Topical Issues of Medicine and Pharmacology - Assignment Example

The drug I chose was Herceptin. Herceptin interferes with the HER2/neu receptor. The HER receptors are cell membrane-embedded proteins that communicate molecular signals from outside to inside the cell, and turn genes on and off. They regulate cell growth, adhesion, survival, migration and differentiation. (Hudis 2007, p. 39). All these are functions that are weakened or amplified in cancer cells. In breast cancer, in 20-30% of the cases, the HER2 is overexpressed, which causes the cells to reproduce uncontrollably, which causes breast cancer.(Hudis 2007, p. 40). Herceptin 田onsists of two antigen-specific sites that bind to the juxtamembrane portion of the extracellular domain of the HER2 receptor and that prevent the activation of its intracellular tyrosine kinase.Hudis 2007, p. 40). One major side effect associated with Herceptin is cardio toxicity, resulting in congestive heart failure and cardiac related death. (Bancillon & Meckercke). Although the mechanism by which Herceptin causes heart problems is little understood, there is a suggestion that HER2 has a role in embyogenesis. (Hudis 2007, p. 43). In the clinical trial I evaluated, Herceptin was used in conjunction with Taxotere for women with HER2 positive breast cancer. (Bancillon & Meckercke). In this study, randomized patients received the control of AC-T (4 cycles of doxorubicin (A) and cyclophosphamide (C) followed by 4 cycles of Taxotere (T), or either two Herceptin and Taxotere based therapies AC-TH (adds 1 year of Herceptin to the AC-T regimen with Herceptin starting concurrently with Taxotere), or TCH (6 cycles of Taxotere and carboplatin (C) with 1 year of Herceptin starting at the first cycle). (Bancillon & Meckercke). The primary goal was disease-free survival (DFS). The secondary goals were overall survival (OS), safety, and pathologic and molecular markers. An Independent Data Monitoring Committee performed the safety analysis. (Bancillon & Meckercke). The patients were 222 women with early stage HER2-positive breast cancer, with positive axillary lymph nodes, as well as those without lymph node involvement. (Bancillon & Meckercke). The clinical trial found that the AC-TH arm had a reduction in the overall risk of death of 41%, and the TCH arm had a reduction in the overall risk of death of 34%, compared to the non-Herceptin-containing control arm. (Bancillon & Meckercke). Relapse was reduced by 39% in the AC-TH arm and 33% in the TCH arm when compared to the control. (Bancillon & Merckercke). 92% of the patients receiving the AC-TH arm were alive at 4 years, and 91% of the patients that were receiving the TCH arm were alive after 4 years, compare to 86% of the AC-T arm. (Bancillon & Meckercke). Of note was the fact that the TCH had comparable statistics to the AC-TH regiment, but had the patients in the TCH group had a five-fold decrease in cardiac toxicity compared to the AC-TH group. (Bancillon & Meckercke). There were 20 congestive heart failure events in the AC-TH group, verses 4 for the TCH group and a 50% decrease in asymptomatic declines in cardiac function with the TCH group verse the AC-TH group. (Bancillon & Meckercke). Moreover, the TCH group showed less sensory and motor neuropathies (36.1% v. 49.7% and 4.2% v. 6.3% respectively), nail changes (28.7% v. 43.6%) and myalgia (38.6% v. 52.8%), but more grade 3 and 4 throbocytopenia (5.4% v. 1.2%) and anemia (5.8% v. 3.1%) when compared to the AC-TH arm. (Bancillon & Merckercke). Question 1 - Explain the mechanism whereby either smoking or diet may contribute to heart disease. Metabolic syndrome, which is associated with overweight/obesity and type 2 diabetes mellitus, presents risk factors for cardiovascular disease, including abnormally high serum triglyceride levels in the fasting state. (Sandoval et al. p. 1). The mechanism that causes increased risk of cardiovascular disease is that raised serum TG levels that cause coronary heart disease highly suggests atherogenicy of TG-rich lipoproteins, include chylmicrons, very low density lipoproteins and their remnants. (Sandoval et al. p. 1). CD36, also known as fatty acid (FA) translocase, belongs to the scavenger receptor class B and is an 88 kD glycoprotein, binds multiple ligands, including oxidized low density lipoproteins and long-chain FAs. CD36 is broadly expressed in many cells, including platelets, monocytes, microvascular endothelial cells, macrophages, skeletal and cardiac myocytes, Kupffer cells, adipocytes and enterocytes. (Sandoval et al. p. 2). Impaired glucose metabolism, increased remnant lipoproteins and low high density lipoproteins cholesterol are risk factors associated with human CD36 deficiency, based upon insulin resistance. (Sandoval et al. p. 2). Human CD36 deficiency might be a genetic precursor for metabolic syndrome. (Sandoval et al. p. 2). Oral fat loading of more than 2 fold has been demonstrated to increase the 菟ostprandial plasma TG and FA responsein CD36 knockout mice. (Sandoval et al. p. 2). Question 2 What is troponin 1 and why might its elevated level indicate MI? Cardiac troponin I (cTnI) is a 途egulatory protein that control[s] the calcium-mediated interaction of actin and myosin.(Grewal & Gin 2004, p. 35). cTnI is found only in cardiac muscle. (Grewal & Gin 2004, p. 35). As cTnI has been demonstrated 殿s [a] being highly sensitive and specific biomarker of mycardial necrosis, and [a] valuable prognostic indicator in patients with acute coronary syndrome (ACS). This discovery led the joint ECS/ACC committee to establish a new definition of [acute myocardial infarction] in 2000.(Grewal & Gin 2004 p. 35). Detecting myocardial injury by the clinical sensitivity of troponin is well-established, as high as 100% at 36 hours after the onset of symptoms. (Grewal & Gin 2004 p. 36). Troponin appears to 12 hours after onset of cardiac injury, peaks at 18 to 24 hour, and can remain elevated for seven to 10 days.(Grewal & Gin 2004 p. 36). The 兎levation of...cTnI above the 99th percentile on at least one occasion in the first 24 hours is the preferred biomarker for diagnosis of AMI.(Grewal & Gin 2004 p. 36). Studies have compared the cardiac troponins, including troponin I and troponin T (cTnT) against traditional biochemical markers for MI, such as total creatine kinase (total CK) and creatine kinase-MB isoenzyme (CKMB), and they showed that cTnI was 都ignificantly more sensitive and specific than the MB inex for the diagnosis of MI, based upon 593 patients, 53 of whom were 菟ositive for both cTnI and the MB index, 21 were cTnI-positive and MB index-negative...25 were cTnI negative and MB index-positive...and 492 were negative for both markers.(Scripps News 1997). As for the superiority of cTnI over CKMB, 130 suspected MI patients were studied, comparing cTnI with CKMB and the relative index value. 典he results of this study were so significant as to prompt the investigators to recommend that their institution increase the use of cTnI assays and decrease the use of CKMB assays in the biochemical confirmation of MI.(Scripps News 1997). The results are below (Scripps 1997). cTnI sensitivity: 96%; specificity: 99%; negative predictive value: 99%; positive predictive value: 96%. CKMB or RIV sensitivity: 93%; specificity: 89%; negative predictive value: 98%; positive predictive value: 69%. CKMB and RIV sensitivity: 81%; specificity: 100%; negative predictive value: 95%; positive predictive value: 100%. Question 3 Explain briefly the nature of a PCI and stenting and the purpose of the co-administered drugs. PCI is a percutaneous coronary intervention. (Chen et al. 2010, p. 794). It is a treatment for persons who experience myocardial ischemia or myocardial infarction. (Torpy 2004, p. 778). The goal is to open up a coronary artery and restore blood flow. Primary PCI is performed as an emergency procedure on patients whose heart muscles have been permanently damaged by a heart attack, and it reduces the death rate from heart attacks. (Torpy 2004, p. 778). In PCI, the femoral artery in the groin provides access to the heart and major blood vessels. A special needles punctures the artery through the skin, and a catheter is threaded through the femoral artery up into the aorta, then into the affected coronary artery, where a balloon is used to open up the coronary artery and restore blood flow. Sometimes a stent is put into place to maintain good blood flow through the damaged area. (Torpy 2004, p. 778). Chronic total occlusion (CTO) is one of the major challenges in PCI, and 途andomized clinical trials have proved that the implantation of a bare metal stent (BMS) acting as a mechanical scaffold, was superior to balloon angioplasty alone due to a significantly reduced rate of acute/subacute reocclusion.(Zhang et al. 2010, p. 789). A drug-eluting stent (DES) reduces the rates of restenosis after PCI, as well as improving clinical outcomes in treating single coronary CTO lesions.(Zhang, H. et al. 2010, p. 789). Several studies have also 途eported the decreased rate of target vessel revascularization (TVR) by CABG relative to percutaneous coronary intervention,which was mainly driven 澱y higher incidence of target lesion revascularization(TLR). (Chen et al. 2010, p. 794). The rate of occurrence of in-stent restenosis (ISR) after PCI reaches 10 to 20% after DES stenting. (Chen et al. 2010, p. 794). Other studies have found that gender is not an 妬ndependent predictor of short-term prognosisfor individuals with acute ST-elevation myocardial infarctions (STEMI) who are treated by sirolimus-eluting stent implantation (SES)-based primary PCI. (Zhang,Q. et al. 2010, p. 782). Therefore, women have the same outcome as men when undergoing this procedure. Question 4 Recent research has highlighted concern that CYP2C19 polymorphisms may reduce the effectiveness of clopidogrel in some patients explain. CYP2C19 gene 妬s one of the member of cytochrome P-450 super family enzymes involved in metabolism of a number of drugs, and accounts for 2% of oxidative drug metabolism in humans.(Ghodke 2009, p. 2). It is also 殿 polymorphically expressed isoenzyme that catalyses the oxidation of several clinically important drugs including proton pump inhibitors, diazepam, proguanil, nelfinavir, antidepressants and some endogenously produced hormones such as steroids.(Satyanarayana et al, 2009, p. 537). The CYP2C19 is considered to be an important activator of clopidrogels antiplatelet function. (Shuldiner et al. 2010, p. 855). The CYP2C19 allele variant is major determinant of adenosine diphospate (ADP)-stimulated platelet aggregation, thus 妬ndividuals with this genotype have reduced protection from clopidogrel in preventing cardiovasular disease-related events following PCI.(Shuldiner et al. 2010, p. 857). ADP, along with its receptor P2Y12 菟lays an important role in platelet activation and its maintenance.Toshikazu, J. 2009, p. 1498). CYP2C19 polymorphism are further 殿ssociated with a weaker antiplatelet response to clopidogrel. Furthermore, the plasma concentration of the activie metabolite of clopidogrel is affected by CY2C19 genotype.(Toshikazu, J. 2009, p. 1498). Because CYP2C19 allele is high in the African American and Asian populations (?33% and ?51% respectively), clopidogrel resistance is particularly important in these populations. Those with the CYP2C19 allele would benefit more from an antiplatelet regimen that does not include clopidogrel, such as ticagrelor, third-generation tienopyridine prasugrel and cangrelor. (Shuldiner et al. p. 857). Question 5a Why might chronic heart failure result in breathlessness? Shortness of breath occurs when the failure occurs in the large chamber on the left side of the heart, which causes blood to back up into the lungs, which causes the lung to fill up with fluid. This causes shortness of breath and fatigue. (Trelogan 2000, p. 1). Question 5b Why might furosemide by prescribed in CHF? Because Furosemide acts as a diuretic, and diuretics control fluid retention, thus relieving the symptoms of CHF. (Ferrara 1996, p. 291). Question 6 Consider Davids pathologic condition and discuss the suitability of amitriptyline for him Amitryptyline would not be an appropriate drug for David, because of his heart condition. Amitryptyline (AMT) is part of a larger group of tricyclic antidepressants, which has shown to cause an increased rate of sudden cardiac deaths (SCD), even in therapeutic doses. (Chopra et al. 2009, p. 183). AMT works on 杜any cardiac membrane receptors, ion channels, transporters, and intracellular proteins which may contribute to the AMTs toxic effect on the heart.(Chopra et al. 2009, p. 183). AMT 妬ncreases RyR2 channel activity in bilayers and causes spontaneous SR Ca2 release events and SR Ca2 store depletion in intact myocites at concentrations relevant in humans,(Chopra et al. 2009, p. 183), which can cause 電elayed afterpolarization that can trigger ventricular arrhythmia and sudden cardiac death.(Chopra et al. 2009, p. 184). Question 7 What are there remedies (St. Johns Wort and Ginkgo Biloba), are they harmless placebos or is there the possibility of interaction with Davids prescribed drugs? There is a possibility of interaction with the Clopidogrel with the St. Johns Wort. This is because the Clopidogrel decreases blood clotting in the body, and taking St. Johns Wort along with Clopidogrel might decrease blood clotting too much, as St. Johns Wort increases how well the body breaks down Clopidogrel. (St. Johns Wort). Likewise, Ginkgo Biloba might adversely interact with the Clopidogrel, because of its antiplatelet activity might prolong bleeding time, and cause a hemorrhage. (Aruna & Naidu, 2006, p. 334). However, one study showed no such adverse reaction, concluding that 田oadministration of ginkgo biloba either with cilostazol or clopidogrel did not enhance antiplately activity compared with individual agents.(Aruna & Naidu, 2006, p. 338). However, this is only one study and, since Clopidogrel is used to improve circulation, Ginkgos antiplatelet activity is something that David should beware of, and he should stop taking the Ginkgo, as it is 澱etter safe than sorry.” Question 8 - What is polypharmacy and why especially might it be a problem in the elderly? Polypharmacy is the act of prescribing multiple drugs concomitantly. (Page et al. 2010, p. 76). It is associated with an increased risk for adverse drug events, as well as adverse drug-disease and drug-drug interactions. Patients taking two drugs have a 13% risk of adverse drug-drug interactions, rising to 38% for individuals taking four drugs and 82% for individuals taking seven drugs or more. (Page et al. 2010, p. 76). Adverse drug events are treated with additional drugs, which leads to 菟rescribing cascades.(Page et al. 2010, p. 77). Another risk related to polypharmacy is decreased medication adherence, which might lead to an increased dose of the initial medication, or another drug being added, which increases the risk for adverse drug events still further. (Page et al. 2010, p. 77). Polypharmacy has special implications for the elderly. It is regarded as a risk factor for falls, which leads to reduced functioning. (Baranzini et al. p. 229). This was seen when an 妬njurious fall risk-increasing drug (antiarrhythmic or antiparkinson drug) was part of the patients therapeutic regimen.(Baranzin et al. p. 234). SOURCES USED Aruna, D. & Naidu, M. (2006), 撤harmacodynamic Interaction Studies of Ginkgo Biloba with Cilostazol and Clopidogrel in Healthy Human Subjects,British Journal of Clinical Pharmacology, vol. 63, no. 3, pp. 333-338. 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(2010), 鏑ong-Term Efficacy and Safety of Drug-Eluting Stent Implantation for Patients with Multiple Coronary Chronic Total Occlusions,Chinese Medical Journal, vol. 123, no. 7, pp. 789-793. Zhang, Q., Qiu, J., Zhang, R., Li, Y., He, B., Jin, H., Zhang, J., Wang, X., Jiang, L., Liao, M., Hu, J., Shen, W. (2010), 鄭bsence of Gender Disparity in Short-Term Clinical Outcomes in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Sirolimu-Eluting Stent Based Primacy Coronary Internation: A Report from Shanghai Acute Coronary Event (SACE) Registry, Chinese Medical Journal, vol. 123, no. 7, pp. 782-788. Read More