Immunosuppressive antimetabolites

Mechanism

Mycophenolate Mofetil CellCept, Myfortic (Sodium)

Pharmacological Group: Immunosuppressant, selective inhibitor of purine synthesis.

Mechanism of Action: It is a prodrug that undergoes rapid hydrolysis to become its active metabolite, mycophenolic acid (MPA). MPA inhibits in a reversible, non-competitive and potent manner the enzyme inosine monophosphate dehydrogenase (IMPDH), specifically the type II isoform, overexpressed in activated lymphocytes. This enzyme catalyzes the conversion of IMP to xanthosine monophosphate, the limiting step for the de novo synthesis of the nucleotide guanosine (GMP). Since T and B lymphocytes lack the purine rescue pathway and depend exclusively on the de novo pathway, mycophenolate suppresses their cell proliferation and inhibits endothelial adhesion mediated by glycosylation.

Management of Hematological and Gastrointestinal Toxicity

Mycophenolate diarrhea can be debilitating and correlates with direct toxicity of the gastrointestinal mucosa. Changing the formulation from mofetil to enteric sodium (Myfortic) reduces upper gastric symptoms. If the absolute neutrophil count falls below 1,300/mm³, the drug dose should be discontinued or reduced and administration of granulocyte colony-stimulating factor (G-CSF) should be evaluated.

Extreme Teratogenicity (REMS Strategy)

Black Box Warning: Mycophenolate is a potent human teratogen. It causes spontaneous abortions in the first trimester (up to 45%) and serious congenital malformations (microtia, cleft lip, cleft palate, agenesis of the corpus callosum, congenital heart disease).
Mandatory Protocol: A negative pregnancy test is required before starting treatment, repeating the test after 8-10 days, and strict use of two effective contraceptive methods during treatment and up to 6 weeks after its completion.

Pregnancy: Category D (Teratogen proven) Breastfeeding: Contraindicated Azathioprine Imuran

Pharmacological Group: Immunosuppressant, purine analogue (antimetabolite).

Mechanism of Action: It is an imidazole-derived prodrug that is cleaved non-enzymatically in the erythrocyte and tissues to release 6-mercaptopurine (6-MP). 6-MP is metabolized in the cell by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to thioguanine nucleotides (6-TGN) and guanosine deoxythioribonucleotides. These metabolites are incorporated into cellular DNA and RNA, causing termination of the nucleotide chain, chromosome breaks and inhibition of de novo synthesis of purines by feedback on the enzyme glutamine-5-phosphoribosylpyrophosphate amidotransferase.

Safety Pearl: TPMT Genotyping and Interaction with Allopurinol

Severe hematological toxicity from azathioprine is closely linked to the enzymatic activity of TPMT. Patients with hereditary homozygous TPMT deficiency (0.3% of the population) metabolize the drug almost entirely through the active 6-TGN pathway, developing fatal pancytopenia with standard doses. Critical Interaction: Allopurinol (xanthine oxidase inhibitor) blocks the main catabolic pathway of 6-MP. If co-administration is essential, the dose of azathioprine should be reduced to 25%-33% of the usual dose and weekly blood counts monitored.

Dosage and Special Warnings

Dosage Adults: Transplant: 3-5 mg/kg/day IV/PO on the day of the intervention, progressively reducing to maintenance of 1-3 mg/kg/day. Autoimmune diseases: 1-2.5 mg/kg/day.
Pediatrics: Same dosage range based on body weight. Not recommended for systemic juvenile arthritis.
Renal Adjustment: CrCl <10 mL/min: administer 50% of the usual dose or increase the interval to 36-48 hours.

Pregnancy: Category D (Crosses placenta, but is used in high-risk pathologies such as lupus nephropathy) Breastfeeding: Not recommended

Indicators and dose

Methotrexate (Immune Dose) Ledertrexate, Metoject

Pharmacological Group: Disease-modifying drug (DMARD), immunosuppressant, folate synthesis inhibitor.

Mechanism of Action: At low weekly doses used in immunology (less than 25 mg/week), its main mechanism differs from classic oncological cytotoxicity. Although it partially inhibits dihydrofolate reductase (DHFR), its systemic anti-inflammatory activity is attributed to the inhibition of the AICAR transformylase enzyme by methotrexate polyglutamate derivatives. This causes an intracellular accumulation of AICAR, leading to the extracellular release of adenosine, a potent anti-inflammatory autacoid mediator that inhibits the activation, adhesion and secretion of proinflammatory cytokines (TNF-alpha, IL-1) in neutrophils, macrophages and T cells.

Clinical Pearl: Rescue and Supplementation with Folic Acid

To significantly reduce the incidence of stomatitis, nausea, macrocytic anemia and elevation of liver enzymes induced by low-dose methotrexate, it is mandatory to prescribe folic acid (5 mg orally) or folinic acid administered once a week, exactly 24 or 48 hours after the methotrexate dose. Its use on the same day as the drug may compromise immunosuppressive efficacy.

Dosage, Safety and Interactions

Dosage Adults (Be careful! Weekly Schedule): 7.5-25 mg once a week PO, SC or IM. Involuntary daily dosing due to prescription or patient intake error causes spinal aplasia and fulminant gastrointestinal toxicity.
Renal Adjustment: CrCl 10-50 mL/min: administer 50% of the dose. CrCl <10 mL/min: contraindicated.
Critical Interactions: The use of acetylsalicylic acid, NSAIDs or penicillins reduces the tubular secretion of methotrexate, dangerously increasing its plasma concentrations.

Pregnancy: Category X (Potent teratogen, abortifacient) Breastfeeding: Contraindicated