Methotrexate 2.pptx

Methotrexate

1. Methotrexate.

2. History 1948, initial use of aminopterin by Sidney Farber to treat childhood leukemias . Noted interference of proliferative connective tissue, in RA, psoriasis and psoriatic arthritis. Approved by the FDA in 1971.

3. Methotrexate Antimetabolite : acts on the metabolism of proliferating cells. Potent competitive antagonist, of dihydrofolate reductase . Structurally similar to folic acid, differs at 2 molecular sites.

4. Pharmacokinetics

5. Pharmacokinetics Routes : oral/ iv/ im / sc. Rapidly absorbed in the gastrointestinal tract. Peak levels are 1 hour after ingestion. Unaffected by concurrent food intake in adults. Well distributed, poor penetration in the blood brain barrier.

6. Pharmacokinetics Phases of Metabolism. 50 % of drug is in unbound form. Drugs increasing the free fraction of Mtx can increase its beneficial effects and toxicity. First Phase 0.75 hours Rapid distribution throughout the body. Second Phase 2 to 4 hours. Renal excretion by GF and tubular secretion. Third Phase 10 to 27 hrs. Slow drug release from tissues.

7. Pharmacokinetics Prodrug is actively transported into cells as Mtx-monoglutamate . Further glutamic residues are added and biologically active polyglutamate is formed. Cannot be transported out of the cell unless hydrolysed to monoglutamate form. Intracellular accumulation of Mtx , and therapeutic effectiveness with once weekly dose.

8. Drug interactions.

9. Drug Interactions

10. Drug Interactions Drugs that increase Mtx level and toxicity : Decreased renal excretion, displace from plasma proteins. Salicylates. NSAID. Sulfonamides. Increased intracell level of Mtx Dipyridamole Probenicid ( decrease renal tubular func .) Displacement from plasma proteins Chloramphenicol Phenothiazines Phenytoin Tetracyclines .

11. Drug Interactions Drugs that may synergistically increase hepatotoxicity: Systemic retinoids . Azathioprine. Alcohol.

12. Mechanism Of Action

13. Mechanism Of Action Competitively binds to DHFR within 1 hour, prevents conversion to THFR. THF necessary to produce 1-C units, which synthesize thymidylate and purine nucleotides needed for DNA, RNA synthesis. After 24 hours, partial reversible inhibition of thymidylate synthase. Mtx is specific for S phase of DNA cycle. Metabolism is bypassed by leucovorin or thymidylate . High dose folinic acid ( leucovorin ) reverses Mtx toxicity.

14. Mechanism Of Action Affects proliferation of lymphoid cells 100x more than keratinocytes. Acts more as an immunosuppressive agent than antiproliferative agent. Demonstration of depression of cutaneous lymphocyte-associated antigen-positive T cells and endothelial E- selectin in patients of psoriasis treated with Mtx .

15. Mechanism Of Action Anti-inflammatory effects: Affinity for enzymes that need folate as cofactor. Includes AICAR transformylase . Release of adenosine that inhibits ROS release by polymorphs and lymphocyte proliferation. AICAR also involved in purine synthesis .

16. Uses

17. Uses FDA Approved indications : Psoriasis Sezary Syndrome

18. Off Label Uses

19. Uses Major clinical use is in psoriasis. Initial response to Mtx within 1-4 weeks, full therapeutic benefit in 2-3 months. Indications for use in psoriasis: Erythrodermic psoriasis. Psoriatic arthritis not resposive to conventional therapy. Pustular psoriasis. Extensive severe plaque psoriasis not responsive to conventional therapy. Unresponsive to phototherapy and systemic retinoids . Impairs social and economic well being.

20. Uses Other proliferative disorders: PRP controlled at 1.5-2 times higher dose. Small doses for PLEVA control. Treats both cutaneous and rheumatological aspects of Reiter’s syndrome. Immunobullous Dermatoses : Especially BP, CP, EBA and Pemphigus. Effective either singly or with other corticosteroids in BP.

21. Uses Autoimmune Connective tissue diseases For dermatomyositis / polymyositis not responding to corticosteroids. 25 mg weekly dose is required, response is assesed by following muscle strebght and change in muscle enzyme levels. Neutrophilic Dermatoses For neutrophilic dermatoses like Behcet’s disease, pyoderma gangrenosum and Sweet’s syndrome. Higher dose of 25 mg/week is required.

22. Dosage

23. Dosage 2 methods of weekly administration of oral Methotrexate. Once weekly dose. 3 divided doses over 24 hours each week : Weinstein Frost Regimen. When nausea is a significant problem. Related to cell cycle kinetics of psoriasis (36 hour cycle). Strict instructions should be given to adhere to the dose. Daily dosing inadvertently causes hematological toxicity .

24. Dosage Initial test dose of 5-10 mg to be given, then CBC and LFT taken 6-7 days later. Gradually increase dose at 2.5-5 mg/week for benefit without noticeable toxicity (stable CBC). Drug response is measured by area of involvement, erythema, induration and scaling. When there is maximal benefit, taper dose by 2.5 mg/week to assess lowest possible dose for disease control.

25. Dosage In c/o renal impairment and elderly, dose increments reduced to 2.5 mg/ week. Weekly dose <15 mg/week have low risk of hepatotoxicity. Maximum dose given is 30 mg/week. For poor patient compliance, and low bioavailability, use i /m or s/c routes (equipotent). Rapid renal clearance leads to tolerance of higher doses. When reintroduced, should be at a lower dose .

26. Contraindications

27. Contraindications Absolute : Pregnancy Category X Lactation Marked anemia, leukopenia, thrombocytopenia Active PUD Severe respiratory disease Severe hepatic compromise

28. Contraindications Relative: Chronic alcoholic (>100g / week) Decreased renal function, on dialysis. Metabolic Syndrome Hepatic disease. Contemplating conceptions. Active infectious disease, possible reactivation of TB infection. Immunodeficiency syndromes.

29. Adverse Effects

30. Hepatotoxicity Aggravated by Cumulative Mtx dose (>1.5 g) Type 2 DM High alcohol intake Obesity Hep B and C Baseline assessment: LFTs (AST, GGT) Hep B, Hep C USG to exclude gross liver pathology. Pretreatment liver biopsy. S. Ferritin to exclude hematochromatosis , Antimitochondrial autoabs to exclude PBC.

31. Hepatotoxicity Gold standard method of detecting hepatotoxicity : Liver Biopsy. Routine liver biopsies are controversial and carry small risk of serious complications. Serial LFTs are unreliable and poorly correlate with histolopathological changes.

32. Hepatotoxicity Non-invasive tests : Pro-collagen III peptides. Liver fibroelastography ( Fibroscan ) Radionuclide Tests. AAD guidelines recommend- In high risk patients, biopsy at the start of therapy, and with each 1.0-1.5 g dose. In low risk patients, no biopsy at the start, after cumulative 4.0 g dose and with each 1.5 g dose.

33. Pulmonary toxicity Acute pneumonitis, idiosyncratic reacion with extremely small doses. Some patients show a slower gradual pulmonary fibrosis.

34. Hematologic Effects Myelosuppression is the most common cause of death due to Mtx in psoriasis patients. . Significantly reduced by routine folic acid supplementation. Major risk factor is poor renal function. Care should be taken with potential drug interactions like TMP-SMX and NSAIDs. Supplement with folic acid (1-5 mg daily). In c/o significant myelosuppression , treat with leucovorin .

35. Gastrointestinal effects Commonly causes nausea and vomiting. Usually starts 12 hours after ingestion and lasts for 3 days. Possible solutions are taking Mtx with food, parenteral routes, dividing into 12 hrly doses once a week. If ulcerative stomatitis/severe diarrhea is present, cease Mtx therapy. Folic acid reduces GI toxicity, without reducing efficacy.

36. Reproductive effects Potent teratogen and abortifacient . Pregnancy is an absolute contraindication. Counsel women on Mtx about birth control. Use contraception for 3 months Men should be also be counseled about birth control and possible reversible oligospermia .

37. Renal effects High dose therapies (more common in t/t of malignancies) may precipitate Mtx in the renal tubules causing renal toxicity. Reduced renal function increases Mtx toxicity.

38. Adverse s/e Mild alopecia, headache, fatigue, dizziness. Recall reaction is seen. Rare s/e : Anaphylaxis, Acral erythema, Papular eruptions, Epidermal necrosis, Vasculitis , Osteopathy.

39. Mtx Overdose Clinically manifests as myelosuppression , mucosal ulceration, rarely acute skin ulceration. Toxicity is increased with interference in renal excretion due to dehydration or drug interactions. Folinic acid should be given immediately, preferably within 4 hours.

40. Mtx Overdose

41. Acute Mtx Toxicity

42. Management of Acute Toxicity Hydration : Approx 3L/m 2 /day till Mtx levels are <0.2μmol/L Alkalinization of urine: With sodium bicarb to prevent cryatallinization and promote excretion. Managing delayed Mtx excretion: Mtx induced nephropathy by crystal nephropathy and direct tubular toxicity. Glucarpidase is FDA approved. Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9

43. Management of Acute Toxicity Mtx induced myelosuppression : Neutropenia and febrile episodes have high risk of sepsis. Use of broad spectrum parenteral antibiotic. Oral care: Sit upright at 90 and lean forward, small frequent meals to be eaten slowly, soft food use straws Avoid acidic foods, spicy foods and tobacco Folinic acid mouth wash 15 mg 4 times/day. Syrup viscous lignocaine before meals. Sucralfate suspension.

44. Monitoring Guidelines

45. Monitoring Guidelines Minimum laboratory evaluations to be done pre-treatment: CBC including platelet count Renal Function Tests Liver enzyme levels Serologic Hep B/ Hep C levels Screening for HIV. In elderly patients, creatinine clearance should be estimated.

46. Monitoring Guidelines Baseline: Examination: Careful history and physical examination. Identification of patients at increased risk for toxicity. Recording other medications that patient is taking. Laboratory: CBC and platelet count. LFT Hep B, C serologic tests. Blood Urea Nitrogen, Creatinine . Screening for HIV.

47. Monitoring Guidelines Baseline Liver biopsy in high risk patients:

48. Monitoring Guidelines Baseline monitoring in low risk patients: Bishnoi P, Kumari R, Thappa DM. Monitoring methotrexate hepatotoxicity in psoriasis. Indian J Dermatol Venereol Leprol 2011

49. Monitoring Guidelines Rapid method of closely approximating the interval of 1.5g doses. Divide the number 12 by the number of 2.5 mg capsules = Number of years it will take to reach 1.5 g. Eg : Patient takes 4 capsules of 2.5 mg weekly, interval till 1.5 g is reached = 12/4 = 3 years.

50. Monitoring Guidelines Follow-up: CBC, Platelet Counts, LFTs 5-6 days after test dose, Every 1-2 weeks for 4 weeks. Gradually decrease the test frequency to every 3-4 months. Renal Function Test, to assess Mtx excretion.

51. Monitoring Guidelines During the initial therapy, patient should be closely monitored, with frequent CBC, LFTs and S. Creatinine measurements. If WBC< 3500/mm, platelet count <100,000/mm 3 ,liver transaminase increase over twice the normal upper values, discontinue or decrease the dose. Increased frequency of monitoring, for dose increase, intercurrent illness, or other drugs are started.

52. Intraesional Methotrexate Uses: Keratoacanthoma Squamous Cell Carcinoma Pyoderma gangrenosum Nail psoriasis Malignant Melanoma Side effects : Ulcer and necrosis at injection site. Pancytopenia on systemic absorption. Deshmukh NS, Belgaumkar VA, Mhaske CB, Doshi BR. Intralesional drug therapy in dermatology. IJDVL 2017.

53. Thank you.