Cisplatin - BioPharma Notes

Cisplatin is platinum coordination complex having broad anti neoplastic activity. Platinum coordination complex are widely used in treatment of testicular cancer, ovarian cancer, cancer of head, neck, bladder, esophagus, lungs and colon.
Cisplatin is 1^st member of platinum coordination complex class of anticancer drugs. Other latest members are carboplatin and oxaliplatin. It is also in World Health Organization’s List of Essential Medicines.

Indications of cisplatin

Useful in treatment of solid tumors like metastatic testicular carcinoma in combination with vincristine and bleomycin, ovarian cancer in combination with cyclophosphamide and as monotherapy for bladder cancer.
In treatment of many other solid tumor of lung, esophagus, head, neck, hepatic and gastric carcinomas.

Figure- Mechanism of action of Cisplatin

It is a prototype drug which enters cell by diffusion. After entering cells (due to low concentration of CL^– ions), its chloride ion is replaced by water and form positively charged molecule. This molecule can bind to nucleophilic sites of DNA and proteins. The favorable binding site is N⁷ of guanine residues and -SH group of cytoplasmic and nuclear proteins. The drug is stable in high concentration of Cl^– ions.
Hence, it forms inter and intra-strand cross- linking in DNA. DNA adducts formed inhibit DNA replication and transcription and lead to miscoding and braking of DNA.
The effect is similar to those of alkylating agent and radiation. It kills cells at any stage of cell cycle. However, its action is more prominent in G₁ and S phases.

It exhibits certain level of resistance. Resistance may occur due to:
- Increased repair of the damaged DNA.
- Reduction in accumulation of drug.
- Cytosolic inactivation of cisplatin.

It is administered by IV infusion. It binds to plasma proteins (more than 90%) and penetrate tissues. and is found in high concentration in liver, kidney, intestine, ovarian and testicular cells. Very low concentration is in CSF (cerebrospinal fluid).
It is slowly excreted unchanged in urine. Its half-life is about 72 hours. Small portion of drug is excreted during first 6 hours, around 25 % is excreted in 24 hours and around 43% of administered dose is recovered in urine by 5 days.

It is highly emetic drug. It can cause severe, persistent vomiting for at least 1 hour after administration and may continue for around 5 days. Antiemetics should be used before its infusion.
Dose- related nephrotoxicity is major toxicity. This can be minimized by aggressive hydration with saline and mannitol/ furosemide. Carboplatin is used instead of cisplatin in patients who cannot tolerate hydration.
Other toxicities include ototoxicity, neuropathy and myelosuppression. Hepatotoxicity may occur in high dose. It can cause nausea and anemia. It can also cause hypersensitivity reactions.

Concurrent administration with aminoglycosides may potentiate nephrotoxic effect. loop diuretics may potentiate its ototoxic effect.
It possesses synergistic cytotoxic effect with other chemotherapeutic agents and radiation. Plasma level of phenytoin is reduced by cisplatin.

Contraindicated in patients hypersensitive to cisplatin or any platinum complexes.
It is contraindicated in patients with severe renal disease, hearing impairment, neuropathy and myelosuppression.
Contraindicated in pregnancy and breastfeeding mothers.
It should be used with caution in children and aged patients. it should be used with caution in patients with hypocalcemia and hypomagnesemia.

https://biomedpharmajournal.org/vol12no1/review-on-pharmacology-of-cisplatin-clinical-use-toxicity-and-mechanism-of-resistance-of-cisplatin/
Pharmacology and Pharmacotherapeutics. 24th edition.
Goodman and Gillman Manual of Pharmacology and Therapeutics.
Lippincott Illustrated Reviews Pharmacology, 6th edition.
Essentials of Medical Pharmacology. 7^th edition.