25 terms

Pharmacology: alkylating agents


Terms in this set (...)

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;
Nitrogen mustard; toxicity: syndrome of inappropriate ADH secretion (SIADH), cardiotoxicity, interstitial pulmonary fibrosis, hemorragic cystitis (vigorous hydration is sufficient to avoid hemorragic cistitis)
Nitrogen mustard; slower metabolism than cyclophosphamide results in larger doses required and thus higher toxicity; toxicity: neurologic toxicity , hemmoragic cystitis, nephrotoxicity
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
Nitrosourea; given IV, but also available in a biodegradable polymer wafer; toxicity: myelosuppresion, phlebitis, pulmonary toxicity
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?
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
Triazene; weak MAO (catecholamine metabolizer) inhibitor (many drug/food interactions)
Triazene; Prodrug, severe N/V
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
platinum agent; toxicity: myelosuppression (DLT), delayed hypersensitivity (unique), N/V
Platinum agent: toxicity: nephrotoxicity/electrolyte wasting (decrease in creatinine clearance), peripheral neuropathy, ototoxicity, 100% N/V
Platinum agent; Toxicity: Peripheral neuropathy (acute peripheral symptoms exacerbated by cold- very unique toxicity), pharyngolaryngeal dysesthesia, N/V
What is the Ethylenimine?
Ethylenimine; alkylates the N-7 position of guanine; given intravesicalularly, IV, PO