Breast Cancer- Clinical Therapeutics
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Breast Cancer- Clinical Therapeutics

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Breast cancer Clinical therapeutics

Breast cancer Clinical therapeutics

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  • Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Women with node-positive disease have a high risk of both local and systemic recurrence. Thus, lymph node status directly indicates the risk of occult distant micrometastasis. In this situation, postop- erative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF proto- col) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival. Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes. Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premeno- pausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/neureceptor, to anthracycline- and taxane-containing adjuvant chemotherapy ben- efits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit.
  • goal of hormonal therapy is to reduce the stimulation of the tumor cells by estrogen. Adjuvant hormonal therapy should be offered to any pa- tient whose tumor overexpresses hormone receptors [either ER or progesterone (PgR)], regardless of patient age, nodal status, or menopausal status. Tamoxifen, a selective estro- gen-receptor modulator (SERM), has been the adjuvant hor- monal therapy most commonly used. In the meta-analysis performed by the EBCTCG of all randomized trials started before 1990, tamoxifen therapy showed a significant reduc- tion in the annual odds of breast cancer recurrence and mor- tality.53 Data from the meta-analysis showed that 5 years of tamoxifen was superior to 1 to 2 years of tamoxifen. A subsequent study (NSABP B-14) showed that 10 years of tamoxifen was inferior to 5 years, so it is recommended that tamoxifen be discontinued after 5 years.54 However, the benefits of tamoxifen must be weighed against the side ef- fects of treatment, particularly when the drug is being used in the adjuvant setting. The most common side effects of tamoxifen include hot flashes and vaginal discharge, but an increased risk of thromboembolic events and endometrial cancer can also occur. third-generation aromatase inhibitors have been extensively studied as first and second-line therapy for metastatic breast cancer. Fulvestrant, an injectable pure estrogen antagonist, has also shown activity in patients with hormone-receptor- positive disease progressing on hormonal therapy. The choice of hormonal therapy is patient-specific and may be influenced by prior therapy in the adjuvant setting, toxicity profiles, cost, and ease of administration. Historically, the antiestrogentamoxifen was the backbone of hormonal therapy. However, the partial agonist activity of tamoxifen, resulting in an in- creased incidence of thromboembolic disease and endome- trial cancer, as well as the development of drug resistance has prompted the development of alternative agents. romatase inhibitors (letrozole, anastrazole, and ex- emestane), which interfere with the final step of estrogen biosynthesis, are another class of compounds used as hor- monal therapy in patients with metastatic breast cancer. Re- cent data suggest that these agents are also effective in the adjuvant setting. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group found superior disease- free survival for anastrozole as adjuvant therapy in post- menopausal women with hormone-sensitive disease when compared to tamoxifen or the combination of tamoxifen and anastrozole.53 As a result, anastrozole was granted acceler- ated approval as adjuvant therapy for breast cancer.
  • Tamoxifen – acts like an anti-estrogen in breast cells, it acts like an estrogen in other tissues, like the uterus and the bones - stop the growth and even shrink tumors in women with metastatic breast cancer. It can also be used to reduce the risk of developing breast cancer in women at high riskAromatase inhibitors: cannot stop the ovaries from making estrogen, so they are only effective in women whose ovaries aren’t working (like after menopause)Fulvestrant - first blocks the estrogen receptor and then also eliminates it temporarily; acts like an anti-estrogen throughout the body
  • median duration of response to the first attempt at hormonal manipulation is usually in the range of 9 to 12 months, and the duration of any subsequent responses is generally shorter. First-line hormonal therapy should be administered for at least 6 to 8 weeks before disease response is assessed. After initiation of therapy, some patients may experience a flare (or worsen- ing) of their disease that may or may not be accompanied by hypercalcemia. If a patient becomes refractory to hormonal therapy at any time, chemotherapy should be given.
  • Adjuvant therapy should be tailored to the individual characteristics of the patient, and the benefits must be weighed against the risks of treatment, recognizing that the threshold for derived benefit of therapy varies be- tween individual patients. The American Society of Clinical Oncology (ASCO) has issued recommended breast cancer surveillance guidelines.63 Generally, women with a history of breast cancer should perform monthly BSE and undergo annual mammography of both the preserved and contralat- eral breast. The patient should also have a complete history and physical examination every 3 to 6 months for the first 3 years after diagnosis, then every 6 to 12 months for 2 years, and then annually.
  • combining an insulin sensitizer (e.g., a TZD or metformin) with insulin or an insulin secretagogue (e.g., a sulfonylurea) can both improve glycemic control in a poorly controlled Type II diabetic patient and lower the dose of each drug required to achieve a therapeutic effect
  • Sulfonylureas and meglitinides inhibit the ß cell K+/ATP channel at the SUR1 subunit, thereby stimulating insulin release from pancreatic ß cells and increasing circulating insulin to levels sufficient to overcome insulin resistanceBIGUANIDES:Mechanism—Activates AMP-dependent protein kinase (AMPPK) to block breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis; increases insulin receptor activity and metabolic responsiveness in liver and skeletal muscleTHIAZOLIDINEDIONES (TZDs):Mechanism—Bind and stimulate the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ), thereby increasing insulin sensitivity in adipose tissue, liver, and musclea-GLUCOSIDASE INHIBITORSMechanism—Carbohydrate analogues that bind avidly to intestinal brush border a-glucosidase enzymes, slowing breakdown and absorption of dietary carbohydrates such as starch, dextrin, and disaccharides. Flatulence, bloating, abdominal discomfort, and diarrhea are common adverse effects, all of which result from gas released by bacteria acting on undigested carbohydrates that reach the large intestine.GLP-1 (Glucagon-like peptide-1) mimetics are the newest class of drugs developed for the treatment of diabetes. On the basis of these trials, sitagliptin was approved in 2006 as an adjunct to diet and exercise to improve glucose control in Type II diabetes. It can be used as monotherapy or in combination with a TZD or metforminThe known physiological functions of GLP-1 include:increases insulin secretion from the pancreas in a glucose-dependent manner.decreases glucagon secretion from the pancreas by engagement of a specific G protein-coupled receptor.increases insulin-sensitivity in both alpha cells and beta cellsincreases beta cells mass and insulin gene expression, post-translational processing and incretion.inhibits acid secretion and gastric emptying in the stomach.decreases food intake by increasing satiety in brain.promotes insulin sensitivity.
  • inhibit the ß cell K+/ATP channel at the SUR1 subunit, thereby stimulating insulin release from pancreatic ß cells and increasing circulating insulin to levels sufficient to overcome insulin resistance1st gen- therefore, should be used cautiously in patients who are unable to recognize or respond to hypoglycemia2nd gen- better suited for nonobese patients
  • TZD- Bind and stimulate the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ), Less hepatotoxicRosiglitazone shares the common Tzd adverse effects but appears to carry more cardiovascular risk than pioglitazone. Concurrent administration of nitrates and insulin putatively enhances the risk of myocardial infarction and is contraindicated; renin-angiotensin system blockers may have a similar risk but are not specifically prohibited.BIG- Activates AMP-dependent protein kinase (AMPPK) toGI distress associated with metformin use is usually transient and can be minimized by slow titration of the dose
  • BIG- Activates AMP-dependent protein kinase (AMPPK) toGI distress associated with metformin use is usually transient and can be minimized by slow titration of the dose
  • Exe-Typically used in combination with metformin or a sulfonylurea to improve glucose controlDigoxin levels should be monitored in patients receiving digoxin and sitagliptinGLP-1 (Glucagon-like peptide-1) mimetics are the newest class of drugs developed for the treatment of diabetes. On the basis of these trials, sitagliptin was approved in 2006 as an adjunct to diet and exercise to improve glucose control in Type II diabetes. It can be used as monotherapy or in combination with a TZD or metforminThe known physiological functions of GLP-1 include:increases insulin secretion from the pancreas in a glucose-dependent manner.decreases glucagon secretion from the pancreas by engagement of a specific G protein-coupled receptor.increases insulin-sensitivity in both alpha cells and beta cellsincreases beta cells mass and insulin gene expression, post-translational processing and incretion.inhibits acid secretion and gastric emptying in the stomach.decreases food intake by increasing satiety in brain.promotes insulin sensitivity.
  • Pioglitazone - metabolized by CYP2C8 and CYP3A4 to active metabolites. Thebioavailability of numerous other drugs also degraded by theseenzymes may be affected by pioglitazone therapy (affects OCPs). Bladder cancerRosiglitazone- rapidly absorbed and highly protein-bound.It is metabolized in the liver to minimally active metabolites. carry more cardiovascular riskAn adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema, especially when the drugs are used in combination with insulin or insulin secretagogues. Both drugs increase the risk of heart failure.Biguanides- insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia. common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), contraindicated in patients with renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction) because of the increased risk of lactic acidosis induced by these drugs.Sitagliptin- Common adverse effects include nasopharyngitis, upper respiratory infections, headaches, and hypoglycemia when the drug is combined with insulin secretagogues or insulin.PriceMetformin- Ansures ER tab 500 mg56's (P392.00/pack) Dimet- P3.85/film-coated tabTHIAZOLIDINEDIONES- Actos, Pioglitazone HCl (P2230.03/pack) to(P3579.68/pack). Pioglitazone Tab 5mg (PIOGLON) 3.50php/tabSulfonylureas- Aforglim (P597.44/box) to (P690.63/box) 1-50php/tabA-glucosidase inhibitors- Xelevia film-coated tab(Sitagliptin)- (P1503.80/box) to (P1503.80/box) Januvia (P1460.00/pack)
  • Sitagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). This enzyme rapidly metabolizes the endogenous incretins, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulino­tropic polypeptide (GIP).1 Metformin acts by reducing hepatic glucose production, mainly due to inhibition of gluconeogenesis. It also increases non-oxidative skeletal muscle glucose disposal and, because of con­sequently less ‘glucotoxicity’, it can improve residual pancreatic beta-cell funcBecause this effect is independent of DPP-4 activity, it is of potential relevance to its combination with sita­gliptin. A further reason for combining these two drugs relates to the fact that, unlike insulin itself and secretagogues such as sulfonylureas, neither sita­gliptin nor metformin is associated with hypoglycaemia or weight gain. In response to the presence of food, GLP-1 is released from the endocrine L cells of the lower small intestine/ colon and GIP from K cells in the upper small intestine. Both hormones increase insulin secretion when plasma glucose concentrations are above the normal fasting range. They have an additive effect, but GLP-1 inhibits gastro­intestinal motility and gastric emptying, and reduces appetite and food intake to a greater extent than GIP, and also attenuates glucagon secretion. DPP-4 inhibition increases plasma concentrations of GLP-1 and GIP, which are reduced in patients with type 2 diabetes, and therefore has a variety of beneficial effects on glycaemia.Sitagliptin and metformin combi­nation therapy is contraindicated in patients:10with renal disease or renal dys­function, usually a serum creatinine level of 133 µmol/L or above in males or 124 µmol/L or above in females, or an estimated creatinine clearance of less than 60 mL/min/1.73 m2. This is because sitagliptin is primarily excreted unchanged in the urine through active tubular secretion, and metformin can also accumulate in patients with renal failure. Sitagliptin and metformin combination therapy should also be temporarily discontinued in patients undergoing radiological studies involving intravascular administration of iodinated contrast materials that may impair renal function.with known hypersensitivity to sitagliptin or metformin.with acute or chronic metabolic acidosis, including diabetic ketoacido­sis, with or without coma. This relates to the reported association between metformin and lactic acidosis, the occurrence of which remains rare.11who are pregnant or lactating.
  • Metformin- cannot use if impaired renal/hepatic function • congestive heart failure (CHF), hypoxic/acidotic states, alcoholism
  • As initial therapy in type 2 DM when diet & exercise do not provide adequate glycemic control. As adjunct to diet & exercise to improve glycemic control in type 2 DM inadequately controlled on metformin or sitagliptin alone, or combination sitagliptin & metformin, or triple combination sitagliptin, metformin or a sulfonylurea, or max tolerated dose of metformin & a PPARγ agonist, or insulin & metformin alone.Individualized dosage. Initially 50 mg/500 mg bd. Max daily dose: Sitagliptin 100 mg/metformin 2 g.Janumet pack= 28s
  • SSRI- Highly selective blockade of serotonin transporter (SERT) • little effect on norepinephrine transporter (NET)Toxicity:Well tolerated but cause sexual dysfunction• risk of serotonin syndrome with MAOIs (characterized by hyperthermia, muscle rigidity, myoclonus, and rapid fluctuations in mental status and vital signs); • Interactions: Some CYP inhibition (fluoxetine 2D6,3A4; fluvoxamine 1A2; paroxetine 2D6)SSRIs lack significant cardiotoxicity, and do not bind as avidly to muscarinic (cholinergic), histamine, adrenergic, or dopamine receptors. As a consequence, SSRIs are generally better tolerated than TCAs. sertraline is more often associated with diarrhea, and paroxetine is associated with constipationSNRI-Moderately selective blockade of NET and SERTToxicity: Anticholinergic, sedation, hypertension (venlafaxine) • Interactions: Some CYP2D6 inhibition (duloxetine, desvenlafaxine)TCA- Mixed and variable blockade of NET and SERTLong half-lives • CYP substrates • active metabolites • Toxicity: Anticholinergic, α-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose • Interactions: CYP inducers and inhibitorsMAOI’s- Blockade of MAO-A and MAO-B (phenelzine, nonselective) • MAO-B irreversible selective MAO-B inhibition (lowdose selegiline)Very slow elimination • Toxicity: Hypotension, insomnia • Interactions: Hypertensive crisis with tyramine, other indirect sympathomimetics • serotonin syndrome with serotonergic agents, meperidine
  • SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)Mechanism—Selectively inhibit reuptake of serotonin and thereby increase synaptic serotonin levels; also cause increased 5HT receptor activation and enhanced postsynaptic responses. At high doses, also bind NE transporter.

Breast Cancer- Clinical Therapeutics Breast Cancer- Clinical Therapeutics Presentation Transcript

  • PROBLEM 1 Breast Cancer Yang, Sheryl Ray B.
  • Detection and Evaluation
  • In stage IIB: • larger than 2 centimeters but not larger than 5 cm. small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes • larger than 2 centimeters but not larger than 5 centimeters. Cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breast bone (found during a sentinel lymph node biopsy); or • larger than 5 centimeters. Cancer has not spread to the lymph nodes.
  • Recurrent Breast Cancer • Recurrent breast cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the breast, in the chest wall, or in other parts of the body.
  • Tamoxifen is beneficial in postmenopausal women when used alone or in combination with cytotoxic chemotherapy Present recommendation: administer tamoxifen for 5 years of continuous therapy after surgical resection. Postmenopausal women who complete 5 years of tamoxifen therapy should be placed on an aromatase inhibitor such as anastrozole for at least 2.5 years In women who have completed 2–3 years of tamoxifen therapy, treatment with an aromatase inhibitor for a total of 5 years of hormonal therapy is now recommended
  • Metastatic Breast Cancer Radiation therapy, hormonal therapy, and chemotherapy have all been used in the treatment of metastatic breast cancer to palliate the patient and possibly prolong survival. Palliation is the primary goal of therapy: the easiest, least toxic treatment that can provide the best possible response is generally preferred. • metastasize to virtually any site • most common sites: bone, lung, pleura, liver, soft tissue, and the central nervous system. • The choice of therapy for metastatic disease is based on the site of disease involvement and the presence or absence of certain patient characteristics.
  • Chemotherapy Chemotherapeutic drugs are most commonly used as palliative therapy in patients who would not be expected to respond to hormonal therapy
  • Radiation Radiation therapy is primarily used to control symptomatic disease such as bone metastases, metastatic brain lesions, and spinal cord compressions.
  • Hormonal therapy The goal of hormonal therapy is to reduce the stimulation of the tumor cells by estrogen. Tamoxifen, has been the adjuvant hormonal therapy most commonly used. most common side effects: hot flashes and vaginal discharge, but an increased risk of thromboembolic events and endometrial cancer can also occur. Fulvestrant, an injectable pure estrogen antagonist, has also shown activity in patients with hormone-receptorpositive disease progressing on hormonal therapy.
  • Efficacy Safety Suitability Cost Antiestrogen Tamoxifen +++ selective estrogen receptor modulator or SERM ++ Disease flare, hot flashes; rare: thrombophlebitis, ocular abnormalities, endometrial cancer ++ premenopausal and postmenopausal women (and men) with ER-positive earlystage breast cancer 1,40 0 Aromatase Inhibitors 3rd gen: anastrazole +++ Blocking aromatase in fat tissue that is responsible for making small amounts of estrogen in postmenopausal women +++ Hot flashes, nausea, vomiting, headache, fatigue; rare: bone fractures, musculoskeletal disorders +++ +++ initial therapy for metastatic 2750 hormone-sensitive breast cancer treat postmenopausal women with advanced breast cancer whose disease has worsened after treatment with tamoxifen Pure Estrogen Antagonist Fulvestrant +++ +++ Hot flashes, headache, nausea, vomiting, injection site reactions ++ postmenopausal women with metastatic ER-positive breast cancer after treatment with other antiestrogens +++ 28,0 00
  • Median duration of response to the first attempt at hormonal manipulation is usually in the range of 9 to 12 months. First-line hormonal therapy should be administered for at least 6 to 8 weeks before disease response is assessed. If a patient becomes refractory to hormonal therapy at any time, chemotherapy should be given.
  • Natural product cancer chemotherapy drugs: Clinical activity and toxicities DRUG MOA TAXANE Inhibits mitosis Paclitaxel ANTHRACYCLINE Doxorubicin Oxygen free radicals bind to DNA causing single- and doublestrand DNA breaks; inhibits topoisomerase II; intercalates into DNA CLINICAL APPLICATIONS ACUTE TOXICITY Breast cancer, nonsmall cell and small cell lung cancer, ovarian cancer, gastroesophageal cancer, prostate cancer, bladder cancer, head and neck cancer Nausea, vomiting, hypotension, arrhythmias, hypersensitivity Myelosuppression, peripheral sensory neuropathy Nausea, red urine (not hematuria) Cardiotoxicity , alopecia, myelosuppre ssion, stomatitis Breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, soft tissue sarcoma, ovarian cancer, non-small cell and small cell lung cancer, thyroid cancer, Wilms’ tumor, neuroblastoma DELAYED TOXICITY
  • DRUG MOA CLINICAL APPLICATIONS ACUTE TOXICITY Breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, bladder cancer Neurotoxicity, Hypersensitiv fluid retention, myelosuppression ity with neutropenia TAXANE Docetaxel Inhibits mitosis Mitomycin Superficial Acts as an bladder cancer, alkylating agent gastric cancer, and forms cross- breast cancer, links with DNA; non-small cell forma- tion of lung cancer, head oxygen free and neck cancer radicals, which (in combination with target DNA radiotherapy) Nausea and vomiting DELAYED TOXICITY Myelosuppression , mucositis, anorexia and fatigue, hemolytic-uremic syndrome
  • DRUG MOA Inhibits Vinblastine mitosis CLINICAL APPLICATIONS ACUTE TOXICITY DELAYED TOXICITY Myelosuppressio n, mucositis, Hodgkin’s and alopecia, non-Hodgkin’s syndrome of Nausea lymphoma, germ inappropriate and cell cancer, secretion of vomiting breast cancer, antidiuretic Kaposi’s sarcoma hormone (SIADH), vascular events
  • The American Society of Clinical Oncology (ASCO) breast cancer surveillance guidelines: • Women with a history of breast cancer should perform monthly BSE and undergo annual mammography of both the preserved and contralateral breast. • The patient should also have a complete history and physical examination every 3 to 6 months for the first 3 years after diagnosis, then every 6 to 12 months for 2 years, and then annually.
  • Bone Pain Problem 2 Zepeda, Monina Mae
  • Basis for Diagnosis • Chief Complaint: Severe (7 out of 10) hip pain • Bone scan: multiple metastases to the right pelvis • Medications: Ibuprofen 200 to 400 mg PO q4– 6h PRN, calcium carbonate 1,000 mg PO TID with meals
  • Treatment Objectives • To decrease the severity of pain • To minimize adverse reactions or intolerance to pain management therapies • To improve the patient’s quality of life and optimize ability to perform activities of daily living
  • Bone  most common site of secondary breast cancer Most common: the spine, skull, pelvis and upper bones of the arms and legs http://orthoinfo.aaos.org/figures/A00654F08.jpg
  • • Pain is defined as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage • most common symptom that provokes people to seek medical attention
  • KEY POINTS • Oral route is preferred unless contraindicated • Cancer pain is continuous • Should be scheduled at regular intervals rather than prn • Adjuvant therapy is used to decrease anxiety and fear with chronic pain (e.g. antidepressants)
  • Opioids • refers broadly to all compounds related to opium, a natural product derived from the poppy • produce analgesia, affect mood and rewarding behavior and alter respiratory, cardiovascular, GI, and neuroendocrine function
  • Strong opioid agonists • • • • Morphine Hydromorphone Fentanyl Methadone
  • Drug Efficacy Suitability Safety Cost Morphine ++++ +++ +++ ++++ Hydromorphone ++++ 4-5x ++ +++ ++ Fentanyl +++ 100x ++ +++ +++ Methadone ++++ 0.3x + +++ +
  • Drug Efficacy Suitability Safety Cost Morphine ++++ ++++ +++ ++++ Hydromorph one ++++ ++++ +++ ++ Fentanyl +++ ++ +++ +++ Methadone ++++ + +++ +
  • Drug Efficacy Suitability Safety Cost Morphine ++++ ++++ +++ ++++ Hydromorph one ++++ ++++ +++ ++ Fentanyl +++ ++ +++ +++ Methadone ++++ + +++ +
  • Side Effects • Common: Constipation, nausea, vomiting and somnolence • Mood changes • Addiction and physical dependence • Respiratory complication
  • Drug Efficacy Suitability Side Effects Safety Cost Morphine ++++ ++++ +++ ++++ • Common: constipation, nausea, vomiting, 60's (P1345.00/pack) miosis and somnolence Hydromorphchanges ++++ ++++ +++ ++ • Mood 28's one (P3640.00/pack) • Addiction and physical dependence • Respiratory depression  most common Fentanyl of death of acute overdose +++ ++ +++ +++ cause 5 × 1's (P2513.00/box) Methadone ++++ + +++ +
  • DOC: Morphine Sulphate - Prototype opioid agonist - exert major pharmacodynamic effects on mureceptors (strong) and kappa-receptors - Main indication is for preoperative pain and chronic malignant pain
  • Plan of Action Initiate Morphine Sulphate immediate release 15mg PO q3-4hours If the opiate requirement is determined, switch to a sustained release formulation
  • Plan of Action Start with: - Senna 1 tablet PO BID - Docusate sodium 100 mg PO BID - Ibuprofen 800mg q8h with food - pamidronate 90 mg IV over 2 hours every 4 weeks (Check SCr prior to each dose)
  • Monitor Efficacy and Toxicity Report any prolonged adverse events, severe confusion/lightheadedness, or difficulty breathing important to take the pain medication around the clock to prevent the pain from recurring
  • Hypercalcemia of Malignancy secondary to Bone Metastases Reported by: Edward Philip I. Villanueva, MD, FPCP, FPGS, FPCCP CHAIRMAN PHARMACOLOGY DEPARTMENT
  • I. Basis for Diagnosis • Breast Cancer: commonly associated with hypercalcemia • Pain on the right hip • Decreased appetite • Increasing fatigue • Constipation • More forgetful • Confusion • Calcium level: 12.5mg/dl (NV: 9.0-10.8mg/dl)
  • II. Treatment Objectives • To reduce serum calcium level • To reverse signs and symptoms of hypercalcemia • Avoid exacerbation of hypercalemia • Reduce gastrointestinal calcium absortion
  • III. Management • Therapeutic • Non pharmacologic
  • Loop diuretics • MOA: Enhances urine flow and also inhibits calcium reabsorption in ascending loop of Henle • A/E: ototoxicity, hypovolemia, K wasting, Hyperuricemia, Hypomagnesemia • Route: Oral, IV
  • Calcitonin • MOA: Lowers plasma Ca⁺² and Phosphate concentrations, blocking bone resorption and increases urinary calcium excretion by inhibiting renal calcium reabsorption • A/E: Nausea, vomiting • Route: SQ, intranasal, oral
  • Gallium Nitrate • MOA: Inhibiting bone resorption, reducing serum calcium in Cancer patient • A/E: Nephrotoxicity • Route: Oral
  • Plicamycin • MOA: Inhibiting bone resorption, reducing serum calcium in Cancer patient • A/E: sudden Thromocytopenia, hemorrhage, hepatic and renal toxicity, hypocalcemia, N/V
  • Phosphate • MOA: Binds to Calcium ions • A/E: Hypocalcemia, ectopic calcification, acute renal failure and hypotension • Route: Oral, IV
  • Biphosphonates • MOA: Mimics Pyrophosphate structure. It also inhibits the activation of enzyme Farnesyldiphosphate synthase (FPPS) which utilizes Pyrophosphate • A/E: Upsets the stomach and inflammation, erosion of esophagus, flu-like symptoms and rarely Osteonecrosis of the jaw • Route: Oral, IV
  • Drug of choice: BIPHOSPHONATES Efficacy Safety Suitability Cost Alendronate +++ +++ ++++ +++ P1,100 Risedronate +++ +++ +++ ++ P1,800 Ibandronate +++ ++ +++ + P17,000 Zolendronate ++++ ++ +++ + P24,000 Pamidronate ++++ +++ +++ ++ P1,700
  • DOC: Pamidronate • Indication: Osteoclast-mediated bone resorption, tumor associated osteolysis, breast and prostate cancer, hypercalcemia • IV: 60-90mg. Over 4 to 24hrs. • Onset: 24-48hrs. • Peak effect: 5-7days • Half life: 21-35hrs. • Excretion: Kidneys
  • Non Pharmacologic • Hold calcium supplement • Patient education: – Confusion, decreased appetite, constipation are due to high levels of calcium – Nausea and vomiting are side effects of Pamidronate – Eat small frequent meals to help with the Nausea and vomiting
  • Type 2 Problem 4 Zagada, Timothy M.
  • Basis for diagnosis • Type 2 diabetes mellitus for 7 years • 20 packs per year tobacco history • Overweight
  • Treatment Objectives • Continue control of blood sugar by maintaining normal or near-normal ranges – KeepHbA1C of <7 • Prevent disease and drug related complications
  • Pharmacologic Intervention • Insulin Therapy • Oral Antidiabetic Regimen – Patients with Type II diabetes are frequently treated with combinations of these drugs and are therefore utilizing multiple strategies
  • Drug Class Action SULFONYLUREA AND MEGLITINIDES Insulin secretagogue BIGUANIDES Insulin Sensitizer THIAZOLIDINEDIONES Insulin Sensitizer Effects • • Decreased endogenous glucose production Reduces insulin resistance • ALPHA-GLUCDIDASE INHIBITOR Competitive inhibitors of the intestinal α-glucosidases • • GLP-1 AGONISTS reduce circulating glucose increase glycogen,fat, and protein formation Glucagon-like peptide-1 • (GLP-1) receptor agonist • Reduce conversion of starch and disaccharides to monosaccharides reduce postprandial hyperglycemia enhances glucose-dependent insulin secretion inhibits glucagon secretion delays gastric emptying, and decreases appetite Clinical Application DM type 2 DM type 2 DM type 2 DM type 2 DM type 2
  • Insulin Sensitizers THIAZOLIDINEDIONES (TZDs) • increases insulin sensitivity in adipose tissue, liver, and muscle – do not increase insulin levels and therefore do not induce hypoglycemia – Ex; Rosiglitazone, Pioglitazone • Toxicities: – Fluid retention – edema, anemia
  • Insulin Sensitizers BIGUANIDES • block breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis • increases insulin receptor activity and metabolic responsiveness in liver and skeletal muscle • Does not induce hypoglycemia, Lowers serum lipids and decreases weight • Adverse effect: GI distress, lactic acidosis • Ex; Metformin
  • GLP-1 AGONISTS AND MIMETICS • Exenatide- Glucagon-like peptide-1 (GLP-1) receptor agonist – – – – enhances glucose-dependent insulin secretion inhibits glucagon secretion delays gastric emptying, and decreases appetite not orally available and must be injected • Sitagliptin- dipeptidyl peptidase-IV (DPP-IV) inhibitor that slows the proteolytic inactivation of GLP-1 and other incretin hormones – Dose adjustment – Kidney disease
  • Class Efficacy Safety Suitability Cost THIAZOLIDINED +++ IONES (TZDs) +++ ++++ ++ BIGUANIDES ++++ ++++ ++++ ++++ GLP-1 AGONISTS ++++ +++ ++++ ++ Sulfonylureas +++ +++ +++ +++ A-glucosidase inhibitors +++ +++ +++ ++
  • Drug Class of Choice • Biguanides and Glucagon-like peptide1 mimetics – Metformin + Sitagliptin
  • Pharmacologic Intervention • Continue Metformin • Discontinue Rosiglitazone, shift to Sitagliptin • Efficacy monitoring: blood glucose, HbA1C in 3 months • If patient requires hospitalization for worsening dehydration or if renal function declines further – hold metformin
  • Sitagliptin + Metformin (Janumet) Per 50/500 mg Sitagliptin 50 mg, metformin HCl 500 mg. Per 50/850 mg Sitagliptin 50 mg, metformin HCl 850 mg. Per 50/1000 mg Sitagliptin 50 mg, metformin HCl 1,000 mg Form Janumet 50 mg/1000 mg tab Janumet 50 mg/500 mg tab Janumet 50 mg/850 mg tab Packing/Price (P867.20/pack) (P800.00/pack) (P842.00/pack)
  • Non pharmacologic Intervention • Counsel KF to; – continue diabetes medications and selfmonitoring. – Remind her of the importance of diet/exercise in the treatment of diabetes. – Remind her to maintain all follow-up appointments for diabetes. – Report any shortness of breath or swelling in the legs to the physician.
  • Problem 5
  • Basis for diagnosis • Present in patients medical history • Use of paroxetine (controlled under current regiment) • Decreased appetite over the past few weeks and increasing fatigue. • Slightly confused
  • Treatment Objectives • Continue monitoring for signs and symptoms of depression • Continue therapy to avoid future episodes
  • Class Efficacy Safety Suitability Cost SSRI ++++ ++++ ++++ ++++ SNRI ++++ +++ +++ + TCA ++++ + ++ +++ MAOI’s ++++ + + +++
  • SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) • Selectively inhibit reuptake of serotonin – increase synaptic serotonin levels – also cause increased 5HT receptor activation and enhanced postsynaptic responses. – At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose.
  • Pharmacologic Intervention • Continue current regimen – controlled with current regimen – Paroxetine, 20 mg PO daily
  • Pharmacologic Intervention • Monitoring parameters: signs and symptoms of depression; depression may worsen with new diagnosis and prognosis • adverse events of paroxetine: – Nausea – vomiting – constipation/diarrhea – sexual dysfunction
  • Non-Pharmacologic Intervention • Counsel KF to continue depression medication unless otherwise directed by her physician. • She should seek a psychologist to discuss her new diagnosis. She should report any new/worsened depression symptoms to her physician.