Transcript Cisplatin_group-pres..

Pharmacology
Group I presentation
Topic: Cisplatin
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
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
Clinical trials
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
Two
Bauknecht et
al., 2003
Feasible as a first-line
treatment
Advanced
Hepatocellular
carcinoma
Topotecan
Two
Lee et al.,
2003
Not effective when used
in dose and schedule
tested
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:
1.
2.
3.
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
Pharmacokinetics
• Vd = 0.17-1.47 L/kg
• Route of Entry
– 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
Pharmacodynamics
Cisplatin
Pass cell membrane
Bind to DNA
The chloride is replaced
by H2O
At the guanine bases
Form intrastrand and
interstrand cross links
Formation of positive
Charge Pt complex
Inhibit DNA, RNA,
synthesis
Cause mutation
Toxic to cell
Cell death
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
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)
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 lifethreatening malignancies,contraindications
to its use are only relative and must be
placed in the context of the patient's
overall well-being.
Contraindications
•
Include:
1.
2.
3.
4.
5.
6.
Renal failure
Severe bone marrow suppression
Peripheral neuropathy
Pregnancy
Hearing disorders
Allergic or anaphylactic-like reactions to platinum
containing compounds.
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.
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
Reference
• IPCSINTOX-Data bank
– http://www.intox.org/databank/documents/pha
rm/cisplat/ukpid21.htm
• BC Cancer Agency
– http://www.bccancer.bc.ca/HPI/DrugDatabase/
DrugIndexPro/Cisplatin.htm