Alkylating Agents Pharmacology Flashcards
Which atom is common in Alkylating agents?
Chlorides
MOA of Alkylating agents
-Cl ion acts as the leaving group
-the drug is now positively charged (+)
-the drug (+) forms a covalent bond with the base of the DNA (permanent)
-second Cl ion leaves -> the drug forms another covalent bond on two different bases
-> Cross-Linking of DNA
What are the possible results of crosslinking DNA?
-base excision
-miscoding
-strand breakage
-DNA adducts
What is a dangerous side effect of alkylating agents?
Secondary malignancies, especially leukemia
bc the drug causes damage binds covalently to other healthy cells and causes mutations
What are the Hallmark toxicities of all cytotoxic agents?
-Myelosuppression
-Mucositis
-Nausea
-Alopecia
What are the unique toxicities of alkylating agents?
-secondary leukemia
-Gonadotoxicity (infertility) -> counsel the patient
When does myelosuppression occur, how long does it last?
typically begins 7–10 days after the initiation of treatment
recovery: starts 3–4 weeks after the treatment
When does mucositis occur, and how long does it last?
mucositis starts 5-7 days
recovery: 2-3 weeks after treatment
What is the unique toxicity of Cyclophosphamide?
Hemorrhagic cystitis
Which toxic metabolite causes hemorrhagic cystitis?
Acrolein (metabolite of Cyclophosphamide)
Acrolein is excreted in the urine -> causes bleeding in the bladder
Which Chemoprotectant prevents hemorrhagic cystitis?
Mesna, it deactivates Acrolein (given at high dose of Cyclophosphamide, before chemotherapy)
usually, hydration is enough to flush out Acrolein
What is the brand name of Cyclophosphamide?
!!!
Cytoxan
Cyclophosphamide is myelosuppressive and ______
immunosuppressive
impairs the function of mature T-cells
(myelosuppressive = killing precursor blood cells, not mature blood cells)
Unique toxicity of Ifosfamide
-Hemorrhagic Cystitis (Acrolein)
-Neurotoxicity (Chloro-acetate aldehyde)
When should Mesna be used?
!!! ALLWAYS with Ifosfamide: + IV hydration
The dose of Ifosfamide is much higher than with Cyclophosphamide -> so it will definitely cause hemorrhagic cystitis if not given with Mesna
-high dose Cyclophosphamide + oral hydration (2-3L)
-impaired renal function and Cyclophosphamide
Besides hemorrhagic cystitis, which side effect may occur with the use of Ifosfomide? Name risk factors.
Neurotoxicity !!!
Risk factors
-Renal function
-Albumin (higher free fraction in Hypoalbuminemia)
What is the brand name of Ifosfamide?
!!!
Ifex
How does Cisplatin work?
Cl- leaves the drug -> ACTIVATION
the drug is positively charged and binds a covalent bond to DNA
-> causes Cross-linking
Cisplatin binds to which specific part of the DNA?
N7 (nitrogen 7) of purine bases (often guanine)
What are the toxicities of Cisplatin?
-N/V !!! (causes the most N/V of cancer drugs)
-Neuropathy (chronic)
-Nephrotoxicity (acute and chronic)
-Ototoxicity
-Gonadal toxicity (risk of infertility,)
The highly reactive intermediate of Cisplatin leads to side effects by binding to which type of cells?
Kidney cells -> Nephrotoxicity
concentration-dependent
What are chronic and acute signs of Nephrotoxicity?
Hypokalemia
Hypomagnesemia
have to give potassium and magnesium
What should be given with Cisplatin to prevent Nephrotoxicity?
IV normal saline (1L) before and after treatment
NaCl is preferred over dextrose bc the reactive positive charged drug binds to Cl(-) from NaCl
increasing the infusion interval can help since it is concentration-dependent
What is the key toxicity in Carboplatin?
Bone marrow suppression -> thrombocytopenia
-has some N/V, mucositis
How is the dose of Carboplatin determined?
Calvert equation
dose (mg) = AUC x (GFR (CrCl) + 25)
don’t use if CrCl above 125 (125 is max that should be used in calculations)
What are the toxicities of Oxaliplatin?
Bone marrow suppression, some nausea
-Unique peripheral neuropathy for a few days (worse at cold temperatures, winter, and cold drinks) !!! Counsel the patient !!!
-chronic use can cause irreversible peripheral neuropathy
