METHOTREXATE

Submitted by-
NAVODITA SETH (ZO-228)
NISHA KESARI (ZO-246)
BMS 2nd YEAR

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 INTRODUCTION OF DRUG
1. It is an antimetabolite.
2. Currently known as amethopterin
3. Trade name of the drug - Otrexup™, Rasuvo®, Rheumatrex®,
Trexall, Dose pack, Xatmep.
4. Used for the treatment of following diseases-
1. Cancer
2. Auto immune disorders
3. Ectopic pregnancy
4. Abortion

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 CHEMICAL FORMULA
1. IUPAC NAME -
(2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl(methyl)amino}phenyl)formamido]pentanedioic
acid
2. Formula - C20H22N8O5
3. Molar Mass – 454.44 g/mol
 HISTORY/ DISCOVERY
1. Discovered by Indian Biochemist Yellapragada Subbarow.
2. It is discovered after the discovery of folic acid structure.
3. Initially, a drug named aminopterin, a chemical analogue of folic
acid was used to treate cancer.
4. But it was found that the therapeutic index of methotrexate was
better than that of aminopterin,
5. So the clinical use of aminopterin was thus abandoned in favour
of methotrexate.

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SYNTHESIS
MECHANISM OF ACTION IN CANCER
TREATMENT
1. Methotrexate competitively inhibits dihydrofolate reductase
(DHFR), an enzyme that participates in the tetrahydrofolate
(FH4)synthesis.
2. DHFR catalyses the conversion of dihydrofolate (FH2) to the active
cofactor tetrahydrofolate.
3. Depletion of the cofactor has its greatest effect on the enzyme
thymidylate synthase, resulting in the lowered synthesis of dTMP
(deoxythymidine mono phosphate)

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 MECHANISM OF ACTION IN CANCER
TREATMENT
Fig.1 – From Patrick Fig.2- From Lehninger

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TYPES OF CANCER TREATED USING
METHOTREXATE
1. Acute lymphoblastic leukemia
2. Breast cancer
3. Gestational trophoblastic disease
4. Head and neck cancer (certain types)
5. Lung cancer
6. Mycosis fungoides (a type of cutaneous T-cell lymphoma)
7. Non-Hodgkin lymphoma (advanced stage)
8. Osteosarcoma

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 ANTI-INFLAMMATORY MECHANISM
1. Within the cell, by action of the enzyme folyl-polyglutamate synthetase (FPGS),
the MTX is converted into polyglutamate forms known as MTXPG.
2. The MTXPG inhibit the enzyme ATIC (AICAR transformylase), which leads to
intracellular accumulation of AICAR {AICA Ribonucleoside / adenosine 5-
aminoimidazole 4- carboxamide ribonucleoside }.
3. This product and its metabolites inhibit two enzymes which are important in the
metabolism of adenosine, adenosine deaminase and AMP deaminase, causing
intracellular accumulation of adenosine nucleotides, that when dephosphorylated,
generate extracellular accumulation of adenosine, a powerful anti-inflammatory
agent.
ANTI-INFLAMMATORY MECHANISM

Flow chart -
by Aastha
TYPES OF AUTO IMMUNE DISORDERS
TREATED USING METHOTREXATE
1. Rheumatoid arthritis
2. Juvenile dermatomyositis
3. Psoriasis
4. Psoriatic arthritis
5. Lupus
6. Sarcoidosis
7. Crohn's disease
8. Eczema

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 DOSAGE
The recommended dosage for methotrexate can vary to different types of cancer, drug tolerance of
the patient and BMI.
Low Dose Methotrexate High Dose Methotrexate
1. Ranges from 7.5mg/m2 to 30mg/m2 1.Range: greater than 500mg/m2
for treatment 2.It is administered only once a week
2.It is administered weekly as a single dose or 3.HDMTX is used to treat various types
split up into three doses which is of cancers.
administered for every 12 hours.
3.LDMTX is used to treat:- Rheumatoid
arthritis, Psoriasis, Psoriatic arthritis
DOSAGE
MECHANISM OF ACTION IN ABORTION
AND ECTOPIC PREGNANCY
1. Main mechanism of action of the drug is same as that in cancerous cells.
2. It interferes with cell growth and specifically interferes with rapidly dividing
cells. Methotrexate primarily affects the trophoblast cells and inhibits its
growth.
3. Methotrexate is used in conjunction with misoprostol.
4. Misoprostol is an analoge of prostaglandin. By interacting with
prostaglandin receptors, mifepristone causes the cervix to soften and the
uterus to contract, resulting in the expulsion of the uterine contents.

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MECHANISM OF ACTION IN ABORTION
AND ECTOPIC PREGNANCY

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 PHARMACODYNAMICS OF MTX
1. Administered both Orally and Parenterally
2. Distribution: Methotrexate is widely distributed into body tissues with
highest concentrations in the kidneys, gallbladder, spleen, liver and skin.
Methotrexate in serum is approximately 50% protein-bound
3. Parenteral - Completely absorbed with T max 30-60 mins
4. Methotrexate has a bioavailability of 64-90%, decreases at oral doses
above 25mg due to saturation of the carrier mediated transport of
methotrexate.
 PHARMACODYNAMICS OF MTX
6. Oral Methotrexate has a T max of 1 to 2 hours.
7. Oral doses of 10-15µg reach serum levels of 0.01-0.1µM.
8. Half life is dose dependent -
– low dose methotrexate is 3 to 10 hours in adults.
– high dose methotrexate is 8 to 15 hours.
9. Pediatric patients-
– acute lymphoblastic anaemia terminal half life of 0.7 to 5.8 hours.
– juvenile idiopathic arthritis terminal half life of 0.9 to 2.3 hours.
10.Does not cross Blood Brain barrier
 PHARMACOKINETICS OF MTX
1. Methotrexate is >80% excreted as the unchanged drug and
approximately 3% as the 7-hydroxylated metabolite.
2. Methotrexate is primarily excreted in the urine with 8.7-26% of an
intravenous dose.
3. The renal clearance of methotrexate is influenced by a no. of compounds
such as probenicid, salicylate and sulfisoxazole which
diminish the renal transport of methotrexate.
4. Dose adjustment required in CKD ( Renaly compromised) patients, Elderly
and Pediatric population
5. Not Recommended during Pregnancy and Lactation (is passed into Breast
Milk)
 TOXICITY
1. Myelosuppression
2. Gastrointestinal epithelial denudation
3. Renal tubular obstruction and Acute kidney Injury
4. Hepatotoxicity
5. Pneumonitis
6. Neurotoxicity
7. Mucositis
SIDE EFFECTS OF METHOTREXATE
1. Drowsiness , Nausea or vomiting , Diarrhea
2. Hair loss
3. Tiredness, dizziness, fever
4. Sores in mouth ,skin
5. Bruising more easily, sun sensitivity
6. Increased risk of infection
7. Stuffy or runny nose, sore throat , lungs and bronchitis
8. Abnormal results on liver function tests

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 REFERENCES
1. An Introduction to Medicinal Chemistry 5th EDITION Graham L. Patrick
2. https://www.cancer.gov/research/progress/discovery/methotrexate
3. https://link.springer.com/chapter/10.1007/978-3-0348-8452-5_1
4. https://en.wikipedia.org/wiki/Methotrexate
5. https://pubmed.ncbi.nlm.nih.gov/10846320-mode-of-action-of-medical-methods-of-abortion/
6. https:// www.healthline.com/health/methotrexate-self-injectable-solution#side-effects
7. DOI: 10.1016 / j.rcreue.2016.08.002
8. https://doi.org/10.1038/s41584-020-0373-9
9. K.D Tripathi: Essentials of MEDICAL PHARMACOLOGY
10. http://chemocare.com/chemotherapy/drug-info/Methotrexate.aspx

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