Review of Pharmacology - 9E (2015)

Review of Pharmacology
Amifostine is indicated for
• Reduction of cisplatin induced
nephrotoxicity.
• to reduce xerostomia in
patients undergoing irradiation
• Cisplatin reduces all ions in serum i.e. causes hypomagnesemia, hypokalemia, hypocalcemia
and hypophosphatemia. (Remember, cyclosporine, an immuno sup pressive
drug cause hyperkalemia).
• Cisplatin has been associated with development of AML, usually 4 years or more after
treatment.
Note:
• Nitrosoureas and ifosfamide may lead to renal failure.
• All alkylating agents are myelosuppressive.
• Nitrosoureas and mechlorethamine have strong vesicant properties (cause local irritation and
damage).
• Alkylating agents also can cause sterility and secondary leukemias (less common with cyclophosphamide).
• All alkylating agents have caused pulmonary fibrosis.
• In high dose, all alkylating agents can cause veno-occlusive disease of liver which can be
reversed by defibrotide.
Antimetabolites
Chemotherapy C: Antineoplastic Drugs
Uses of Methotrexate
Inhibit – Immunosuppressant
C
A
N
C
E
R
– Crohn’s disease
– Abortion
– Non Hodgkin Lymphoma
– Choriocarcinoma
– Ectopic pregnancy
– Rheumatoid arthritis
Methotrexate is the drug of
choice for the treatment of choriocarcinoma.
The toxicity of methotrexate to
normal cells can be reduced
by administration of N 10
formyltetrahydrofolic
acid (folinic acid,
citrovorum factor or leucovorin).
These drugs act in the S-phase of cell cycle (CCS drugs), thus only dividing cells are responsive.
These drugs possess immunosuppressive properties apart from their antineoplastic effects.
Folic Acid Analogs
Methotrexate and pemetrexed are the inhibitors of dihydrofolate reductase (DHFRase).
These drugs also inhibit thymidylate synthase (TS) and the enzymes involved in early purine
synthesis. Methotrexate forms polyglutamates inside the cell that helps to trap it within
the cells and thus is important for cytotoxicity to neoplastic cells. Methotrexate resistance
can occur due to impaired transport of methotrexate into cells, production of altered forms of
DHFRase that have decreased affinity for the inhibitor, increased concentrations of intracellular
DHFRase through gene amplification or altered gene regulation, decreased ability to synthesize
methotrexate polyglutamates and increased expression of a drug efflux transporter, of the
MRP (multidrug resistance protein) class. Methotrexate can be sequestered in third-space
collections and leech back into general circulation, causing prolonged immunosuppresion.
Clearance of methotrexate depends on renal function and vigorous hydration is required
to prevent its crystallization in renal tubules. It is the drug of choice for the treatment of
choriocarcinoma. It is also useful for acute leukemias, non-Hodgkin lymphoma, cutaneous
T-cell lymphoma and breast cancer. It can be used by intrathecal route for meningeal
leukemias. Pemetrexed is approved for treatment of mesothelioma. Folic acid and vitamin B 12
supplementation decreases the toxicity of pemetrexed without interfering with its clinical efficacy.
Methotrexate is also indicated in the management of rheumatoid arthritis, psoriasis and
ectopic pregnancy. Adverse effects of methotrexate are bone marrow suppression and
mucositis. The toxicity of methotrexate to normal cells can be reduced by administration of
N 10
formyl- tetrahydrofolic acid (folinic acid, citrovorum factor or leucovorin). This strategy
is known as leucovorin rescue. Leucovorin do not prevent neurotoxicity. Alkalinization of urine
can also reduce methotrexate toxicity. In extreme cases, toxicity can be treated by dialysis
or administration of GLUCARPIDASE, a methotrexate cleaving enzyme. Long term use of
methotrexate may also lead to hepatotoxicity, pulmonary infiltrates and fibrosis. NSAIDs like
aspirin, penicillins and cephalosporins may decrease the renal excretion of methotrexate and
result in toxicity. Pralatrexate is a similiar drug indicated for peripheral T-cell lymphoma.
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In extreme cases, methotrexate
toxicity can be treated by dialysis
or administration of GLUCARPI-
DASE, a methotrexate cleaving
enzyme.
Purine analogs
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are the purine antimetabolites that
are activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRTase). The
resulting nucleotides inhibit several enzymes in purine biosynthesis and metabolism. 6-MP
is metabolized by xanthine oxidase. When administered along with allopurinol (xanthine
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