Platinum agents

Platinum agents Include

-PLATIN

• Include:

1. Cisplatin

2. Carboplatin

3. Oxaliplatin

WHICH OF THE PLATINUM COMPOUNDS ARE DIVALENT AND WHICH IS TETRAVALENT?

Cisplatin and carboplatin are divalent, inorganic, water-soluble, platinum-containing complexes.

Oxaliplatin is a tetravalent complex

The coordination of platinum with various organic adducts reduces its renal toxicity and stabilizes the metal ion.

MOA

Enter cells by an active transporter→ interact with various sites on DNA forming cross-links → DNA platinum adducts inhibit replication & transcription.

• Leads to DNA strand breaks, miscoding & apoptosis.

*compared to other alkylating agents, instead of using alkyl group to form dimers they use platinum to form dimers of DNA

Cisplatin PK

• Given IV over 4- 6 hrs(slow infusion). *NEVER A BOLUS → TO PREVENT NAUSEA AND ACUTE RISE IN SERUM CREATININE.

• > 90% is covalently bound to plasma proteins.

• Penetrates poorly into the CNS.

• Excreted mainly via the kidneys.

When administering cisplastin what is done to prevent renal toxicity

To prevent renal toxicity, infuse 1-2 L of normal saline prior to treatment (chloride diuresis)

What precaution should be taken when administering cisplatin?

Should avoid aluminium containing equipment

Cisplatin should not come in contact with infusion equipment containing aluminium as aluminium inactivates it.

Clinical uses

• Useful in:

Testicular cancer.

Carcinoma of the ovary, cervix & endometrium

Cancers of the bladder, head and neck, lung & rectum

• It also sensitizes cells to radiation therapy and enhances control of locally advanced lung, esophageal, and head and neck tumors when given with irradiation.

Clinical toxicities of cisplatin

• • Nephrotoxicity.

• Ototoxicity.

• Marked nausea and vomiting.

• Peripheral motor and sensory neuropathy.

• Mild to moderate myelosuppression.

• Electrolyte disturbances - REDUCES ALL IONS IN SERUN

  • reduces hypomagnesemia, hypokalemia, hypocalcemia and hypophosphatemia

• 2° malignancies eg. AML

— is used to reduce cisplatin induced nephrotoxicity

Amifostine - it is a thiophosphate cytoprotective agent that reduces renal toxicity.

• it is also used to reduce xerostomia in patients undergoing irridiation of head and neck involving the parotid

Carboplatin

Advantages of carboplatin compared to cisplatin

Causes less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin.

• Carboplatin is an effective alternative in patients unable to tolerate cisplatin.

*CISPLATIN IS MORE NEPHROTOXIC CARBOPLATIN IS MORE HEMATOTOXIC (bone marrow suppression) primarily thrombocytopenia.

Disadvantages of carboplatin compared to cisplatin

1. it is more hematotoxic

2. it is more likely to cause hypersensitivity rxns

Dosage of carboplatin

Given once every 21- 28 days.

Uses of carboplatin

Effective in the treatment of:

ovarian cancer

Small cell & non-small cell lung cancer

Oxaliplatin characteristic

• Has a very brief t12 in plasma, probably as a result of its rapid uptake by tissues.

• No dose adjustment is required for patients with a CrCl ≥20 mL/min & in hepatic dysfunction.

Clinical use of oxaliplatin

Clinical uses-

Colorectal ca. (combined with 5-FU) & gastric ca.

Toxicity

• Dose-limiting toxicity of oxaliplatin is peripheral neuropathy.

> Acute form may be caused by rapid release of oxalate, with depletion of calcium and magnesium.

Responds to infusion of these electrolytes.

• Mild to moderate hematological toxicity

• Nausea

• Leukemia and pulmonary fibrosis.

• Acute allergic response with urticaria, hypotension, and bronchoconstriction.