Alkylating agents and platinums

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Cyclophosphamide Genuxal

Pharmacological Group: Alkylating antineoplastic agent, nitrogen mustard (oxazaphosphorine group).

Mechanism of Action: It is an inactive prodrug that requires hepatic oxidative biotransformation by the cytochrome P450 system (mainly CYP2B6 and CYP3A4) to generate 4-hydroxycyclophosphamide, in equilibrium with its tautomer aldophosphamide. Aldophosphamide is spontaneously cleaved in target tissues to produce the active cytotoxic compound phosphoramide mustard and a toxic and reactive byproduct, acrolein. Phosphoramide mustard produces the formation of inter- and intra-strand covalent cross-linking at the N7 position of the guanines of DNA, preventing replication and transcription during the S and G2 phases of the cell cycle.

Pathophysiology and Prevention of Hemorrhagic Cystitis: MESNA

Acrolein excreted in urine is a highly reactive electrophile that damages the capillaries of the bladder transitional epithelium. To prevent this serious complication, the antidote MESNA (sodium mercaptoethane sulfonate) and forced hydration are administered together. MESNA contains a free thiol group (nucleophile) that covalently binds to acrolein inside the urinary bladder, forming a stable, non-toxic and water-soluble adduct that is eliminated in the urine without attacking the mucosa.

Oncological and Immunosuppressive Emergency Dosage

Oncology (IV): Various regimens, usually 500 to 1500 mg/m² IV as part of combined regimens (e.g. FAC regimen for breast).
Immunology (Lupus Nephritis): NIH protocol: 500-1000 mg/m² IV monthly for 6 months. Euro-Lupus Protocol: 500 mg IV every 2 weeks for a total of 6 doses.
Renal Adjustment: CrCl <10 mL/min: reduce dose by 25-50% due to accumulation of polar active metabolites.

Pregnancy: Category D (Teratogen proven, skeletal malformations) Breastfeeding: Contraindicated Cisplatin Platinol

Pharmacological Group: Inorganic antineoplastic agent based on heavy metals (platinum coordination).

Mechanism of Action: Upon entering the tumor cell (where the chloride concentration is significantly lower than in the extracellular stream), cisplatin undergoes a displacement reaction of its chloride ligands by water, becoming a positively charged reactive species. This electrophilic intermediate binds covalently to DNA, with a preference for the N7 position of purines (especially guanine). It forms intrastrand guanine-guanine adducts (1,2-intrastrand d(GpG)) that severely distort the double helix, preventing cellular replication and transcription and inducing a G2 phase arrest and the subsequent apoptotic cascade mediated by p53.

Clinical Pearl: Hydration and Emetic Control Protocol

To minimize severe renal toxicity, cisplatin is never administered without aggressive prehydration and posthydration of 2 to 3 liters of isotonic saline with the addition of potassium chloride, magnesium sulfate, and mannitol to ensure a urine output greater than 100 mL/hour. Extreme emetogenic potential requires triple premedication with 5-HT3 receptor antagonists (ondansetron), neurokinin-1 antagonists (aprepitant), and intravenous dexamethasone.

Dosage and Critical Adjustments

Usual Dose: 50-100 mg/m² IV administered as an infusion over 4-6 hours in cycles of 3 or 4 weeks.
Renal Adjustment: Should not be administered if serum creatinine is greater than 1.5 mg/dL or CrCl is less than 50 mL/min. In patients with CrCl 50-60 mL/min, consider substitution with carboplatin or reduce the dose by half.

Pregnancy: Category D (Mutagenic and teratogenic effects) Breastfeeding: Contraindicated