1. Pharmacology Group I presentation
Topic: Cisplatin

2. Drug background was first synthesized in 1845 Alkylating agent
an inorganic complex formed by an atom of platinum surrounded by chlorine and ammonia atoms in the cis position of a horizontal plane

3. Drug usage This medication is used to treat:
metastatic testicular tumors
metastatic ovarian tumors
advanced bladder carcinoma
also used to treat other kinds of cancer

4. Clinical trials which cisplatin have been involved in include:
Type of Cancer
Cisplatin in combination with:
Phase
Carried out by:
Result
NSCLC
Mitomycin C, Vinorelbine
Two
Keon et al., 2002
Active against advanced NSCLC
Vinorelbine
One & Two
Hotta et a., 2001
Promising anti-tumour activity
Advanced Ovarian Cancer
Gemcitabine
Bauknecht et al., 2003
Feasible as a first-line treatment
Advanced Hepatocellular carcinoma
Topotecan
Lee et al., 2003
Not effective when used in dose and schedule tested

5. Clinical trials
Cisplatin has also been involved in clinical trials to determine its toxicity.
Omidvari et al., 2004 concluded their study by advising that cisplatin should be added to a list of agents causing hypokalemic paralysis. However clinical trials which have regulated the dose of cisplatin between 75 – 80mg/m² have shown that this helps minimise toxicity
Future clinical trials involving Cisplatin:
Cancer research in the UK are currently recruiting people for clinical trials involving cisplatin. These include:
Irinotecan & cisplatin for the treatment of ca of the penis
Cisplatin & temozolomide for children diagnosed with glioma
Cisplatin & 5-fluorouracil to prevent recurrence of anal cancer

6. Pharmacokinetics Vd = 0.17-1.47 L/kg Route of Entry Distribution organ
Mainly by intravenous
Distribution organ
Kidney
Also high concentration of drug can be found in liver, intestine
Target
DNA synthesis
Little effect on protein and RNA synthesis
Elimination
By renal clearance
15 to 30% of drugs will eliminate at first 2-4 hr
20 to 80% of drugs will recoverd at the first 24hr

7. Pharmacodynamics

8. Factor affecting kinetics
Chemical factors
Lipophilicity
water soluble
Chirality
cis isomer provided relief and inhibited several forms of cancer
trans isomer is inactive
slowly changes from the cis to the trans form in aqueous solution
Protein binding capacity
rapidly bound to tissue and plasma proteins
protein-bound drug (nonfilterable): elimination rate declines rapidly, prolonged excretory phase

9. Factors affecting kinetics
Biological factors
Dose
saturation of plasma-protein binding sites may lead to significance rise in the plasma concentration of free compound
increase toxicity
Age
Children are more sensitive to the effects of cisplatin
Disease
terminal half life of total platinum
8.1 to 49 minutes (normal renal function)
1 to 240 hours (patient with severe renal failure)

10. Contraindications
A factor that renders the administration of a drug or the carrying out of a medical procedure inadvisable:
A previous allergic reaction to penicillin is a contraindication to the future use of that drug.
Because cisplatin is used to treat life-threatening malignancies,contraindications to its use are only relative and must be placed in the context of the patient's overall well-being.

11. Contraindications Include: Renal failure
Severe bone marrow suppression
Peripheral neuropathy
Pregnancy
Hearing disorders
Allergic or anaphylactic-like reactions to platinum containing compounds.

12. Toxicology Data
The principal target organ for cisplatin toxicity is the kidney:
This toxicity is manifested by reduced renal function and leads to serum electrolyte changes and pathological changes in the urine analysis.
Doses of cisplatin which produce changes in renal function may cause no histopathological changes.
Higher doses of the drug lead to interstitial nephritis.
Nephrotoxicity characterised by oliguria, azotaemia, renal tubular acidosis and acute renal failure may occur.
Electrolyte disturbances, particularly hypomagnesaemia and hypocalcaemia, may occur as a result of renal toxicity
Cisplatin also causes bone marrow hypoplasia and is ototoxic. Bone marrow depression may be severe, with decreased leucocyte and platelet counts.

13. Toxicology Data Neurotoxicity is also commonly seen with cisplatin:
Neurotoxicity includes peripheral neuropathy with numbness,tingling and decreased vibratory sensation. Autonomic neuropathy may also occur with gait difficulties, involuntary movements and loss of deep tendon reflexes.
Central nervous system toxicity includes confusion, extrapyramidal effects and focal convulsions progressing to grand mal convulsions.
Other reported effects of cisplatin neurotoxicity include tachycardia, acute respiratory failure, metabolic acidosis, transient elevation of alkaline phosphatase, and serum bilirubin
Prevention of cisplatin toxicity:
Hydration is considered important for the prevention of cisplatin toxicity.
Severe nausea and vomiting may be managed with antiemetics

14. Reference IPCSINTOX-Data bank BC Cancer Agency
BC Cancer Agency