Methotrexate in dermatology

pharmacokinetics, uses, side effects etc. of methotrexate in dermatology.

1. By : Dr. Kriti Maheshwari 1 st year Resident (M.D. DVL) Methotrexate in Dermatology

2. Structure : Methotrexate (4-amino-N10methyl pteroylglutamic acid) is a potent competitive antagonist (inhibitor) of the enzyme dihydrofolate reductase . It is structurally similar to folic acid, the natural substrate for this enzyme. Absorption and distribution: - MTX can be administered orally, intravenously, intramuscularly, or subcutaneously. - Concurrent food intake, especially milk-based meals, may reduce bioavailability in children. However, in adults the drug is unaffected by concurrent food ingestion. - The drug is well distributed throughout the body except in the brain, penetrating the blood–brain barrier poorly

3. Metabolism and Excretion : - Once absorbed, the level of MTX in the plasma has a triphasic reduction. - The first phase occurs rapidly (0.75 h) and reflects distribution of the drug throughout the body. - The second phase of the plasma level reduction is represented by renal excretion and occurs over 2–4 hours. - The third phase represents the terminal half-life and varies between 10 and 27 hours. This phase shows a slow release of MTX, primarily bound to dihydrofolate reductase , from the tissues. - 50% of MTX is bound to plasma proteins.

4. Mechanism Of Action DNA synthesis effects: inhibition of cell division being specific for the S phase (DNA synthesis) T cell effects: blocks migration of activated T cells into certain tissues Immunosuppresive effects : Suppresion of primary and secodary antibody responses Anti inflammatory effects: mediated by adenosine (which is anti inflammatory) Concurrent use of folic acid with MTX: controversial role - may decrease risk of GI side effects and pancytopenia - decreased chances of macrocytic anemia - Stops liver enzymes from increasing

5. Clinical Uses FDA Approved Indications : - Psoriasis - Sezary syndrome. Off label uses: Proliferative dermatoses : Pityriasis rubra pilaris , PLEVA, Reiter’s disease Immunobullous dermatoses : Pemphigus vulgaris , Bullous pemphigoid , Cicatricial pemphigoid , Epidermolysis bullosa acquisita . Autoimmune connective tissue diseases : Dermatomyositis , Subacute cutaneous lupus erythematosus , Systemic lupus erythematosus , Systemic scleroderma, Morphea /localized scleroderma, Scleredema diabeticorum . Vasculitis – neutrophilic dermatoses : Leukocytoclastic vasculitis , Cutaneous PAN, Behcet’s disease, Kawasaki disease, Pyoderma gangrenosum . Dermatitis : Atopic dermatitis Other dermatoses : Sarcoidosis , Keloids , Lymphomatoid papulosis , Keratoacanthomas ( intralesional ), Mycosis fungoides , Cutaneous Crohn’s disease, Chronic idiopathic urticaria

6. Contraindications Absolute : Pregnancy (Category X), Lactation. Relative : - Unreliable patients - Decreased renal function - DM, obesity - Hepatic diseases: active hepatitis, cirrhosis, h/o liver disease - Severe haematological abnormality - Man/ woman contemplating conception - Active infection. - Immunodeficiency syndromes.

7. Indications of MTX therapy of psoriasis Erythrodermic psoriasis. Psoriatic arthritis: not responsive to conventional therapy. Pustular psoriasis: generalized or debilitating localized disease. Psoriasis that adversely affects ability to maintain employment. Extensive, severe plaque psoriasis: not responsive to conventional therapy (usually > 20% surface involvement). Lack of response to phototherapy (PUVA and UVB) or retinoids .

8. Adverse Effects Hepatotoxicity : PIIINP serum test to help assess hepatic fibrosis Pulmonary toxicity – acute pneumonitis , pulmonary fibrosis. Haematologic effects - pancytopenia Malignancy induction - lymphomas GI effects – diarrhoea , vomiting, ulcerative stomatitis ( Stop MTX) Potent teratogen and abortifacient Oligospermia Renal toxicity on high dose treatment Others: mild alopecia, headache, fatigue, dizziness, potentially phototoxic.

9. Metotrexate Toxicity C/F – commonly pancytopenia , deranged LFT Rare – SJS, burning sensation of skin. Treatment – Leucovorin (or folinic acid) given within 12 hours of last MTX dose.

10. Drug Interactions

11. Therapeutic Guidelines 2 regimens Single weekly dose 3 divided doses/week over a 24 hr period ( eg . 8am and 8pm on the 1 st day and 8am on the 2 nd day) k/a Weinstein frost regimen. Adv : reduced GI upset - Disadv : increased risk of hepatic fibrosis. Generally , starting dose is 5-10mg/week Max dose – 25mg/week

12. Other Antifolate agents Also act by inhibiting  dihydrofolate reductase (DHFR). Proguanil : Malaria - prevention and treatment Trimethoprim : treatment & prophylaxis for  pneumocystis jiroveci pneumonia, malaria and toxoplasmosis. Pyrimethamine : used in malaria, toxoplasmosis Pemetrexed : used in non small cell lung carcinoma and mesothelioma

13. Thank you