Methotrexate

This presentation is about a skincare drug methotrexate

1. Methotrexate

2. Objectives: Overview of the drug Pharmacology Indications in dermatology Dosage Adverse effects Contraindications Monitoring

3. Introduction: Synthetic DMARD that interferes with: Cell growth Slows production of new cells Reduces inflammation Used as: Chemotherapeutic Immunosuppressive Anti-inflammatory

4. Introduction: Toxic Folic acid analogue Formula: C 20 H 22 N 8 O 5

5. Common Brand Names: Cytotrexate 2.5 mg

6. History: Formarly known as Amethopterin Used in 1958 by Edmundson & Guy in treatment of Psoriasis Berlin suggest intermittent dosage schedule in 1963 Weinstein and Frost introducd weekly dosage schedule in 1971

7. Administration,Absorption and distribution: Administered orally, I/V, I/M or S/C Intrathecal in some chemotherapeutic regimens Triphasic reduction in plasma level distribution renal excretion termination

8. Mechanism of action: DNA synthesis effects: Inhibit Dihydrofolate reductase which converts dihydrofolate to tetrahydrofolate Tetrahydrofolate is essential for DNA synthesis DNA Replication effects: Inhibit thymidylate synthase Decrease dTMP sythesis

9. Continued: Anti-inflammatory effects: Inhibits AICART enzyme and increase adenosine concentration Inhibits MTHFR and decrease methionine concentration T-cell effects: Inhibit T cells activation Suppression of intracellular adhesion molecules

10. Mechanism of action:

11. Pharmacokinetics Bioavailability : 60% Protein Binding : 35-50% Carrier protein: RFC1 Metabolism: Hepatic and intracellular Half Life : 6-8 Hrs Excretion : Urine (8-100%),bile (small amount)

12. Dermatological Indications: Severe Psoriasis Immunobullous disorders Pemphigus Bullous pemphigoid Cicatricial pemphigoid

13. Continued: Connective tissue disorders: Dermatomyositis Lupus erythromatosus Scleroderma Vasculitides Neutrophilic dermatosis Pyoderma gangrenosum Sweet syndrome

14. Continued: Inflammatory disorders Atopic eczema Sarcoidosis Cutaneous crohn disease Chronic idiopathic urticaria Proliferative disorders Mycosis fungoides Sezary syndrome Pityriasis lichenoides Petyriasis rubra pilaris

15. Contraindications: Absolute: Pregnancy Lactation Hypersensitivity Relative: Diabetes Mellitus Obesity Blood dyscrasias Alcohol intake Hepatic and renal impairment Immunodefeciency and latent infection

16. Dosage and preparations: 0.2-0.4 mg/kg Varies from 2.5 to 25mg Should not exceed 25mg weekly Oral: 2.5 mg 10 mg Injectable: ( I.M, I.V, S.C) 5 mg 50 mg 500mg Accumulation dose: 1.5 gm

17. Adverse effects: Systemic: Myelotoxicity Hepatotoxicity GI toxicity Nephrotoxicity Reproductive toxicity Pulmonery toxicity Malignancy

18. Continued: Cutaneous: Aphthous stomatitis Alopecia Hyperpigmentation Phototoxicity Toxic epidermal necrolysis Ulceration in psoriatic plaques Acral erythema Vasculitis

19. Drug-drug interactions:

20. Folate supplementation Folic acid: Competes with MTX for DHFR Reduce bone marrow,GI tract and liver adverse effects 5 mg once weekly on day following MTX Folinic acid: Also known as leucovorin Used in MTX toxicity Bypass step catalyzed by DHFR and competes with MTX for RFC1 intracellular transportation Rescue bone marrow and GI cells 5 mg three doses at 12 hrs interval after 24 hrs of MTX weekly dose if folic acid is not improving GI symptoms,liver abnormalities or macrocytosis

21. Pretreatment screening: Patient information leaflet Risk counselling Infection Bone marrow suppression Skin malignancy Contraception Sun protection measures Blood tests CBC U/E LFTs Hep B/C Serology

22. Continued: Vaccinations Pneumococcal Influenza Hep B Vericella zoster virus Pregnancy test CXR

23. Monitoring: Close monitoring in elderly and renal patients Blood tests: CBC,LFTs and creatinine Weekly for 1 month 2 weekly for 2 months Monthly for 3 months 3 months afterwards Symptoms of bone marrow supresssion Avoidence of drugs which interact with MTX Serum liver fibrosis markers Procollagen-III aminoterminal propeptide,hyaluronic acid,tissue inhibitor of matrix metalloproteinase-1

24. Take home message: MTX is a human teratogen and abortificient -avoid pregnancy Requires regular blood tests monitoring Used for a veriety of dermatological diseases