25 terms

Pharmacology: alkylating agents

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What are the Nitrogen Mustards?
Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, bendamustine, chlorambucil
What are the alkylators? MOA?
Nitrogen mustards, nitrosoureas, alkyl sulfonate, Triazenes, platinum agents, ethylenimines; MOA: form strong electrophiles through the formation of carbonium ion intermediates - results in the formation of covalent linkages by alkylation of various nucleophile moioeties. They also alkylate DNA, RNA and proteins (predominantly N-7 of guanine)
Mechlorethamine (parent drug)
nitrogen mustard; Bi-functional alkylator; results in the release of Cl- and the formation of a highly reactive ethylenimium intermediate (aziridinium ion) that has a reaction with guanine at N-7;
Cyclophosphamide
Nitrogen mustard; toxicity: syndrome of inappropriate ADH secretion (SIADH), cardiotoxicity, interstitial pulmonary fibrosis, hemorragic cystitis (vigorous hydration is sufficient to avoid hemorragic cistitis)
Ifosfamide
Nitrogen mustard; slower metabolism than cyclophosphamide results in larger doses required and thus higher toxicity; toxicity: neurologic toxicity , hemmoragic cystitis, nephrotoxicity
MESNA
rescue agent that must be given with ifosfamide and high doses of cyclophosphamide to avoid hemorrhagic cystitis (secondary to metabolite acrolein); Mech: The sulfhydrl group binds with acrolein to form a stable nontoxic product, reducing the complications of hemorrhagic cystitis
Melphalan (alkeran)
nitrogen mustard; toxicities: delayed nausea/ vomiting, mucositis (severe inflammation of GI tract)
Bendamustine (treanda)
nitrogen mustard; bifunctional mechlorethamine derivative with a purine like ring; produces double- and single stranded breaks in DNA; toxicities: nausea/vomiting, fevers, and myelosuppression. Hypersensitivity reactions may occur
Chlorambucil (Leukeran)
aromatic analog of nitrogen mustard; forms a positively charged ethylene immonium ion which binds to electron rich nucleophilic sites on biologic molecules; preferred binding site of alkylation is N-7 position of guanine; toxicites: myelosuppresion (neutropenia), N/V, hyperuricemia
What are the Nitrosoureas?
Carmustine, lomustine, streptozocin; bind to O-6 of guanine, highly lipophilic, cross blood brain barrier, cause prolonged myelosuppression
Carmustine
Nitrosourea; given IV, but also available in a biodegradable polymer wafer; toxicity: myelosuppresion, phlebitis, pulmonary toxicity
Lomustine
Nitrosourea; given PO (oral) only; toxicity: melosuppresion, N/V
Streptozocin (zanosar)
Nitrosourea; metabolites cross the blood brain barrier; selectively concentrates in pancreatic beta cells (due to glucose moiety); concurrent use with steroids may result in sever hyperglycemia
What is the alkyl sulfonate?
Busulfan
Busulfan
alkyl sulfonate; alkylates N-7 of guanine, cross-linking causes cytotoxic effects; toxicity: pulmonary fibrosis, seizures, veno-occlusive disease; therapeutic drug monitoring
What are the Triazenes (non-classical alkylators)?
procarbazine, decarbazine, temozolamide; create single stranded breaks, contain N-methyl group but lack bifunctionality, alkylate O-6 of guanine
Procarbazine
Triazene; weak MAO (catecholamine metabolizer) inhibitor (many drug/food interactions)
Decarbazine
Triazene; Prodrug, severe N/V
Temozolomide
Triazene; oral equivalent of dacarbazine, highly lipophilic, spontaneous hydrolysis
What are the platinum agents? Mechanism?
Cisplatin, carboplatin, oxaliplatin; mechanism similar to alkylating agents; formation of intrastrand cross links with DNA or RNA; exchange chloride ions for nucleophilic groups of various kinds. Binds to N7 of guanine or adenine; intrastrand (90%) or interstand (5%) linking; forms DNA adducts
Carboplatin
platinum agent; toxicity: myelosuppression (DLT), delayed hypersensitivity (unique), N/V
Cisplatin
Platinum agent: toxicity: nephrotoxicity/electrolyte wasting (decrease in creatinine clearance), peripheral neuropathy, ototoxicity, 100% N/V
Oxaliplatin
Platinum agent; Toxicity: Peripheral neuropathy (acute peripheral symptoms exacerbated by cold- very unique toxicity), pharyngolaryngeal dysesthesia, N/V
What is the Ethylenimine?
Thiotepa
Thiotepa
Ethylenimine; alkylates the N-7 position of guanine; given intravesicalularly, IV, PO
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