Methotrexate ppt

1. METHOTREXATE
PRESENTED BY:- DR. PABITRA KUMAR PANDA
MODERATED BY :- DR. NITIN RANASINGH

2. INTRODUCTION
• Old name: Amethopterin
• Biochemical name: 4-amino-N10-methyl pteroylglutamic acid
• Anti metabolite
• FDA Approval:
-Psoriasis – 1971
-RA – Late 1980s
• Irreversible inhibitor of DHFR
• Competitive antagonist of Folic acid

3. HISTORY
• In 1951 Gubner and colleague recognized that folic acid
antagonist (Aminopterin) were excellent for treatment of
Psoriasis.
• Shortly Mtx (Amethopterin) was recognized
• It took 20 yrs for US FDA to approve its use in Psoriasis.
• In late 80s for RA

4. PHARMACOLOGY
• STRUCTURE :-
 Methotrexate (4-amino-N10-methyl pteroylglutamic acid) is
a potent competitive antagonist of enzyme DHFR.
 Structurally similar to folic acid.
Differ only at 2 molecular sites: Amino group at 4C & Methyl
group at N10

5. Difference in structure of folic acid and methotrexate

6. •ABSORPTION AND DISTRIBUTION
Routes:- Oral and Parenteral (IV, IM, SC and intrathecal)
Rapidly absorbed through the G.I tract
Peak level occur after 1 hr after ingestion
Distributed through out the body
 Poor penetration in BBB (so used intrathecal in some
chemotherapy regimens)
Milk and decreases absorption in children; no effect in adults .
Non absorbable antibiotics like neomycin may reduce with
absorption .

7. METABOLISM AND EXCRETION :-
• Once absorbed it undergoes triphasic reduction
• 50% of the drug is plasma protein bound, unbound fraction
is active form and responsible for the drug interaction.
1.DISTRIBUTION
( 0.75 hr )
2. RENAL EXCRETION
( 2-4 hr )
3. TERMINAL HALF LIFE
(10 – 27 hr )

8. • Mtx is actively transported into the cell.
• Metabolised intracellularly (including liver) to
polyglutamates responsible for hepatoxicity .
• Polyglutamates also inhibit DHFR (adds to toxicity)

9. Mechanism of Action :-
(A)DNA synthesis effect :-
 By competitive and reversible inhibition of enzyme DHFR with
in 1 hr.
 Greater affinity than folic acid.
 Partially reversible inhibition of thymidylate synthetase after
24 hrs.
Inhibition of Cell division

10. (B) T-cell effect :-
 Jeffs and collegue found that effect of Mtx in psoriasis is due to
its immunosuppressive action rather than antiprofilerative
action on keratinocytes .
 Antiproliferative action over lymphoid cells (1000 times more
potent effect)
Inhibition of migration & proliferation of activated T-cells

11. (C) Anti – inflammatory Effects :-
 Increases local concentration of adenosine , anti
inflammatory mediator , by blocking AICART enzyme. It
decreases the concentration of S-adenyl methionine ( SAM ,
proinflammatory mediator ) by blocking methionine
synthetase .

12. Folic acid effect on methotrexate
• Controversial .
• Not much studies in dermatology , literatures from
rheumatology present .
• Daily dosage ( 1-5mg ) except on the day of methotrexate is
found beneficial in minimizing side effects without interfering
with therapeutic responses .

13. Preparations available :-
• Oral ( tablet form ) :-
 2.5 mg , 5 mg , 7.5 mg , 10 mg and 15 mg .
• Injectable form :-
 2 ml vials with 2.5mg/ml and 25mg/ml .

14. • DOSING :-
A test dose of 5mg is given .
After 7 days routine laboratory monitoring done .
Gradual escalation of dose at a rate of 2.5-5 mg / week
(improvement less than 25-50% of baseline ) ; till clinical
response is seen .
After a maximal dose of 25-30 mg  check response
after 3 wk .
Tapering the dose (2.5 mg / week ) till minimum
maintenance dose .
Regular monitoring as per guidelines .

15. • Start with a test dose ( 5 – 10 mg ) .
• Measure CBC , LFT after 7 days .
• Gradual escalation of doses .
• Higher doses tolerated via IM / IV route due to rapid renal clearance .
Weekly dosage or 3 divided doses over 24hr interval (WEINSTEIN- FROST
REGIMEN )
Weekly dose of 10-15 mg is sufficient , maximum up to 30 mg .
Once full response is obtained gradual tapering to know the lowest
possible maintenance dose .

16. INDICATION :-
• FDA Approved ( dermatological condition )
 Psoriasis
 Sezary syndrome
Controversies for use of Methotrexate:-
Selection of patient.
Laboratory monitoring .
Need of liver biopsy for surveillance .

18. PSORIASIS

19. • 75 – 80% of psoriatic patients demonstrated initial response
within 1-4 week , full therapeutic response in 2-3 months.
• 60% of treated patients reached a PASI score of 75 within 12
weeks of therapy .

20. Other off label uses :-
1. Pityriasis rubra pilaris
 less response as compared to psoriasis .
 1.5 – 2 times higher doses than psoriasis for same body surface
area involvement .
Daily low dosage regimen rather than weekly dosage  high risk
of toxicity .
 secondary role .
2. PLEVA and PLC
 Small doses (2.5 – 5 mg ) are helpfull

21. 3. Reiter's disease :-
 dosage higher than psoriasis .
 improves both cutaneous and rheumatological features .
4. Immunobullous dermatosis :-
 Pemphigus, Bullous pemphigoid , Cicatricial pemphigoid , EBA
responds to Methotrexate in conjunction with steroid and dapsone
Useful for decreasing the high requirement of steroid .
Dosage – 7.5 – 12.5 mg sufficient .

22. 5. Autoimmune connective tissue disease :-
 higher doses  30 – 35 mg weekly for dermatomyositis /
polymyositis not responding to steroid .
 onset of response within 4 – 8 week.
 response seen in recalcitrant cases of chronic and subacute
lupus erythematosus, morphea and extra genital lichen
sclerosus.
 progressive systemic sclerosis shows only cutaneous
improvement .
 no response in scleredema.

23. 6. Vasculitis and neutrophilic dermatoses :-
PAN, Kawasaki, Behcet, Pyoderma gangrenosum, Sweet
syndrome
 used in high dosage in some cases as steroid sparing agent .
7 . Recalcitrant Atopic dermatitis in adult.

24. Contraindications
• Absolute contraindications
Hypersensitivity to Methotrexate
Chronic liver disease/Cirrhosis
Severe renal dysfunction
Pre-existing blood dyscrasias
Pulmonary disease
Marrow dysfunction or failure
Intrauterine pregnancy, or willing to conceive
Breastfeeding
Active TB or Hepatitis
Active peptic ulceration
Concurrent Trimethoprim therapy

25. • Relative contraindications
Mild to moderate hepatic dysfunction
Mild to moderate renal dysfunction
Hepatitis B & C
Gastritis
Alcohol excess
Patient unreliability
Recent live vaccination
Male partners of women wishing to conceive

26. ADVERSE EFFECT
• Cutaneous adverse effect :-
 Aphthous stomatitis
Alopecia
Hyperpigmentation
Toxic epidermal necrolysis
Erythema recall OR Radiation recall syndrome.
Ulceration in psoriatic plaque ( in toxicity )

27. • Systemic adverse effect :-
Hepatotoxicity
Mucositis
Nausea , vomiting
Abdominal pain
Pancytopenia
Nephrotoxicity ( high doses )
Osteopathy .

28. Hepatoxicity :-
 reversible
 seen more in psoriatic patient due to concomitant
obesity and steatohepatitis .
If cumulative dose > 4 gm  risk of liver fibrosis &
cirrhosis
 less risk at less than 1.5 gm
 GOLD STANDARD for Methotrexate induced hepatic
fibrosis  LIVER BIOPSY
Role of liver biopsy is controversial .

29. • Recent non-invasive test :-
1.Aminoterminus of type III procollagen peptide (PIIINP) serum
level.
-Lacks site specificity
-Not available in India
2. Ultrasonography
3. Radionuclide scan
4. MRI
5. Dynamic hepatic scintigraphy
6. FibroSure test
7. Transient elastography (Fibroscan)

30. • Algorithm that calculates the risk of hepatic fibrosis
based on :-
• Age , sex and certain biochemical parameters :-
Alanine transaminase
Haptoglobin
Apolipoprotein A1
Gamma glutamyl transpeptidases
Total bilirubin

31. RISK FACTOR FOR HEPATOTOXICITY :-
History of or current greater than moderate alcohol
consumption .
Persistent abnormal liver chemistry studies .
History of liver disease including Hep B or C .
Family history of inheritable liver disease .
Diabetes mellitus
Obesity
Hyperlipidemia
History of significant exposure to hepatotoxic drugs .

32. Pulmonary toxicity :-
 Rare .
Can be idiosyncratic  acute pneumonitis
Can have a gradual course  pulmonary fibrosis
Risk factors :-
Preexisting lung disease , cigarrete smoking .
Chest X-ray required if :-
Symptoms are present .
Age > 40 yrs
h/o any lung disease .

33. Haematological toxicity :-
Pancytopenia (greatest potential for loss of life)
Significant reduction by folic acid supplementation
Avoid SMX-TMP and NSAIDS
Frequent CBC for bone marrow toxicity
Risk factor for pancytopenia are :-

35. Malignancy induction :-
 few cases of lymphoma associated with EBV reported .
Mainly in patients of connective tissue disease .
Rare reports in psoriasis .
Gastrointestinal side effect :-
Nausea, anorexia, diarrhea, vomiting, ulcerative stomatitis
Severe diarrhea and ulcerative stomatitis warrants drug
stoppage.

36. Reproductive effects :-
Teratogen
Abortifacient
Category X drug
No risk in previously treated patients
Reversible oligospermia in men

37. CONTRACEPTION DURING METHOTREXATE THERAPY
Advised usage of at least 2 methods of
contraception during therapy
Avoid conception for at least 3 months for both male
and female .

38. Renal effect :-
Seen with high doses (50 – 250 mg/m2)
Not seen with low doses .
Due to precipitation of drug in renal tubule .
Osteopathy :-
Triad of 1. Severe pain localized in distal tibia .
2. Osteoporosis
3. Compression fracture of distal tibia .
Can be confused with psoriatic arthritis .
Management is withdrawal of Methotrexate .

39. Others :-
 Phototoxic drug
Previously irradiated skin develops a toxic reaction
with administration of drug
Increased homocysteine level

40. DRUG INTERACTION

41. Among NSAIDS  Celecoxib having no interaction
Others  Naproxen, Diclofenac, Ibuprofen and Indomethacin
 documented interaction
If co prescription necessary  monitoring 2 weekly .
COPRESCRIPTION :-
Biologics
Cyclosporine
UV-B
Retinoids

42. MONITORING GUIDELINES

43. • Chest X-ray  to rule out latent focus of TB
• Pregnancy test
• Serum protein, albumin
• Varicella zoster status
• Live vaccine must be given at least 4 weeks prior to therapy
• eGFR

44. Important points :-
RENAL FUNCTION TEST :-
Serum blood urea nitrogen and creatinine are not
reliable measures in old patient .
Estimation of creatinine clearance based on S.creatinine,
age, weight and gender must be done
Creatinine clearance = {[140 – age]*weight}/{72}*serum
creatinine} (multiply by 0.85 for women ).
Cautious use if clearance less than 50 ml/min.
If creat. Clearance 20-50  reduce the dose to half .
If less than 20  stop .

45. LIVER BIOPSY :-
Pretreatment biopsy is not necessary :-
Not all pt. with psoriasis improve with Methotrexate
Some patient cannot tolerate drug even in small
amount .
Long term Methotrexate may not be required after
an initial clinical response .

46. MONITORING OF HEPATOTOXICITY IN PATIENTS WITH NO RISK FACTOR FOR
HEPATOTOXICITY :-
No baseline liver biopsy .
Monitor LFT monthly for first 6 months and then every 1-3 mnths
thereafter .
For elevation less than 2 fold of upper limit of normal  repeat in 2-4
weeks .
For elevation > 2 fold but less than 3 fold  closely monitor, repeat in
2-4 week and repeat the dose as needed.
For persistent elevation in transaminases level over a 12 month period
or if there is a decline in S.Albumin below normal range with normal
nutritional status , in a pt with well controlled disease  liver biopsy .
Consider liver biopsy after 3.5 – 4.0 gm of cumulative dosage .

47. MONITORING OF HEPATOTOXICITY IN PATIENTS WITH RISK FACTORS:-
Consider of use of a different systemic agent .
Consider delayed baseline liver biopsy (after 2- 6 months of
therapy to establish medication efficacy and tolerability)
Repeat liver biopsy when cumulative dose = 1.5 gm .
Liver biopsy repeated after every 1.5 gm cumulative doses .
Time interval after which biopsy required = 12/ no. of 2.5mg
tablets per week.

48. METHOTREXATE THERAPY AND LIVER
BIOPSY (Roenigk criteria)
BIOPSY GRADES LIVER HISTOPATHOLOGY REMARKS
I Normal , mild fatty infilteration
and portal inflammation
MTX can be given
II Moderate to severe fatty
infilteration and portal
inflammation .
MTX can be given
IIIA Mild fibrosis . MTX can be given but another
biopsy after 6 mnths
IIIB Moderate to severe fibrosis . MTX cannot be given .
IV cirrhosis MTX cannot be given .

49. Significant changes :-
CBC  WBC less than 3500 / mm3 .
TPC less than 1 lakh / mm3 .
LFT  Double rise from baseline .
Drug can be stopped to restart at low doses when
parameters normalize .

50. ACUTE METHOTREXATE TOXICITY :-
• MTX inhibits mitosis of the cells by antagonizing folic acid
required for DNA synthesis
• Once in the cell, MTX inhibits DHFR.
• Reduction in thymidylate and purine biosynthesis. DNA synthesis
eventually halts and cells can no longer divide.
• Polyglutamination of MTX prolongs its intracellular presence.
• Cells with the capability of effective polyglutamination such as
leukemic myeloblasts, synovial macrophages, lymphoblasts, and
epithelia are more susceptible to the action of MTX.
• Acute MTX toxicity presents as pancytopenia, gastrointestinal
(GI) mucositis, hepatotoxicity, pulmonary toxicity, and acute
renal failure.

51. Mainly seen in :-
Declined renal function
Misunderstanding dosage regimen
Concomitant use of folate antagonist

52. Common case scenario of acute MTX toxicity:-
• Sudden onset of erosions or ulcers in psoriatic plaques
• Sudden onset of severe mucosal ulceration in the oral cavity.
• Onset of fever secondary to infection.
• Paradoxically, may have hypothermia due to the development
of sepsis.
• Many-a-times, scaly psoriatic plaque may not be visible due to
profound effects of MTX toxicity.

53. Chronological events in Methotrexate toxicity :-
Acute toxicity No. of days after methotrexate use
Mucositis 3 – 5
Maculopapular rash 1-5
Hepatitis 1-10
Myelosuppression 7-10
Renal toxicity 1-3

54. Two manifestation of methotrexate toxicity :-
Type 1 
Superficial erosion on preexisting plaque .
Commonly seen
Type 2 
Deep ulceration on non psoriatic skin .
Rare .

55. Histopathological features are same in both as follows :-
• Apoptotic keratinocytes in epidermis
• Cell vacuolization in the junction zone
• Hyperkeratosis
• Interstitial dermatitis
• Perivascular infiltrates of lymphocytes .

58. • Laboratory investigation :-
Myelosuppression .
Abnormal renal function test and liver function test
.

59. TREATEMENT :-
• Hospitalization .
• Three broad targets :-
Folinic acid rescue .
Elimination of methotrexate from body .
Organ specific care .

60. • Folinic acid rescue :-
Antidote of choice .
S . Methotrexate must be done ideally .
Started within 24-36 hrs with 15-25 mg of folinic acid
orally every 6 hrs for 6-10 doses .
Available preparation :- Biovorin / Bevorin .
Oral – 5/10/15/25 mg .
Inj . Solution – 10mg/mL.
Powder – 50/100/200/350/500.

61. • It decreases the antiepileptic effect of
phenobarbitone / phenytoin .
• Side effect :-
Allergic reaction .
Fever
Immune system disorder .
Contraindicated in pernicious anaemia /
megaloblastic anaemia .

63. • Elimination of methotrexate from body :-
1. HYDRATION :-
input  3L/m2/day
output  600ml urine over 6 hrs .
Till methotrexate level  0.2 micromole/L .
2. ALKALINIZATION OF URINE :-
Mtx and its metabolites are poorly soluble at acidic pH .
40-50 mEq of NAHCO3 / L of IV fluids .

64. 3. Managing delayed methotrexate excretion :-
 seen in patients with renal disorders .
May cause nephrotoxicity by :-
Crystal nephropathy .
Direct tubular toxicity .
US FDA approved for delayed methotrexate clearance
 GLUCARPIDASE ( CARBOXYPEPTIDASES )

65. • Mechanism of action of glucarpidase :-
Rapidly metabolize circulating methotrexate into two inactive
metabolite 
Glutamate .
2,4 – diamino N – 10 –methylpteroic acid .

66. • USAGE :-
Administered as bolus IV injection .
When methotrexate level >= 10 micromole/L .
Rise in creatinine = 100% .
This drug reduces methotrexate level by 97% or more within
15 mins .

67. • The drug is sold as a sterile, preservative-free white lyophilized
powder with 1000 units per single-use vial.
• Each vial also contains lactose monohydrate (10 mg), Tris-HCl
(0.6 mg), and zinc acetate dihydrate (0.002 mg).
• Each vial should be reconstituted (immediately prior to use)
with 1 ml sodium chloride 0.9% and administered over 5 min by
bolus IV injection.
• A caution should be borne that both folinic acid and its active
metabolite, 5-methyl THF (5-mTHF) are substrates for
glucarpidase and may reduce folate levels.
• Therefore, to minimize a clinically significant drug-drug
interaction, patients should receive folinic acid 2 h before or
after a dose of glucarpidase.[9]

68. • Organ specific care :-
Myelosuppression 
Packed red blood cells and platelet infusion .
G-CSF may be given .
Oral care 
Of erosions .

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