Drugs pdf - د. منوع

Fifth stage

Medicine

Lec-11

د . منوع

1/1/2014

Cancer Chemotherapy

Vinka alkaloids (animation and ADR)

•

Microtubule Synthesis animation

•

Inhibition of spindle function

ADR

• Severe neurotoxicity

– Paresthesias

– Loss of reflexes

– Foot drop

– Ataxia

–

VinBlastine

Uses ; (ABVD)

Hodgkin’s disease Lymphomas

Carcinoma Breast

Testicular tumors

Toxicity:

Bone marrow

suppression, anorexia,

nausea, vomiting &

Diarrhea, Alopecia

VinCristine (oncovan)

Uses: (MOPP)

Childhood leukemias

Childhood tumors-Wilm’s tumor, Neuroblastoma, Hodgkin’s disease

Toxicity:

Peripheral neuritis with

Paresthesia, Muscle weakness

***Vincristine has marrow sparing effect

Etoposide & Teniposide

• Acts by inhibiting topoisomerase II

• These drugs are most active in late S and early G2 phase

• Used in combination Tx of small cell carcinoma of lung, prostrate and testicular

carcinomas

Other topoisomerase inhibitors:

• Topotecan, Irinotecan

– Both act by inhibiting topoisomerase-I

Topoisomerase inhibitors

Paclitaxel & Docetaxel

• These drugs act by interfering with mitotic spindle

• They prevent micotubule disassembly into tubulin monomers

•

Taxanes animation

ADR

• Neutropenia

• Peripheral neuropathy

Questions

• What is the diff between MOA of taxanes and Vinca alkaloids

• Which is the marrow sparing anticancer drug

• Topoisomerase-1 inhibitors

• Topoisomerase-2 inhibitors

Anticancer Antibiotics

• Anthracyclines:

– Doxorubicin (Adriamycin)

– Daunorubicin

• Bleomysin

• Dactinomycin

• Mitomycin

Doxorubicin & Daunorubicin

• These drugs intercalate between base pairs, inhibit topoisomerase II and also generate

free radicals

• They block RNA and DNA synthesis and cause strand scission

• *These are CCNS drugs

• Used as a component in ABVD regimen in Hodgkin’s lymphoma

ADR

• Cardiac toxicity (due to generation of free radicals)

• Acute form: arrthythmias, ECG changes, pericarditis, myocarditis

• Chronic form: ***Dilated cardiomyopathy, heart failure

• ****Rx with dexrazoxane

– This is an inhibitor of iron mediated free radical generation

• Bone marrow depression, Total alopecia

• Radiation recall reaction

Bleomycin

• Acts through binding to DNA, which results in single and double strand breaks

following free radical formation and inhibition of DNA synthesis

• The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and

leads to chromosomal aberrations

• CCS drug that causes accumulation of cells in G

Uses

• ABVD regimen for Hodgkin’s

• Intracavitary therapy in ovarian and breast cancers (Sclerosing agent)

ADR

• ***Pulmonary fibrosis

Questions

• ADR of anthracyclines? (clinical symptoms)

• Why ADR with anthracyclines?

• How to treat it?

• ADR of bleomycin?

Hormonal agents

• Glucocorticoids

• Sex hormone antagonists

• GnRH analogs

• Aromatase inhibitors

Glucocorticoids (Prednisone)

• Because of their marked lympholytic action, they are used in acute leukemias and

lymphomas.

• Have anti-inflammatory effect

• Increase appetite

• Produce euphoria (feeling of well being)

• Increase body weight

• Suppress hypersensitivity reaction due to certain anticancer drugs

• Control hypercalcemia

• Control bleeding

• Have non-specific antipyretic effect

• Increase the antiemetic effect of ondansetron/granisetron/ metoclopramide

Sex hormone antagonists

Tamoxifen

• Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat

tissue

• It is used in receptor positive breast carcinoma

• Also useful in progestin resistant endometrial carcinoma

ADR:

• Hot flushes, vaginal bleeding and venous thrombosis

Other drugs

• Flutamide: androgen receptor antagonist used in prostatic carconima

• ADR for flutamide includes: gynecomastia, hot flushes

MOA of drugs

GnRH analogs

• Leuprolide, gosarelin and naferelin

• Effective in management of Prostatic carcinomas

• When given in constant doses they inhibit release of pituitary LH and FSH

• These drugs suppress gonadal function due to down regulation and desensitization of

Gn-RH receptors

ADR

• Leuprolide may cause gynecomastia, hematuria, impotence and testicular atrophy

Aromatase inhibitors

• The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from

androstenedione

• This takes place in liver, fat, muscle, skin, and breast tissue, including breast

malignancies.

• Peripheral aromatization is an important source of estrogen in postmenopausal women.

• Aromatase inhibitors decrease the production of estrogen in these women.

• Anastrozole and Letrozole

• These drugs inhibit the aromatase enzyme

• ****Used in Tx of postmenopausal women with metastatic breast ca (1

line drug)

• ADR includes: bone pain and peripheral edema

Miscellaneous agents Asparaginase, imatinib, interferons, monoclonal
antibodies

Asparaginase

• L-Asparaginase catalyzes the deamination of asparagine to aspartic acid and

ammonia.

• L-Asparaginase is used in combination therapy to treat childhood acute lymphocytic

leukemia

• Its mechanism of action is based on the fact that some neoplastic cells require an

external source of asparagine because of their limited capacity to synthesize
sufficient amounts of that amino acid to support growth and function.

• L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of

this amino acid, which is needed for protein synthesis

ADR

• Acute pancreatitis*****

Imatinib

• Example of a drug, whose development was guided by knowledge of a specific

oncogene

• Used for the treatment of chronic myeloid leukemia

• Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl

oncogene

• This gene is expressed in CML

MOA of imatinib

Interferons

• Human interferons have been classified into three types—α, β, and



—on the basis of

their antigenicity.

• The α interferons are primarily leukocytic, whereas the β and



interferons are produced

by connective tissue fibroblasts and T lymphocytes, respectively.

• Recombinant DNA techniques in bacteria have made it possible to produce two species

designated interferon-α-2a and -2b used in Tx of neoplastic diseases.

• ***Interferon-α-2a is presently approved for the management of hairy-cell leukemia,

chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related
Kaposi sarcoma.

• ***Interferon-α-2b is approved for the treatment of hairy-cell leukemia, melanoma,

AIDS-related Kaposi's sarcoma, and follicular lymphoma.

Monoclonal Antibodies

• They are created from B lymphocytes (from immunized mice or hamsters) fused with

“immortal” B-lymphocyte tumor cells.

• The resulting hybrid cells can be individually cloned, and each clone will produce

antibodies directed against a single antigen type.

• Recombinant technology has led to the creation of “humanized” antibodies that

overcome the immunologic problems previously observed following administration of
mouse (murine) antibodies.

• Currently, several monoclonal antibodies are available in the United States for the

treatment of cancer.

• Trastuzumab, rituximab, bevacizumab, and cetuximab

Trastuzumab

• In patients with metastatic breast cancer, overexpression of transmembrane human

epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 % of patients.

• Trastuzumab is a recombinant DNA–produced, humanized monoclonal antibody,

specifically targets the extracellular domain of the HER2 growth receptor that has
intrinsic tyrosine kinase activity.

• Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of

cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S
phase.

FDA approved MAb

Questions???

• What are Flutamide and Leuprolide and mention their uses?

• MOA of tamoxifen?

• MOA of anastrozole and letrozole?

– Important clinical indication for these drugs?

• Important ADR of L-asparaginase?

– Clinical symptoms of ADR (including lab)

• MOA and use of imatinib?

• MABs used in cancer chemotherapy (know four of them circled above)

Treatment of Specific cancers

Hodgkin’s disease:

• ABVD regimen (doxorubicin,bleomycin,vinblastine,dacarbazine)

• MOPP regimen (mechorethamine,vincristine,procarbazine,prednisone)

• NHL: CHOP regimen (cyclophosphamide,doxorubicin,vincristine,prednisone)

• Multiple myeloma : MP protocol (melphalan and prednisone)

Breast ca:

• CMF protocol (cyclophosphamide-MTX-fluorouracil)

• Tamoxifen

• Anastrozole, letrozole