METHOTREXATE &INTRAVENOUS IMMUNOGLOBULINS : METHOTREXATE &INTRAVENOUS IMMUNOGLOBULINS R.P.SHARMA
Prof. & Head
L.L.R.M.Medical College Meerut(U.P)
Email :- firstname.lastname@example.org METHOTREXATE (Mtx.) : INTRODUCTION
Methotrexate is a Antimetabolite agent with
antiinflammatory properties and possibly
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:-
Dihdrofolate reductase irreversible inhibition
partial reversible inhibition
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 :-
Psoriasis including non- responsive or disabling plaque psoriasis of more than 20% BSA,
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).
Vasculitis (as a steroid sparing agent)
Sarcoidosis, keloides, lymphomatoid papulosis, keratoacanthomas, cutaneous crohn’s d’s. Mtx. cont Mtx. Cont. : Contraindication:-
Absolute C/I :-
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 :-
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 :-
Past history of hepatitis
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.
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.
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: Thank y u