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Alkylating Agents. Presented by : Clinical Pharmacist: Heba Sabry,Reem Ahmed,Dina redda,Dalia El-Magraby and Heba Othman. Pharm-D 4 (2009) Group 1. Alkylating Agents.
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Alkylating Agents Presented by : Clinical Pharmacist: Heba Sabry,Reem Ahmed,Dina redda,Dalia El-Magraby and Heba Othman. Pharm-D 4 (2009) Group 1.
Alkylating Agents • Contain an alkyl group (highly reactive chemical group which allow them to form irreversible covalent bond with other molecules specially at the cross link of DNA). • In DNA, the N-7 position of guanine is especially susceptible to alkylation, it interferes with separation of the strands and prevent mitosis.
COMMON STRUCTURE or CH2CH2 + -- - Nu N Ar Enzyme, proteins DNA, RNA CH2CH2Cl
Alkylating Mechanism of Mechlorethamine With Guanine Base + N7-N7 Biguanyl DNA cross link
2-Formation of cross bridges, bonds between atoms in the DNA.
3-Induction of mispairing of the nucleotides leading to mutations.
Classification of alkylating agents Nitrogen Mustard Nitrosourea Ethylenamines Alkylsulfonate Triazine Metal salts Melphalan Carmustine Thiotepa Busulfan DTIC Cisplatin Chlorambucil Lomustine Carboplatin Ifosfamide Oxatiplatin Cyclophosphamide
Metabolism of IfosfamideGeneration of CAA may explain differing antitumoral activities of IFO and cyclophosphamide and Suppression of CAA metabolic pathway , although it may be beneficial as a means of reducing neurotoxic responses, may also be associated with a reduction in antitumor effect.
Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite, 4-carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide have been shown to interact with DNA.
Prophylaxis against hemorrhagic cystitis • Against hemorrhagic cystitis, hyperhydration and mesna given. IV dose of mesna is 20% given at 0, 4, 8 hours or (1mg/mg drug). May be given orally at 4, 8 hours at 40% of the drug dose diluted in water or juice. • Patients are encouraged to: - drink plenty of water ( fluids) during therapy( most adults will require at least 2L/day ) . -Void frequently . - Avoid taking the drug at night . • Mesna react with acrolein and urotoxic metabolites to form nontoxic metabolites . • Oral absorption of mesna is 50% bioavailability so oral dose should be double that of IV dose.
Mesna Upon entering the bloodstream mesna is immediately converted to an inactive disulfide form, dimesna (dithiodiethanesulfate) which is subsequently filtered and secreted by the kidneys, where the enzymes thiol transferase and glutathione reductase reduce dimesna back to mesna. The free sulfhydryl (thiol) groups of mesna combine directly with a double bond of acrolein and with other urotoxic 4-droxyoxazaphosphorine metabolites (4-hydroxycyclophosphamide and 4-hydroxyifosfamide) to form stable nontoxic compounds. The metabolite acrolein has been implicated as the major causative agent in oxazaphosphorine-induced urothelial toxicity
Radiation and Platinum Drug Interaction Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects. The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships.
Recommendations for minimizing Nephrotoxicity include: • Prepare cisplatin in saline containing vehicles. • Infusion rate of cisplatin. • Vigorous hydration(2 L glucose and normal saline) + KCl + MgSO4 before cisplatin administrarion. • Simultaneous administration of either mannitol or furosemide. • Maintaining urine output 100-150 ml/hr for 24 hours after cisplatin administration. • Avoid other nephrotoxic agents (aminoglycosides,amphotericin…etc.).
