Methotrexate

MOA, pharmacokinetics, adverse effects, monitering, indications

2. 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.

3. 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.

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

5.  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)

6. (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.

7. (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.

8. (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.

9. 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.

10. 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.

11. 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.

12. Contraindication:-

Absolute C/I :-
Pregnancy
Lactation

13. 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

14. 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) .

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

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

17. 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

18. 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.

19. 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.

20. Biopsy grade Liver histopathologyRemarks
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.

21. 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.

23. 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.

24.  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.

25. 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.

26. IV Immunoglobuline structure

27. 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).

28. 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.

29. 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

30. 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

31. 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.

32. 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) .

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

34. 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.

35. 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.

36. 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.