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:-

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.

METHOTREXATE

FOLIC ACID

N H

CH3(Methyl group)

OH

NH2(Amino group)

Pteroyl monoheptaglutamate

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.

(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.

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 (with systemic involvement)

Mycoses fungoides (Patch and plaque stage).

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.

side effect of methotrexate.

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

(SGOT, SGPT)

levels two times that of the baseline indicate hepatotoxicity.

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 Remarks

I Normal, mild fatty,

infiltration, and portal

inflammatiion

MTX can be given

II Moderate-to-severe fatty

infiltration and portal

inflammation

MTX can be given

IIIA Mild fibrosis MTX can be given but

another liver biopsy after

6 months

IIIB Moderate-to-severe

fibrosis

MTX cannot be given

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

after discontinuation of methotrexate.

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 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.

The half life is 3 to 5 weeks.

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 Indication Doses and duration Doses and duration

Autoimmune bullous disorders, e.g., pemphigus Autoimmune bullous disorders, e.g., pemphigus

vulgaris vulgaris

2g/kg i.v. single dose monthly or 2g/kg i.v. single dose monthly or

1g/ kg/day× 3 days every month, or1g/ kg/day× 3 days every month, or

0.5g/kg/day ×5 days every month0.5g/kg/day ×5 days every month

Toxic epidermal necrolysisToxic epidermal necrolysis 0.8-5.8 g/kg for 1-5 days 0.8-5.8 g/kg for 1-5 days

Autoimmne connective tissue disorders, e.g. Autoimmne connective tissue disorders, e.g.

dermatomyositisdermatomyositis

2g/kg i.v. single dose monthly for 2-4 months 2g/kg i.v. single dose monthly for 2-4 months

Graft versus host disease (GVHD)Graft versus host disease (GVHD) 250-500 mg/kg weekly from day 8 to day-111 250-500 mg/kg weekly from day 8 to day-111

after BMT for pevention of GVHDafter BMT for pevention of GVHD

IIndication ndication Doses and duration Doses and duration

Kawasaki diseaseKawasaki disease 2 g/ kg i.v. as single dose2 g/ kg i.v. as single dose

Hypersensitive dermatoses, e.g. autoimmune Hypersensitive dermatoses, e.g. autoimmune

urticariaurticaria

0.4g/kg/day for 5 day0.4g/kg/day for 5 day

AAgammaglobulinemia/ gammaglobulinemia/

hypogammaglobulinemia : congenital or hypogammaglobulinemia : congenital or

acquiredacquired

> 0.25 g/kg every 3 weeks in childhood. > 0.25 g/kg every 3 weeks in childhood.

ScleromyxedemaScleromyxedema 2g/kg i.v. monthly for 3 months 2g/kg i.v. monthly for 3 months

Pyoderma gangrenosumPyoderma gangrenosum 1-2/kg iv. monthly for 2-4 months 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 to minimize the risk of transmission.

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.