Pharmacology_lec.12.pdf

Pharmacology Steroid Hormones and Their Antagonists Lec 12 Pharmacology | Steroid Hormones and Their Antagonists Contents : introduction 4 Tamoxifen 6 Fulvestrant and raloxifene 10 Aromatase inhibitors 12 Leuprolide, goserelin, and triptorelin 16 Antiandrogens 20 Platinum Coordination Complexes 21 T...

Pharmacology Steroid Hormones and Their Antagonists Lec 12 Pharmacology | Steroid Hormones and Their Antagonists Contents : introduction 4 Tamoxifen 6 Fulvestrant and raloxifene 10 Aromatase inhibitors 12 Leuprolide, goserelin, and triptorelin 16 Antiandrogens 20 Platinum Coordination Complexes 21 Topoisomerase Inhibitors(Camptothecins) 29 Etoposide 33 Monoclonal antibodies 35 Pharmacology | Steroid Hormones and Their Antagonists Contents : Tyrosine Kinase Inhibitors 37 Immunotherapy 40 Miscellaneous Agents 43 Immuno-modulating agents 45 Proteasome inhibitors 47 Pharmacology | Steroid Hormones and Their Antagonists Tumors that are sensitive to steroid hormones may be either: 1. Hormone responsive, in which the tumor regresses following treatment with a specific hormone. 2. Hormone dependent, in which removal of a hormonal stimulus causes tumor regression 3. Both Pharmacology | Steroid Hormones and Their Antagonists Removal of hormonal stimuli from hormonedependent tumors can be accomplished by : 1. surgery (for example, in the case of orchiectomy— surgical removal of one or both testes—for patients with advanced prostate cancer) or 2. by drugs (for example, in breast cancer treatment with the antiestrogen tamoxifen prevents estrogen stimulation of breast cancer cells). For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone. Pharmacology | Steroid Hormones and Their Antagonists A. Tamoxifen Tamoxifen is a selective estrogen modulator (SERM). It is an estrogen antagonist in breast tissue and an agonist in other tissues, such as bone and the endometrium. Tamoxifen is used for first-line therapy in the treatment of estrogen receptor–positive breast cancer. It is also used for prevention of breast cancer in high-risk women. Pharmacology | Steroid Hormones and Their Antagonists Mechanism of action Tamoxifen competes with estrogen for binding to estrogen receptors in the breast tissue, and inhibits estrogen induced growth of breast cancer. The result is 1. depletion (down-regulation) of estrogen receptors. 2. growth-promoting effects of the natural hormone and other growth factors are suppressed. Pharmacology | Steroid Hormones and Their Antagonists Pharmacokinetics Tamoxifen is effective after oral administration. It is partially metabolized by the liver. Some metabolites possess estrogen antagonist activity, whereas others have agonist activity. Unchanged drug and metabolites are excreted predominantly through the bile into the feces. Tamoxifen is an inhibitor of CYP3A4 and Pglycoprotein. Pharmacology | Steroid Hormones and Their Antagonists Adverse effects Adverse effects caused by tamoxifen include : 1. Hot flashes 2. Nausea 3. Vomiting 4. skin rash 5. vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue). Tamoxifen has the potential to cause endometrial cancer, thromboembolism and effects on vision. Pharmacology | Steroid Hormones and Their Antagonists B. Fulvestrant and raloxifene Fulvestrant is an estrogen receptor antagonist that is given via IM injection to patients with hormone receptor–positive metastatic breast cancer. This agent binds to and causes estrogen receptor down regulation on tumors and other targets. Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption. Pharmacology | Steroid Hormones and Their Antagonists This agent reduces the risk of estrogen receptor– positive invasive breast cancer in postmenopausal women. Both drugs are known to cause hot flashes, arthralgias, and myalgias. Pharmacology | Steroid Hormones and Their Antagonists C. Aromatase inhibitors The aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. Aromatase inhibitors decrease the production of estrogen in these women. Pharmacology | Steroid Hormones and Their Antagonists Pharmacology | Steroid Hormones and Their Antagonists 1. Anastrozole and letrozole Anastrozole and letrozole are nonsteroidal aromatase inhibitors. These agents are considered first-line drugs for the treatment of breast cancer in postmenopausal women. They are orally active and cause almost a total suppression of estrogen synthesis. Pharmacology | Steroid Hormones and Their Antagonists Anastrozole and letrozole do not predispose patients to endometrial cancer. Both drugs are extensively metabolized in the liver, and metabolites and parent drug are excreted primarily in the urine. Pharmacology | Steroid Hormones and Their Antagonists Exemestane A steroidal, irreversible inhibitor of aromatase, Exemestane, is well absorbed after oral administration and widely distributed. Hepatic metabolism occurs via the CYP3A4 isoenzyme. Because the metabolites are excreted in urine, doses of the drug must be adjusted in patients with renal failure. Major toxicities are nausea, fatigue, and hot flashes. Alopecia and dermatitis have also been noted. Pharmacology | Steroid Hormones and Their Antagonists D. Leuprolide, goserelin, and triptorelin Gonadotropin-releasing hormone (GnRH) is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones: 1. Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes. 2. Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen. Pharmacology | Steroid Hormones and Their Antagonists Leuprolide, goserelin, and triptorelin are synthetic analogs of GnRH. As GnRH analogs, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen synthesis are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy with regression of tumor and relief of bone pain. Pharmacology | Steroid Hormones and Their Antagonists These drugs have some benefit in premenopausal women with advanced breast cancer and have largely replaced estrogens in therapy for prostate cancer. Leuprolide is available as: 1. subcutaneous daily injection. 2. A subcutaneous depot injection. 3. An intramuscular depot injection to treat metastatic carcinoma of the prostate. Pharmacology | Steroid Hormones and Their Antagonists Goserelin acetate is a subcutaneous implant. triptorelin pamoate is injected intramuscularly. Levels of androgen in prostate cancer patients may initially rise, but then fall to castration levels. The adverse effects of these drugs, including: 1. Impotence 2. hot flashes 3. tumor flare, are minimal compared to those experienced with estrogen treatment. Pharmacology | Steroid Hormones and Their Antagonists E. Antiandrogens Flutamide, nilutamide, bicalutamide, and enzalutamide are oral antiandrogens used in the treatment of prostate cancer. They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate. Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain. Rarely, liver failure has occurred with flutamide. Nilutamide can cause visual problems. Pharmacology | Steroid Hormones and Their Antagonists Platinum Coordination Complexes A. Cisplatin, carboplatin, and oxaliplatin Cisplatin was the first member of the platinum coordination complex class of anticancer drugs, but because of severe toxicity, carboplatin was developed. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. It has found wide application in the treatment of solid tumors Such as: 1. metastatic testicular carcinoma in combination with VBL and bleomycin 2. ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma. Pharmacology | Steroid Hormones and Their Antagonists Carboplatin is used when: patients cannot be vigorously hydrated, as is required for cisplatin treatment or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. Oxaliplatin is a closely related analog of carboplatin used in the setting of colorectal cancer. Pharmacology | Steroid Hormones and Their Antagonists Mechanism of action The mechanism of action of these agents is similar to that of the alkylating agents. In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses chloride in the low-chloride milieu. It then binds to guanine in DNA, forming inter- and intrastrand cross-links. Pharmacology | Steroid Hormones and Their Antagonists The resulting cytotoxic lesion inhibits both polymerases for DNA replication and RNA synthesis. Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable to the actions of these drugs in the G1 and S phases. Pharmacology | Steroid Hormones and Their Antagonists Pharmacokinetics These agents are administered via IV infusion. Cisplatin and carboplatin can also be given for ovarian cancer and intra-arterially to perfuse other organs. The highest concentrations of the drugs are found in the liver, kidney, and intestinal, testicular, and ovarian cells, but little penetrates into the cerebrospinal fluid (CSF). The renal route is the main pathway of excretion. Pharmacology | Steroid Hormones and Their Antagonists Adverse effects Severe nausea and vomiting occurs in most patients after administration of cisplatin and may continue for as long as 5 days. Premedication with antiemetic agents is required. The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be prevented by aggressive hydration. Pharmacology | Steroid Hormones and Their Antagonists Other toxicities include ototoxicity with highfrequency hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic. The dose-limiting toxicity is myelosuppression. Oxaliplatin has a distinct adverse effect of coldinduced peripheral neuropathy that usually resolves within 72 hours of administration. Pharmacology | Steroid Hormones and Their Antagonists It also causes myelosuppression and cumulative peripheral neuropathy. Hepatotoxicity has also been reported. These agents may cause hypersensitivity reactions ranging from skin rashes to anaphylaxis. Pharmacology | Steroid Hormones and Their Antagonists Topoisomerase Inhibitors These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA. A. Camptothecins Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. Irinotecan and topotecan are semisynthetic derivatives of camptothecin. Pharmacology | Steroid Hormones and Their Antagonists Topotecan is used in 1. metastatic ovarian cancer when primary therapy has failed and 2. also in the treatment of small cell lung cancer. Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal carcinoma. Pharmacology | Steroid Hormones and Their Antagonists Mechanism of action These drugs are S-phase specific and inhibit topoisomerase I, which is essential for the replication of DNA in human cells. SN-38 (the active metabolite of irinotecan) is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. The topoisomerases relieve torsional strain in DNA by causing reversible, single strand breaks. Pharmacology | Steroid Hormones and Their Antagonists Adverse effects Bone marrow suppression, particularly neutropenia, is the dose-limiting toxicity for topotecan. Frequent blood counts should be performed in patients receiving this drug. Myelosuppression is also seen with irinotecan. Acute and delayed diarrhea with irinotecan may be severe and require treatment with atropine during the infusion or high doses of loperamide in the days following the infusion. Pharmacology | Steroid Hormones and Their Antagonists B. Etoposide Etoposide is a semisynthetic derivative of the plant alkaloid, podophyllotoxin. This agent blocks cells in the late S to G2 phase of the cell cycle, and the major target is topoisomerase II. Binding of the drug to the enzyme–DNA complex results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double-strand breaks. Pharmacology | Steroid Hormones and Their Antagonists Etoposide finds its major clinical use in the treatment of: lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma. Etoposide may be administered either IV or orally. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity. Pharmacology | Steroid Hormones and Their Antagonists Monoclonal antibodies Monoclonal antibodies are an active area of drug development for anticancer therapy and other nonneoplastic diseases, because they are directed at specific targets and often have different adverse effect profiles as compared to traditional chemotherapy agents. All of these agents are administered intravenously, and infusion-related reactions are common. Pharmacology | Steroid Hormones and Their Antagonists Tyrosine Kinase Inhibitors The tyrosine kinases are a family of enzymes that are involved in several important processes within a cell, including signal transduction and cell division. The tyrosine kinase inhibitors are administered orally, and these agents have a wide variety of applications in the treatment of cancer. Pharmacology | Steroid Hormones and Their Antagonists Pharmacology | Steroid Hormones and Their Antagonists Pharmacology | Steroid Hormones and Their Antagonists Immunotherapy Immunotherapy with intravenous immune checkpoint inhibitors is a rapidly evolving option for cancer treatment. The goal of immune checkpoint inhibitors is to block the checkpoint molecules, such as the programmed death (PD-1) receptor, that normally help to keep the immune system in check. By blocking these molecules, the immune system is better able to attack the tumor and cause destruction. Pharmacology | Steroid Hormones and Their Antagonists The two most commonly used checkpoint inhibitors are pembrolizumab and nivolumab. The adverse reaction profiles of these agents consist of potentially severe and even fatal immune-mediated adverse events. This is because turning off the immune checkpoints allows attack of the tumor, but can also lead to unchecked autoimmune response to normal tissues. Pharmacology | Steroid Hormones and Their Antagonists Adverse events Include diarrhea, colitis, pneumonitis, hepatitis, nephritis, neurotoxicity, dermatologic toxicity in the form of severe skin rashes, and endocrinopathies such as hypo- or hyperthyroidism. Patients should be closely monitored for the potential development of signs and symptoms of toxicity and promptly treated with corticosteroids if necessary. Pharmacology | Steroid Hormones and Their Antagonists Miscellaneous Agents Abiraterone acetate Abiraterone acetate is an oral agent used in the treatment of metastatic castration–resistant prostate cancer. Abiraterone acetate is used in conjunction with prednisone to inhibit the CYP17 enzyme (an enzyme required for androgen synthesis), resulting in reduced testosterone production. Pharmacology | Steroid Hormones and Their Antagonists Pharmacology | Steroid Hormones and Their Antagonists Coadministration with prednisone is required to help lessen the effects of mineralocorticoid excess resulting from CYP17 inhibition. Hepatotoxicity may occur, and patients should be closely monitored for hypertension, hypokalemia, and fluid retention. Joint and muscle discomfort, hot flushes, and diarrhea are common adverse effects with this agent. Pharmacology | Steroid Hormones and Their Antagonists Immuno-modulating agents Thalidomide, lenalidomide, and pomalidomide are oral agents used in the treatment of multiple myeloma. Their exact mechanism of action is not clear, but they possess antimyeloma properties including antiangiogenic, immune-modulation, antiinflammatory and antiproliferative effects. These agents are often combined with dexamethasone or other chemotherapeutic agents. Pharmacology | Steroid Hormones and Their Antagonists Adverse effects Include thromboembolism, myelosuppression, fatigue, rash, and constipation. Thalidomide was previously given to pregnant women to prevent morning sickness. However, severe birth defects were prevalent in children born to mothers who used thalidomide. Because of their structurally similarities to thalidomide, lenalidomide and pomalidomide are contraindicated in pregnancy. Pharmacology | Steroid Hormones and Their Antagonists Proteasome inhibitors Bortezomib, Ixazomib, and Carfilzomib are proteasome inhibitors commonly used as the backbone therapy in the treatment of multiple myeloma. These agents work by inhibiting proteasomes, which in turn prevents the degradation of proapoptotic factors, thus leading to a promotion in programmed cell death (apoptosis). Malignant cells readily depend on suppression of the apoptotic pathway; therefore, proteasome inhibition works well in multiple myeloma. Pharmacology | Steroid Hormones and Their Antagonists Bortezomib can be administered IV, but the subcutaneous route is preferred because it is associated with less neuropathy. Other adverse effects include myelosuppression, diarrhea, nausea, fatigue, and herpes zoster reactivation. Patients should receive antiviral prophylaxis if they are receiving therapy with bortezomib. Ixazomib is an oral agent with an adverse effect profile similar to bortezomib. Pharmacology | Steroid Hormones and Their Antagonists Carfilzomib is administered intravenously, and common adverse effects include myelosuppression, fatigue, nausea, diarrhea, and fever.