Methotrexate.pptx

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 :- 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 M tx in psoriasis is due to its immunosuppressive action rather than antiprofilerative action on keratinocytes . A ntiproliferative 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 S ezary syndrome Controversies for use of Methotrexate:- Selection of patient. Laboratory monitoring . Need of liver biopsy for surveillance .

17. PSORIASIS

18. 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 .

19. Other off label uses :- 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

20. 3 . Reiter's disease :- dosage higher than psoriasis . improves both cutaneous and rheumatological features . 4. Immunobullous dermatosis :- Pemphigus, B ullous 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 .

21. 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.

22. 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.

23. 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

24. 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

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

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

27. 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 .

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

29. 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

30. 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 .

31. 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 .

32. 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 :-

33. 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.

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

35. 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 .

36. 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 .

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

38. DRUG INTERACTION

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

40. MONITORING GUIDELINES

41. 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

42. 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 .

43. 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 .

44. 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 .

45. 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.

46. 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 .

47. 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 .

48. 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.

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

50. 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.

51. 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

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

53. 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 .

54. Laboratory investigation :- Myelosuppression . Abnormal renal function test and liver function test .

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

56. 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.

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

58. Elimination of methotrexate from body :- 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 .

59. 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 )

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

61. 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 .

62. 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]

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

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