemplating conceptions(3 months off drug for man & off one ovulation cycle for woman)  Immunodeficiency syndrome

Doses and preparations : 7.5-15 mg/ week (rarly exceeds 30 mg)  ORAL- Neotrexate, Mexate 2.5 mg tablet.  INJECTABLE- ( I.M, I.V, S.C ) Imutrex 15 mg/ ml (2 ml injection) .

Adverse Effects:-  Systemic adverse effects :Mucositis, nausea, vomiting, abdominal pain, hepatotoxicity, pancytopenia, nephrotoxicity (with high doses), stress fractures.

Cutaneous adverse effects:Aphthous stomatitis , alopecia, hyperpigmentation, toxic epidermal necrolysis , ulceration in psoriatic plaques with methotrexate toxicity, erythema recall after discontinuation of PUVA therapy.

     Drugs may increase Mtx. serum l evels( potential toxicity)displace from plasma proteins :Tetracylines , anticonvulsants, antipsychotic, chloraphenicol phenytoin , phenothiazines. Drugs may increase Mtx. Reducing renal excretion & displace from plasma proteins :Sulfonamide, NSAID Drugs may decrease Mtx. Serum level – other mechanism Ciprofloxacin, penicilline, amiodarone Mtx. May increase serum level of therse drugs Xantines , thephyllines Mtx. May decrease serum level of therse drugs Ionotropic, digoxin

THERAPEUTIC GUIDELINES :  Various studies have shown that a single dose of 7.5 mg/ week is equally effective as that of three doses of 2.5 mg/12 hrs apart per week. Folic acid supplementation (5 mg/ day except on methotrexate days) prevents G.I.T.

Text Frequency Complete blood count Every 2-4 weeks for 1 months followed by once in 3 months, lymphocyte count of less than 3500/ cu mm and platelet count of less than 100,000/cu min indicate toxicity. Liver enzymes levels two times that of the baseline indicate hepatotoxicity. (SGOT, SGPT) Chest X-ray At baseline and after 6 months Liver biopsy After cumulative dose of 1.5 g (usually 6 months) and after every another 1.5 g of dose.

Biopsy grade Liver histopathology I Normal, mild infiltration, and Remarks fatty, MTX can be given portal inflammatiion II Moderate-to-severe infiltration and fatty MTX can be given portal inflammation IIIA Mild fibrosis MTX can be given but another liver biopsy after 6 months IIIB Moderate-to-severe MTX cannot be given fibrosis IV Cirrhosis MTX cannot be given.

Risk factors for methotrexate- induced cirrhosis are :        Alcoholism Past history of hepatitis Obesity Diabetes mellitus Daily methotrexate regimens cumulative dose exceeding 2.5 g Impaired kidney function Contraception for 3 months is required

INTRODUCTION : Intravenous immunoglobulins are heterogenous human gammaglobulins containing IgG with trace of IgA and IgM prepared by cold ethanol fractionalization of pooled human sera harvested

 IVIG is an important safe, effective (but costly) therapeutic option an immunomodulatory agent in the management of skin disorders where corticosteroids and immnosuppressive agents cannot be used.

   Peak serum level concentrations occure immediately after intravenous injection and are dose related . Within 24 hrs , up to 30% of the dose may be removed by catabolism and distribution . IVIg distributes itself throughout the intravenous (60%) and extravascular (40%)spaces , cross the placenta and may be excreted in milk.

IV Immunoglobuline structure

Mechanism of action:   Suppression of antibody production due to infusion of high doses of IVIG. Suppression of idiotypic antiboides (idiotype-antiidiotype interactions regulate autoimmunity). Saturation of Fc receptors on macrophages (Fc receptors play role in cytotoxic cell-mediated immunity and opsonization).

 Neutralization of microbe or toxin.  Inhibition of cytokines like IL-1, IL-6, and TNF-α.  Superantigen neutralization  Modulation of complement activation.  Acceleration of IgG catabolism.

Indication Doses and duration Autoimmune bullous disorders, e.g., pemphigus vulgaris 2g/kg i.v. single dose monthly or 1g/ kg/day× 3 days every month, or 0.5g/kg/day ×5 days every month Toxic epidermal necrolysis Autoimmne connective 0.8-5.8 g/kg for 1-5 days tissue disorders, e.g. 2g/kg i.v. single dose monthly for 2-4 months dermatomyositis Graft versus host disease (GVHD) 250-500 mg/kg weekly from day 8 to day-111 after BMT for pevention of GVHD

Indication Doses and duration Kawasaki disease 2 g/ kg i.v. as single dose Hypersensitive dermatoses, e.g. autoimmune 0.4g/kg/day for 5 day urticaria Agammaglobulinemia/ hypogammaglobulinemia > 0.25 g/kg every 3 weeks in childhood. : congenital or acquired Scleromyxedema 2g/kg i.v. monthly for 3 months Pyoderma gangrenosum 1-2/kg iv. monthly for 2-4 months

Side effects:Side effects are rare, mild and usually self - limited and may be related to the infusion rate. They can be prevented or minimized by slowing the infusion rate or By prior administration of intravenous corticosteroids and antihistamines. 

Common side effects are:Headache, backache, nausea/ vomiting, chills, fever, myalgia.  Hypersensitivity reaction including anaphylaxis (due to IVIG or thimerosal, maltose, or sucrose in infusion solution) .

 Acute renal failure (irreversible, IVIG containing sucrose more likely to lead to this complicaton “osmotic nephrosis”)  Fluid overload and electrolyte disturbances.   Hemolysis Neutropenia.

Therapeutic Guidelines :Peak serum concentrations of IVIG are achieved immediately following the interavenous injection and is dose related. 30% of the dose is eliminated by catabolism within 24 hr. Serum half life is 3-5 weeks.   All batches of IVIG should undergo testing for HIV, syphilis, hepatitis B, and hepatitis C

 Anaphylaxis to IVIG is more common when IgA is deficient.  IVIG are the immunoglobulins,which can interact with live virus vaccine. Such vaccines should not be given 14 days before or 3 months after IVIG dministration.

 IVIG has a theoretical risk of autoimmunity owing to infusion of antiboides.  Sudden infusion of IVIG may suppress antibody production and rebound flare up can occur after the discontinuation of therapy. High cost (for monthly Tt. Of a Pt. of 75 kg the average cost / yr b/w 90,000 & 120,000 Euro) of this therapy IVIG should be given to carefully selected patients whose disease severity is recalcitrant to alternative immunosuppressive therapies or who experience or are at risk for significant adverse effects these alternative therapies.

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