methotrexate

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METHOTREXATE &INTRAVENOUS IMMUNOGLOBULINS : 

METHOTREXATE &INTRAVENOUS IMMUNOGLOBULINS R.P.SHARMA Prof. & Head L.L.R.M.Medical College Meerut(U.P) Email :- doc_rp@indiatimes.com

METHOTREXATE (Mtx.) : 

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. METHOTREXATE (Mtx.)

PHARMACOLOGY : 

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:- Amino group in the 4- carbon position takes the place of hydroxyl group , & a methyl group at the N-(10) position substitutes for for the hydrogen atom. PHARMACOLOGY

METHOTREXATE AND FOLIC ACID :- : 

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

ABSOPTION AND DISTRIBUTION :- : 

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) ABSOPTION AND DISTRIBUTION :-

MECHANISM OF ACTION MTX. CONT. : 

(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. MECHANISM OF ACTION MTX. CONT.

Mtx. Cont. : 

DNA Synthesis Effects:- Folic acid Dihdrofolate reductase irreversible inhibition METHOTREXATE Tetrahydrofolate partial reversible inhibition Thymidylate synthetase DNA Mtx. Cont.

Mtx. Cont. : 

(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. Mtx. Cont.

Mtx. Cont. : 

(C) T-Cell Effects The effect of methotrexate on the proliferation of lymphoid cells is one thousand times greater than its effect on human keratinocytes, it is most likely that methotrexate acts via an immunosuppressive mechanism, rather than as an antiproliferative agent directed against the keratinocyte. It affects the prolifiration of lymphocytes ,& also block migration of activated T cells into certain tissue. Mtx. Cont.

Mtx. Cont. : 

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. Mtx. Cont.

Mtx. Cont. : 

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

Mtx. cont : 

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. Mtx. cont

Mtx. Cont. : 

Contraindication:- Absolute C/I :- Pregnancy Lactation Mtx. Cont.

Mtx. Cont. : 

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 Mtx. Cont.

Mtx. Cont. : 

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) . Mtx. Cont.

Mtx. Cont. : 

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

Mtx. Cont. : 

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

DRUGE INTERACTION :- : 

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 DRUGE INTERACTION :-

Mtx. Cont. : 

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. side effect of methotrexate. Mtx. Cont.

Monitoring Guidelines For Methotrexate Therapy Mtx.cont. : 

Monitoring Guidelines For Methotrexate Therapy Mtx.cont.

Methotrexate therapy & liver biopsy Mtx.cont. : 

Methotrexate therapy & liver biopsy Mtx.cont.

Mtx. Cont. : 

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 after discontinuation of methotrexate. Mtx. Cont.

INTRAVENOUS IMMUNOGLOBULINS (IVIG) R.P.SHARMA Prof. & Head L.L.R.M.Medical College Meerut(U.P) : 

INTRAVENOUS IMMUNOGLOBULINS (IVIG) R.P.SHARMA Prof. & Head L.L.R.M.Medical College Meerut(U.P)

INTRAVENOUS IMMUNOGLOBULINS (IVIG) : 

INTRAVENOUS IMMUNOGLOBULINS (IVIG) 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 from 1000 of donors.

IVIG. cont. : 

IVIG. cont. 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.

Pharmacology:- : 

Pharmacology:- 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. The half life is 3 to 5 weeks.

Structure of IMMUNOGLOBULIN-G : 

Structure of IMMUNOGLOBULIN-G IV Immunoglobuline structure

IVIG cont. : 

IVIG cont. 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).

IVIG cont. : 

IVIG cont. 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 & dose of intravenous immunoglobulins IVIG cont. : 

Indication & dose of intravenous immunoglobulins IVIG cont.

Indication & dose of intravenous immunoglobulins IVIG cont. : 

Indication & dose of intravenous immunoglobulins IVIG cont.

IVIG cont. : 

IVIG cont. 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.

IVIG cont. : 

IVIG cont. 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) .

IVIG cont. : 

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

IVIG cont. : 

IVIG cont. 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 to minimize the risk of transmission.

IVIG cont. : 

IVIG cont. 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 cont : 

IVIG cont 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.

Slide 38: 

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