Anti-neoplastic Drugs

1. Anti-neoplastic Drugs المعلومات بالداخل موثوق بها لأنها مراجعه و معتمده من Certified from Pharmacists_coffee magazine

2. Anti-neoplastic Drugs: • Anti-neoplastics: Are drugs that inhibit DNA synthesis; these can be classified as: • Interfering with DNA, RNA, & Protein: (anti-metabolites) • Methotrexate  Folic acid antagonist. • 6 mercapto-purine  Purine antagonist. • 5 fluoro-uracil  Pyrimidine antagonist. • Cytorabine  Pyrimidine antagonist. • Inhibiting Protein Synthesis: • L-asparaginose  used in leukemia. • Interfering with Replication & Translation of DNA: (alkylating agents) • Nitrogen mustard (Mechlor-ethamine). • Cyclophosphamide. – Actinomycin D. • Interfering with Mitotic Spindle Formation: Vinca alkaloids • Vincristine. – Vinplastine. Another Classification: • Alkylating Agents: • These are highly reactive agents which can alkylate or bind covalently with cellular components of DNA. • They interfere with mitosis, resulting in chromosomal damage, mutation & suppression of normal immune response, by interfering with DNA cross-linkage. • These include: d Mechlor-ethamine (N-mustard)  given IV. d Cyclophosphamide (Cytoxan)  Oral & parentral. d Chlorambucil (Leukeran) Oral. d Melphalan (Alkeran)  Oral d Busulfan (Myleran)  Oral d Endoxan d Procarbazine: is possibly an alkylating agent used to treat Hodgkin’s disease. • Antimetabolites: • They interfere with the cell synthesis of essential components by competing for the enzyme involved or through synthesis of abnormal cell constituents. d Methotrexate  Folic acid antagonist. d 6 mercapto-purine  Purine antagonist. d 5 fluoro-uracil  Pyrimidine antagonist. d Cytosine arabinoside (Cytorabine)  Pyrimidine antagonist.

3. Alkaloids: • These agents block microtubular precipitation which is necessary for mitosis, i.e. they bind with the tubulin thus interfere with the assembly of spindle proteins during mitosis. (interfere with mitotic spindle formation). These include: d Vincristine (Oncovin). d Vinplastine (Velban). d Taxol d Taxotere d Eptoside • Hormones: • Corticosteroids  in lymphocytic leukemia. • Androgens  in breast cancer. • Estrogens  in prostatic carcinoma. • Progestins  in endometrium carcinoma. • Antibiotics: • They inhibit DNA synthesis & are used in treatment of colon, stomach, pancreas, breast & bladder cancer. • These are cytotoxic drugs. d Actinomycin D  (D-actinomycin). d Mithramycin  Mithracin. d Mitomycin  Mutamycin. d Doxo-rubicin • Miscellaneous Group: • Procarbazine (Natulane): used in treating Hodgkin’s disease (lymph node enlargement). It is possibly an alkylating agent. • Nitrosoureas: in GIT malignancies. • L- asparaginase (Elspar): it hydrolysis L-asparagin, thus inhibiting protein synthesis. • Radio-active isotopes: • These are isotopes of elements that emit a, b, & g ionizing radiations. Only g, & b radiations are used in cancer chemotherapy. They produce: d Inhibition of mitosis. d Inhibition of bone marrow. d Produce fetal abnormalities & chromosomal mutation. d Affection of the reproductive system (amenorrhea in females & sterility in males). • These include: d Iodine 131: has t ½ of ~ 8 days; given orally as NaI 131. It emits b & g radiations. It is used in hyperthyroidism & thyroid cancer. d Gold 198: has t ½ of ~ 2.7 days, it is given parentrally. It emits b & g radiations. It is used to inhibit ascitis & pleural effusion in metastatic neoplasma. d Na phosphorous 32: has t ½ of ~ 14.3 days, it is given orally or IV. It emits b radiations only. It is used to treat polycythaemia vera as it follows the PO4 pool in the body & is concentrated in the bone, bone marrow spleen & lymph nodes.

4. Methotrexate: is a folic acid antagonist. • Additionally, it suppresses psoriasis & produces remission in 70% of patients. • It may also be used in rheumatoid arthritis (initial dose is 7.5 mg / week). • Main side effect is GIT ulceration which is treated with folic acid • 5-Fluorouracil: is a cytotoxic agent (its chemical structure is a modified pyrimidine, similar to thionine & uracil). It acts as an anti-metabolite (pyrimidine antagonist). • It interferes with the synthesis of ribonucleic acid (RNA). • It is administered as an IV injection & sometimes as a lotion or cream (Efudex), but is not given orally as it is irregularly absorbed from the GIT. • Used topically to treat pre-malignant actinic keratosis (do not use occlusive dressing). • Used IV to treat carcinomas of the colon, rectum, breast & ovaries. • Its main side effects include: nausea, anorexia, vomiting & leucopenia (in toxicity). • Mechlorethamine: is a nitrogen mustard used to treat Hodgkin’s disease. It is given IV only (if given IM it causes severe tissue damage). It causes nausea with ordinary doses; oral chlorambucil is less toxic. • Dantrolone Sodium Injection (Dantrium): used to treat malignant hyperthermia. • Cell cycle specific anti-neoplastic agents act on: • DNA Synthesis (S phase) • Mitosis • RNA Synthesis

5. What is polycythemia treated with: • NaP 32. • Hemorrhagic cystitis is caused by: • Cyclophosphamide c. Methotrexate • Indomethacind. Phenyl butazone. • Toxicity of anti-neoplastic therapy will cause: • Alopecia b. Bone marrow depression • Ulcers due to methotrexate therapy can be prevented by: • Follinic acid b. Niacine c. Folic acid • The main mechanism of action of anti-neoplastic drugs is: • Interference with DNA b. Affecting the genotype of the cell • Mutagenesis is: • Genetic change in DNA c. Change in DNA characters • Caused by mutagenic agents • Vincristine mechanism of action: • Topisomerase d. Inhibits mitotic spindle formation • Alkylating agent e. Interferes with RNA synthesis • Stops reproduction in the meta phase • Which enzyme helps DNA strands to attach to one another: • Topisomerase (necessary for DNA replication & RNA transcription) • Ligase • Site of action of anti-neoplastic drugs: • DNA c. Transcription e. All • Mitosis d. G1 phase • Tamoxiphen is used to treat: • Breast cancer b. Hodgkin’s disease • Fluorouracil : • Is a modified pyrimidine (similar to uracil) • Given either by IV injection or topically (Efudex) • a-feto protein: • Is a protein elevated remarkably in patients with hepatic cellular carcinoma • Anti-emetics in cancer chemotherapy: • Can loose efficacy after some time

6. Some Tests: • Vanoen Bergh Test: is a serum test used to differentiate between bound & unbound bilirubin. It is a measure of soluble conjugated bilirubin. • White Cells Differential Count: is a laboratory procedure used to determine the relative proportions of various types of WBCs. • Creatinine Phospho Kinase (CPK): is an enzyme found primarily in muscle tissue. It is released in the blood in response to muscle injury or damage (e.g. MI). • Metyrapone: is used as a diagnostic agent for anterior pituitary function. • D-xylose: is used as a diagnostic agent to evaluate intestinal absorption. • Butazol: tests the secretory function of the stomach (gastric secretion) • Schilling’s Test: is a test for detection of perinaceous anemia. It utilizes orally administered vitamin B12 labeled with Co57 or Co58. • If Co58 appears in the feces  anemia is due to deficiency of intrinsic factor. • If Co58 appears in the urine  anemia is due to vitamin B12 deficiency. • Technetium Tc 99 sulfur colloid: is used for liver imaging. • Technetium Tc 99 albumin colloid: is used for lung imaging. • Technetium Tc 99 bisicate: is used for brain imaging. • Technetium Tc 99 glucoceptate colloid: is used for kidney imaging. • Coomb’s Test: is an anti-globulin test used to test the antigen antibody reaction. Certain drugs give false +ve Coomb’s results (e.g. cephalosporins, penicillins, methyl dopa, vit. C) • SGOTT & SGPTT: both are liver function tests. • SGOTT: Serum glutamic oxalo-acetic transaminase test. • SGPTT: Serum glutamic pyruvic transaminase test. • Erythrocyte sedimentation rate (ESR): It increases in: • Tissue necrosis. • Chronic infection. • Malignancy. • Rheumatoid. ESR is useful to differentiate MI (# ESR) from angina (normal ESR).

7. N = N OH N = N OH DYES • Bromosulfophthaline excretion test (BSP): is a measure of liver function. It is a synthetic dye, which when injected (usually 5 mg/kg IV) measures the excretory function of the liver. The normally functioning liver will remove 95% of the dye from blood within 45 min. • Phenolphthalein (Phenol red): used for determination of kidney function. • Evan’s Blue: used for determination of blood volume. • Javus Green: used to detect mitochondria. • Cogno Red: is used for detection of Amyloidosis (in blood). • Azuresin: used for detection of achlorohydra (deficiency of HCl secretion in stomach). • Leucobase: Leuco = colorless, i.e. colorless dye. • N = N & b-naphthol: form an azodye with the formula (pyridium) is used as a urinary analgesic  urine discoloration. Azodye Not an azodye (b hydroxy) (No b hydroxy)

8. Normal Values • pH of blood  7.35 – 7.45 • pH of eye 7.4 • pH of skin 5.5 • pH of stomach 1 – 2 • pH of colon 7 • pH of vagina  4.5 – 5 • Creatinine clearance 100 – 200 ml / min (a kidney function test) • Serum Creatinine  1 mg / L (a kidney function test) • Blood urea nitrogen (BUN)  9 – 20 mg N2 / dl (a kidney function test) • Hemoglobin  12 – 18 gram / dl (male 14-18, female 12-16) • Hematocrite 40–54% (in males) or 38–45% (in females) (% measure of the relative volume of RBCs in a settled volume). • Bilurubin (0.1 0.4 mg %) 0.1 – 1 mg / dl (is the end product of Hb breakdown in the liver & excreted in bile) (used for liver function) • Uric acid  2 – 8 mg / dl • Glucose tolerance test  Not more than 120 mg / dl (test for diabetes) • Prothrombine time (PT) 11 – 12.8 seconds • Activated Partial thromboplastine time (APTT) 30 - 45 seconds • Coagulation time  3 – 5 min • Serum Na+  135 – 145 mEq / L (315 – 340 mg% ) • Serum K+  3.5 – 5.5 mEq / L • Blood count RBCs females 3.5 – 5 million / cm3 RBCs Males 4.3 -6 million / cm3 WBCs: 4,000 – 11,000 / cm3 Platelets: 150,000 – 300,000 / cm3 (life span 7 days) Precursors of platelets are karyoblasts • N.B: mg / dl = mg / ml (%) • Maximum Drug Levels: • Digoxin not more than 2 nanomoles /L • Phenytoin not more than 10 – 20 mg / ml • Lithium not more than 2 mmoles / L ( 2 mEq / L ) • Iron not more than 60 – 200 mg / dl Life span of RBCs = 120 days

9. Na+ 135 – 145 meq / L • K+ 3.5 – 5.5 meq / L • Ca++ 23 – 28 meq / L • Mg++ 1.2 – 2 meq / L • Cl –  100 – 106 meq / L • PO43 –  3.2 – 4.3 meq / dL • ESR  0 – 20 mm / hr • HCT or PCV (Haemato-Cytic Value or Peak Cell Value): • If HCt $ Anemia (Over hydration) • If HCt #  Polycythemia (Dehydration) • MCV (Mean Cell Value) • MCV = HCt X 10 / RBCs count in million (Normal = 90+ 10) • If MCV $ Microcytic anemia (Due to iron deficiency) • If MCV #  Macrocytic anemia (Due to B12 & folic acid deficiency) • MCH (Mean Cell Hemoglobin) • MCH = Hb X 10 / RBCs count in million (Normal = 30 + 4) • MCHC (Mean Cell Hemoglobin Concentration) • MCHC = Hb X 100 / HCt (Normal = 34 + 3) • If MCHC $ Hypochromia (Pale RBCs due to $ Hb & $ iron) • RDW  $ RDW (factor deficiency anemia, Fe, B12 & folic acid). • Agranulocytosis (Type II hypersensitivity mechanism: is a condition characterized by marked leucopenia & neutopenia. It occurs as a hypersensitivity reaction to many drugs: • Phenyl butazone – Thiouracil derivatives • Chloramphenicol – Sulfonamides • Trimethadione (petit mal) – Gold preparations • Chloropromazine (major tranquilizer) – Thiazide diuretics • K Roll System: • F 1 Rx • F 5 Drug • F 7 Doctor • F 8 Patient • F 9 Sig (directions for use)

10. Duquenois Reagent: when acidified produces a blue color in presence of marijuana (Hashish). The intensity of the color is determined by the amount of tetrahydrocannabinol (THC) present. It is a test for cannabis alkaloids. • Marquis Reagent: is a formaldehyde / H2SO4 compound which forms a purple complex with opium alkaloids (test for morphine in urine). • Test for strychnine: it forms a blue violet color in presence of H2SO4 & K+ dichromate. • Para-amino benzoic acid (PABA): is used to test for indole structure in alkaloids. (Enrlish test  blue violet color). • Determination of Iodine value: depends on the addition of I2 across the double bond of unsaturated fatty acids; thus used to determine the degree of fatty acid unsaturation (iodometric method). • Fehling solution  red color with glucose & with acetaldehyde. • Specific tests for ions: • Zinc  forms insoluble ppt with diphenyl thiocarbazone. • Strantium  flame test  red color. • Ammonium  Blue color of litmus paper (strong base). • Saccharimeter: measures the optical rotation of plain polarized light. • Flame photometry: is used to quantitatively measure Na & K ions (as well as other metals). • Sodium  yellow flame Potassium  purple flame • Calcium  brick flame Barium  green flame • Lead  blue flame • Colorimetry: is the measurement of absorption of light at a given wavelength. • Nuclear Magnetic Resonance (NMR): is mainly used for identification of chemical substances. It is based on the fact that different molecular arrangements possess different magnetic spin characteristics. • Refractometric Method of Analysis: the principle of this method depends on densities between 2 substances. • The visible range of light is: wavelengths between 4000 – 7000 angstrom. • Below 4000  ultraviolet Above 7000  infra-red. • Nephelometry: this method relies mainly on the reflection of light & is used for suspensions.

11. Advantages of Fluorometric Assay over Spectrophotometric Assay: • Extremely sensitive method for quantitating compounds. • 200 times more sensitive than absorption spectrophotometry. • Widely used in quantitative assays of vitamin B preparations (e.g. riboflavin & thiamine). • Spectrophotometry is not a good technique for the assay of small quantities of drug contaminants, since the total amount of substance injected in a mass spectrophotometer is very small; thus contaminants of less than 3% can not be determined. • The base peak in Mass Spectroscopy: indicates peak of the solvent. • Gravimetric assay is used to check impurities. • In Radio-immunoassay, the titer is the antibody (immunoglobulin) ?? • In Mass Spectro-photometry, more technological aspects  FAB ?? • In Mass Spectrometry, molecular ion (M+) is more bombarded. ??