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Brief Review of Renal Failure With Chemotherapeutic AgentsBYRAMESH.KASARLAPHARM D(PB) 5th YEARSVCP

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WHAT is CHEMOTHERAPY ..??Chemotherapy:In the original sense, a chemical that binds to and specifically kills microbes or tumor cells. The term chemotherapy was coined in this regard by Paul Ehrlich(1854-1915).In oncology, drugtherapyfor cancer. Also called "chemo" for short.It may consist of single drugs or combinations of drugs. Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.

Renal damage with chemotherapeutic drugsSome chemotherapy drugs can damage the kidneys (nephrotoxicity). The kidneys break down and remove many chemotherapy drugs from the body. When chemotherapy drugs break down, they make products that can damage cells in the kidneys, ureters and bladder etc

WHAT ARE THE SYMPTOMS OF KIDNEY DAMAGE..?Decrease in amount of urine or frequencyPain or urgency with urinationDark urine , Blood in urine ,FatigueMuscle weakness , Swelling in feet or anklesNausea or vomiting , Confusion, seizure

HOW IS KIDNEY DAMAGE DIAGNOSED ..?Blood urea nitrogen (BUN): BUN levels range from 10-25 mg/dL(milligrams per deciliter) of blood.Creatinine: creatinine levels range from 0.7-1.4 mg/dL(milligrams per deciliter) of blood. GFR-glomerular filtration rate :- valuesare < 60 mL/min (they statenormal valuesas 90-120 mL/min)

Cytotoxic agents classification Alkylating agentsAnti- MetabolitesCyclophosphamide**Methotrexate**Ifosfamide**Gemcitabine**Carmustine*CapecitabineStreptozocin*FludarabineMelphalanRaltitrexedDacarbazineAsparaginasProcarbazineCytarabineBendamustine5- Fluoro UracilChlorambucilPemetrexedTemozolomideBusulfan

Anti-Tumor AntibioticsPlant Alkaloids/ Microtubule InhibitorsMitomycin c **EtoposideDaunorubicinTopotecanBleomycinDocetaxelIdarubicinIrinotecanActinomycin D / DactinomycinPaclitaxelDoxorubicinVinblastineDoxorubicin (pegylated liposomal)VincristineEpirubicinVinorelbineMitoxantroneDNA Linking AgentsCisplatin**Carboplatin*Oxaliplatin

First FRCR Examination Clinical Pharmacology moduleList of Anti-Cancer Drugs

DNA Linking AgentsMechanism of Action DNA Linking Agents then binds with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links that cause changes in the conformation of the DNA and affects DNA replicationCisplatinOne of the most widely used and most nephrotoxic chemotherapeutic agents. Used for lymphoma, testicular carcinoma, bladder, gastric, head and neck, non-small cell lung, ovarian, and small cell lung cancers. Nephrotoxicity Profile:-Primarily injures the S3 segment of the proximal tubule.Tubular injury also stimulate inflammatory response causing further damage.Also induces vasoconstriction in the renal vasculature thus reducing renal blood flow and causing ischemic injury.It is usually dose dependent.

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Pathophysiology

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Higher dosesPrevious cisplatin therapyUnderlying kidney dysfunction Older ageFemale genderSmokingHypoalbuminemia Risk FactorsClinical FeaturesClinically, Nephrotoxicity is seen usually within 10 days of Cisplatin administration.It is manifested by acute renal failure, hypokalemia , hypomagnesemia and Fanconi like syndrome. Hypomagnesemia may exacerbate Cisplatin toxicity.UOP typically remains above 1 liter/day (unless renal dysfunction is severe) due to induction of a concentrating defect, due to platinum induced damage to the loop of henle or decrease in aquaporin water channels in collecting tubules. It is also believed that cisplatin treatment may lead to long term reduction in GFR as well.

Prevention Lower doses of cisplatin Administration of intravenous saline.Sodium thiosulphate- binds to cisplatin and render it non-toxic. Used in setting of IP cisplatin.Amifostine: an organic thiophosphate, donates a thiol group selectively in normal tissues and not in malignant tissues, to bind to cisplatin. Major concerns are cost and possible interference with tumor efficacy.Cimetidine-inhibitor of OCTs- could be used to decrease uptake. Imatinib, an anti-cancer agents also decreases uptake by affecting OCTs.Antioxidants have been tried-unclear benefit.Other agents that have been explored include N-acetylcysteine, theophylline,glycine etc. Dose modification Dosage: 20-50 mg/m2 GFR (ml/min) Dose >60 100% 45-59 75%