Methotrexate is a Antimetabolite agent
antiinflammatory properties and possibly
In 1971 US FDA approve methotrexate
for use in Psoriasis & for Rheumatoid arthritis
Methotrexate (4-amino-N methyl pteroylglutamic
acid)is a potant competitive antagonist
(inhibitor)of enzyme dihydrofolate
It is structurally similar to folic acid ,
the natural substrate for this enzyme .
Mtx. Differing from folic acid in only two areas:-
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
of adenosine, antiinflammatory mediator,by
blocking AICART enzyme . It decreases the
concentration of S-adenyl methionine (SAM,
proinflammatory mediator) by blocking
Relative C/I: Unreliable
patient – including excessive
Decrease renal function test(dose must
Diabetes mellitus or obesity.
Severe hematologic abnormalities.
Man or woman contemplating
conceptions(3 months off drug for man &
off one ovulation cycle for woman)
Cutaneous adverse effects:Aphthous stomatitis , alopecia,
hyperpigmentation, toxic epidermal
necrolysis , ulceration in psoriatic plaques
with methotrexate toxicity, erythema
recall after discontinuation of PUVA
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
THERAPEUTIC GUIDELINES :
Various studies have shown that a single
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
on methotrexate days) prevents G.I.T.
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.
levels two times that of the baseline indicate hepatotoxicity.
At baseline and after 6 months
After cumulative dose of 1.5 g (usually 6 months) and after
every another 1.5 g of dose.
fatty, MTX can be given
fatty MTX can be given
MTX can be given but
another liver biopsy after
MTX cannot be given
MTX cannot be given.
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
Intravenous immunoglobulins are
heterogenous human gammaglobulins
containing IgG with trace of IgA and
prepared by cold ethanol
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
IVIg distributes itself throughout the
intravenous (60%) and extravascular
(40%)spaces , cross the placenta and
may be excreted in milk.
Mechanism of action:
Suppression of antibody production
due to infusion of high doses of IVIG.
Suppression of idiotypic antiboides
Saturation of Fc receptors on
macrophages (Fc receptors play role in
cytotoxic cell-mediated immunity and
Neutralization of microbe or toxin.
Inhibition of cytokines like IL-1, IL-6, and
Modulation of complement activation.
Acceleration of IgG catabolism.
Doses and duration
Autoimmune bullous disorders, e.g., pemphigus
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
0.8-5.8 g/kg for 1-5 days
e.g. 2g/kg i.v. single dose monthly for 2-4 months
Graft versus host disease (GVHD)
250-500 mg/kg weekly from day 8 to day-111
after BMT for pevention of GVHD
Doses and duration
2 g/ kg i.v. as single dose
Hypersensitive dermatoses, e.g. autoimmune 0.4g/kg/day for 5 day
> 0.25 g/kg every 3 weeks in childhood.
2g/kg i.v. monthly for 3 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/
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
complicaton “osmotic nephrosis”)
Fluid overload and electrolyte
Therapeutic Guidelines :Peak serum concentrations of IVIG are
achieved immediately following the
interavenous injection and is dose
30% of the dose is eliminated by
within 24 hr. Serum half life is 3-5 weeks.
All batches of IVIG should undergo testing
HIV, syphilis, hepatitis B, and hepatitis C
Anaphylaxis to IVIG is more common
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
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.