Methotrexate is a synthetic drug that interferes with cell growth and reduces inflammation. It is used as a chemotherapeutic, immunosuppressive, and anti-inflammatory agent to treat several dermatological conditions like psoriasis, immunobullous disorders, and vasculitis. It works by inhibiting dihydrofolate reductase and thymidylate synthase, decreasing DNA synthesis and replication. Common side effects include myelotoxicity, hepatotoxicity, and gastrointestinal toxicity. Due to its teratogenic effects, pregnancy is contraindicated and regular monitoring of blood tests is required when taking 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: C20H22N8O5

6. Common Brand Names:
 Cytotrexate 2.5 mg

7. 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

8. 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

9. 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

10. 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

11. Mechanism of action:

13. 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)

14. Dermatological Indications:
 Severe Psoriasis
 Immunobullous disorders
 Pemphigus
 Bullous pemphigoid
 Cicatricial pemphigoid

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

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

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

18. 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

19. Adverse effects:
 Systemic:
 Myelotoxicity
 Hepatotoxicity
 GI toxicity
 Nephrotoxicity
 Reproductive toxicity
 Pulmonery toxicity
 Malignancy

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

21. Drug-drug interactions:

22. 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

23. 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

24. Continued:
 Vaccinations
 Pneumococcal
 Influenza
 Hep B
 Vericella zoster virus
 Pregnancy test
 CXR

25. 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

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