Treatment of Pathophysiological Cases - Case Study Example

1. Jack is a 72 year old gentleman who has congestive cardiac failure and atrial fibrillation. On admission he has swollen ankles and an irregular pulse. He is taking digoxin, furosemide and warfarin and his furosemide has been increased on admission. a) Explain, in terms of the underlying pathophysiology why he has swollen ankles and an irregular pulse. (25%) Edema is a symptom of excessive fluid in the interstitium resulting from several deregulatory mechanisms and one of these is impaired venous return. In general, the opposing effects of vascular hydrostatic pressure and plasma colloid osmotic pressure are the major factors that govern movement of fluid between vascular and interstitial spaces. Normally the exit of fluid into the interstitium from the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end; a small residuum of excess interstitial fluid is drained by the lymphatics. Either increased capillary pressure or diminished colloid osmotic pressure can result in increased interstitial fluid. (Kumar, 2005, p120) Congestive heart failure is a syndrome where the heart has an inherent dysfunction, or pathology causing it to be unable to pump efficiently, thus causing the signs and symptoms which include dyspnea, fatigue edema and rales. In this disease, there is initial left ventricular dysfunction, which may be the result of left ventricular remodelling. This may then lead to functional mitral regurgitation, with overloading of the ventricles because it now has to pump against a higher pressure, and the dysfunction of the atrium, the fibrillation, does not help to push the cardiac volume forward, instead retaining much of the volume because there is no electrical impulse that travels throughout the myocardium that is enough to trigger a contraction. This may then lead to pulmonary congestion, and the symptom of dyspnea because of the fluid accumulation that is hindering the lungs from expanding to its full capacity. According to Harrison (2008, p. 1446) the mechanical burdens that are engendered by LV remodeling can be expected to lead to decreased forward cardiac output, increased LV dilation (stretch), and increased hemodynamic overloading, all of which are sufficient to contribute to the progression of HF. The peripheral edema comes from the chronic passive congestion due to the right sided failure that results from the initial left sided heart failure due to the transmission of the pressure overload and volume overload. In heart disease, edema primarily results from elevated RA pressures or associated peripheral venous disease. Right heart failure most commonly results from left heart failure, pulmonary disease, or RV dysfunction and tricuspid regurgitation, or constrictive pericarditis. (Tierney, 2008) The patient was also noted to have irregular pulses and is a known case of atrial fibrillation. Atrial fibrillation (AF) is caused by multiple reentrant waveforms within the atria, which bombard the atrioventricular (AV) node, commonly leading to a tachycardia that is irregularly irregular. The rate at which atrial fibrillation causes a ventricular contraction is dependent upon the refractory state of the AV node. There is loss of atrial contraction and its contribution to ventricular filling, also referred to as loss of atrial kick. In addition, this loss of contraction can lead to stagnation of blood in the atrium and can promote thrombus formation. Patients may be at risk for embolization when atrial fibrillation converts to sinus rhythm as organized atrial contractions can now cause the dislodging or fragmentation of the atrial thrombus into the systemic circulation. The symptoms of atrial fibrillation include an irregular heartbeat transmitted peripherally as irregular pulses, and is most often tachycardic at 110-140 beats per minute, and rarely exceeding 160 beats per minute. (Borczuk, 2010) b) Discuss why the dosage of furosemide was increased and outline how the drug works (pharmacodynamics). (20%) Furosemide is a loop diuretic. Diuretics are drugs that increase the rate of urine flow, and in the process of excreting Na, they bring with it Cl-. The content of Nacl in the body determines the extracellular fluid volume. By acting on the reabsorptive functions of the kidney, they help to reduce extracellular fluid volume by decreasing the total body NaCl content. (Brunton, 2006) Drugs in this group of diuretics inhibit the activity of the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle; hence these diuretics also are referred to as loop diuretics. By blocking active NaCl reabsorption in the thick ascending limb, inhibitors of Na+-K+-2Cl- symport interfere with a critical step in the mechanism that produces a hypertonic medullary interstitium. Therefore, loop diuretics block the kidneys ability to concentrate urine during hydropenia. Also, since the thick ascending limb is part of the diluting segment, inhibitors of Na+-K+-2Cl- symport markedly impair the kidneys ability to excrete a dilute urine during water diuresis. Loop diuretics, particularly furosemide, acutely increase systemic venous capacitance and thereby decrease left ventricular filling pressure. This effect, which may be mediated by prostaglandins and requires intact kidneys, benefits patients with pulmonary edema even before diuresis ensues. (Brunton, 2006) c) Explain why Jack has been prescribed warfarin for his atrial fibrillation. (20%) Warfarin is an inhibitor of vitamin K dependent production of Factors VII, II, IX and X that are produced in the liver. It also inhibits Protein C and S, which are natural anticoagulants in the body. For the first three days of initiation of treatment, warfarin acts mostly as a procoagulant since it consumes the circulating natural anticoagulants, and has no effect on the already circulating tissue factors. The antithrombotic effect of warfarin depends on a reduction in the functional levels of factor X and prothrombin, clotting factors that have half-lives of 24 and 72 h, respectively. Because of the delay in achieving an antithrombotic effect, initial treatment with warfarin is supported by concomitant administration of a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux, in patients with established thrombosis or at high risk for thrombosis. (Tierney, 2006) After these circulating factors have been consumed because of their natural tissue half-life, the anticoagulant effects of warfarin begin because it blocks the factors from being produced. These factors are important in the coagulation cascade. In atrial fibrillation, the electrical activity does not correlate with an actual overall myocardial contraction and only small areas of the heart are stimulated. In this case, the blood that is supposed to be pumped towards the system undergoes stasis. If the blood is static, it will promote clotting and coagulation. The thrombus formed may cause an embolus if it is dislodged into the bloodstream. When the heart pumps and the thrombus is dislodged, it may clog up the smaller blood vessels, causing blockage of the areas supplied by these vessels. If this emboli, for instance, reaches the brain, then it may cause a stroke affecting the areas of the distribution of the involved blood vessel. Warfarin is used to prevent the possible adverse events that could ensue if there is stasis of blood due to inefficient pumping by the heart, as seen in heart failure and atrial fibrillation. d) What advice/ education with regard to his anticoagulant therapy would you provide Jack with on discharge? (20%) The most common complication of any anticoagulant therapy is bleeding. This may be in the form of gum bleeding, epistaxis, or hematuria, or, in more severe forms, gastrointestinal bleeding or retroperitoneal. Life-threatening intracranial bleed is also a possible complication. To minimize the risk of complications, it is therefore important to advice the patient about maintaining the INR at the therapeutic range. The patient should be advised to follow-up whenever there is any sign of bleeding, and to have his prothrombin time checked regularly. Since hemorrhage and anticoagulation intensity correlate well with each other, it would benefit the patient that he is constantly monitoring his INR. Patient should also be warned of the other, but relatively rarer, side effect of warfarin which is skin necrosis. This is usually seen during the initiation part of the treatment. (Fauci, 2008) A rare complication of warfarin, skin necrosis, is usually seen 2–5 days after initiation of therapy. Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the border of these lesions reveals thrombi in the microvasculature. (Fauci, 2008) e) Warfarin therapy is managed by measuring International ratio (INR) regularly. Explain what this is and why measurement is necessary. (15%) The INR is a measurement used to check for the efficiency of anticoagulation therapy, whether to increase the dosage so that the target INR is reached or titrate the dose in order to maintain the INR at the target level of 2, wherein most anticoagulation is still at the therapeutic range. The risk of hemorrhage is closely related to the intensity of anticoagulation. With an increasing duration of treatment, the risk of major hemorrhage increases cumulatively. When anticoagulant therapy is initiated, bleeding often occurs at the site of preexisting anatomical lesions. It is thus important to define the range of prothrombin times, usually expressed in terms of the international normalized ratio (INR), within which a highly protective antithrombotic effect is combined with an acceptable risk of bleeding. (Fauci, 2008) Warfarin therapy is most often monitored using the prothrombin time, a test that is sensitive to reductions in the levels of prothrombin, factor VII, and factor X. The test is performed by adding thromboplastin, a reagent that contains tissue factor, phospholipid, and calcium, to citrated plasma and determining the time to clot formation. Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors. Thus, less sensitive thromboplastins will trigger the administration of higher doses of warfarin to achieve a target prothrombin time. This is problematic because higher doses of warfarin increase the risk of bleeding. (Fauci, 2008) 2. Fiona, a 45 year old woman, has been taking Ibuprofen, a non-steroidal anti-inflammatory drug (NSAIDs) on a regular basis for rheumatoid arthritis. On endoscopy she is diagnosed with a duodenal ulcer. a) Discuss what gastric symptoms Fiona is likely to have experienced and explain, using your knowledge of pathophysiology, why they have occurred. (50%) The symptoms for duodenal ulcers are usually nonspecific. Fiona may have experienced epigastric discomfort or pain, worse when patient has not eaten anything for awhile. It is usually described as burning in quality, and may awaken the patient at night or early morning. This correlates with the physiologically increased acid secretion during these hours of day. Epigastric tenderness is the most frequent physical examination finding, found from the right upper quadrant to the midline. (Fauci, 2008, p1858) Prostaglandins play a central role in gastric epithelial defense/repair. The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution. A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2), each having distinct characteristics regarding structure, tissue distribution, and expression. COX-1 is expressed in a host of tissues, including the stomach, platelets, kidneys, and endothelial cells. Fiona’s ulcer has developed as a side-effect of the NSAIDs but it has been recommended that she continue with them as treatment for her RA. Therefore she has been prescribed Etoricoxib (a cyclo-oxygenase-2 selective inhibitor) once the ulcer has healed after treatment with Esomeprazole. . b) Explain why Ibuprofen has caused a duodenal ulcer and why the risk is reduced by the use of Etoricoxib. (30%) The duodenal mucosa resists damage from the effect of aggressive factors, such as gastric acid and the proteolytic enzyme pepsin, with the help of several protective factors, such as a mucous layer, bicarbonate secretion, and protective prostaglandins, especially PGE. (Thomson, 2009) Ibuprofen, a nonselective COX inhibitor, decreases Prostaglandin production by inhibiting the Arachidonic Acid pathway, in which the COX 1 plays a major role. By this action, prostaglandin E production is blocked, and its protective role in relation to stimulating bicarbonate and mucus layer production against acid and pepsin. This will result in erosion of the gastric mucosa because it is now exposed to acid more often. A duodenal ulcer occurs when an alteration occurs in the aggressive and/or protective factors such that the balance is in favor of gastric acid and pepsin. Any process that increases gastric acidity (eg, individuals with increased maximal and basal acid output), decreases prostaglandin production (eg, NSAIDs), or interferes with the mucous layer (eg, H pylori infection) can cause such an imbalance and lead to peptic ulcer disease. (Thomson, 2009) Etoricoxib is a selective Cyclooxygenase 2 inhibitor such that it does not inhibit the COX 1 isoform, which is necessary for prostaglandin production; hence it lessens the possibility of injury to the gastric mucosa since the bicarbonate and the mucus layer are still produced in response to the presence of Prostaglandin E through the COX 1 pathway. The non-selective non-steroidal anti-inflammatory agents like Ibuprofen blocks both isoforms of COX: COX-1 and COX-2, thus blocking the prostaglandin production that is necessary for stimulation of gastric bicarbonate and mucus production that is necessary to protect the gastric mucosa and prevent it from being eroded by the acid. c) How does Esomeprazole work to promote healing of the ulcer? (20%) Esomeprazole is a proton pump inhibitor, and works by inhibition of acid production. Studies have shown that it is useful in treating gastroesophageal reflux disease and diseases where there is excessive acid production, like Zollinger- Ellison, and can be used to help heal peptic ulcers because of its long duration of acid suppression at the level of the parietal cells. Since the most common cause of duodenal ulcers is anything that can breach the natural defences available in the mucosa like infection with Helicobacter pylori and chronic NSAID use, which is common among patients who also suffer from diseases like the arthritides, studies have been done regarding its usefulness in conjunction with these anti-inflammatory agents that erode the gastric mucosa, and have proven that esomeprazole is able to decrease the incidence of duodenal ulcers diagnosed in chronic NSAID users. 3. Eric, aged 78 years, is terminally ill with primary prostate cancer and metastatic spread to his bones. To control his pain he has been prescribed modified release morphine. a) Discuss how primary tumours can spread within the body and secondary tumours develop (40%). At the molecular level, the body has genes to promote proliferation or growth of cells and there are genes that control the cells that are no longer functional and casue these cells to die by apoptosis. In the case of cancer, these regulatory mechanisms have malfunctioned and allowed the specific cell types that have mutated to continue proliferating without dying. DNA repair genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes, including protooncogenes, tumor suppressor genes, and genes that regulate apoptosis. Any changes in these genes could result to mutations that could later progress to neoplastic transformation. (Kumar, 2005, p288) Primary tumors can spread via different paths: by lymph vessels and by hematogenous spread and implanting themselves where they are able to find the necessary requirements for cell proliferation and growth. By hematogenous spread, it mean that the tumors are shed in the bloodstream and goes to the circulation to be distributed throughout the body, while by lymphatic spread, the tumor is shed into the interstitial fluid and is drained into the lymph vessels to be filtered, and this fluid also passes through the other organs systems. There are several requirements in order for a tumor to successfully metastasize or to have secondary tumors. One would be that the primary cancer should first gain access to the circulation via the blood or the lymphatics. Second would be that the tumor is presumed to have survived the separation from the primary tumor and should be able to lodge into a new organ and extravasate into the tissues where it tries to sustain its growth and survive the environment. Tumor spread beyond the affected organ, known as metastases, usually follow a pattern that is inherent in the mutated tumor cells. It goes to sites that are most accessible and most easily invaded by tumor growth and able to sustain the angiogenesis necessary for the new tumor to survive. Secondary tumors may develop because of the process called “dormancy”, in which there is seemingly no more tumor in the original site, and there is gradual recurrence of the tumor in a different site, after several years or months. This is possibly explained by the persistence of a solitary tumor in another site, for instance the liver or the bone marrow. (Brunicardi, 2005, p.260) b) Morphine is an opioid agonist. What does this mean? (10%) Opioid receptors are found within the central nervous system, and in other structures like the gastrointestinal tract and the urinary bladder. Opioid agonists stimulate these receptors by binding to them and causing hyperpolarization of the nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release. Morphine is an example of an opioid agonist, and is often used for treating chronic pain. It binds to kappa receptors in lamina I and II of the substancia gelatinosa of the spinal cord, decreasing the release of substance P, which modulates pain perception in the spinal cord. (Harvey, 2006, p 159) Opioid agonists produce analgesia by binding to specific G protein-coupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain. The principal effects of opioid analgesics with affinity for receptors are on the CNS; the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects. (Katzung, 2006) Opioids relieve pain both by raising the pain threshold at the spinal cord level, and by altering the brain’s perception of pain. c) Eric experienced constipation, nausea, and a dry mouth as side-effects of morphine. Explain why these occur and what drugs may be prescribed to counteract them? (40%) Constipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use; that is, tolerance does not develop to opioid-induced constipation Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS. In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion of hydrochloric acid is decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea. (Katzung, 2006) Oral laxatives are the mainstay in the treatment of constipation induced by opioids and may be classified into two general categories, softening and peristalsis-inducing agents. Docusate is the stool softening agent and is one of the most widely used in palliative care. It acts to increase secretions in the gastrointestinal tract, as well as absorption of these secretions by hard stool. Since the problem is usually not in the actual stool, but on the motility of the gastrointestinal organs, this is of little benefit to the patients. (Herndon, 2002) Other options include the use of suppositories and enema, although these two are more unpleasant for the patients. Also, the use of naloxone, the antidote for morphine toxicity and other opioid receptor antagonists, may help to alleviate constipation since they actually provides a laxative effect, and may be used in patients who are using morphine for palliation. The exact mechanism of action is theorized to reside within the myenteric plexus, where most gastrointestinal opioid side effects originate.(Herndon, 2002) Nausea and vomiting is a common side effect of morphine, and can be due to the presence of the receptors at the level of the medulla. Emesis or vomiting is coordinated at the vomiting center located in the medulla, wherein an important source of stimulation is an area in the postrema called the chemoreceptor trigger zone (CTZ). Since this area is not protected by the blood-brain barrier, it can easily be stimulated by any drugs or toxins circulating in the blood, hence the effect of morphine on this area. The patient can be given antiemetics to control the urge to vomit. The CTZ also has many dopamine receptors, hence it is also stimulated by drugs that are dopaminergic. The dopamine receptor antagonists thus can be used as antiemetics. An example would be metoclopramide, which is also a prokinetic drug in terms of the propulsive actions of the gastrointestinal organs. It helps to promote gastric emptying and also acts on the dopamine receptors. Since the CTZ area also contains 5HT receptors, which, when triggered also result in symptoms of nausea and vomiting, the 5HT antagonists like Ondansetron, can be useful to control nausea and vomiting. d) Why is a modified release prescription beneficial in this situation? (10%) The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. (Katzung, 2006) Diseases like cancer also give the patient chronic pain, especially if the cancers are already with metastases to other sites like the bone, the lungs and liver. The modified release formulations of morphine, or the patient’s pain killers is advantageous because it is easier to manipulate the dose, and if taken correctly, protects the patient from taking in a fatal amount in order to relieve the pain. It also helps that the available products vary in form that may be more flexible in terms of administration to the patients, and from a study done on the different available formulations; there was no significant difference in the Cmax and Tmax of the different tablets, regardless also of the salts used. In summary, the modified release forms give the advantage of a stable dosing for the patient due to its controlled release from the capsules. In this case, the patient is an elderly and may have low tolerance for the side effects of morphine, it is advantageous for him to have the modified release form for his prescription since the controlled and sustained supply of the drug to his body is enough to control the pain and minimize the side effects like vomiting, nausea, pruritus and respiratory depression. (Wiffen, 2007, p.1) REFERENCES: 1. Fauci, A et.al 2008, Heart Failure and Cor pulmonale, 17th edition, Harrisons Principles of Internal Medicine, McGraw-Hill Companies, Inc., USA. 2. Fauci, A et. Al 2008, Antiplatelet, Anticoagulant and Fibribolytic Drugs, 17th Edition, Harrison’s principles of Internal Medicine, McGraw-Hill Companies, USA. 3. Tierney, L et.al 2008, Oncology, Current Medical Treatment and Guidelines, McGraw-Hill Companies, Inc. USA. 4. Tierney, L et.al 2008, Common Symptoms:Edema, Current Medical Treatment and Guidelines, McGraw-Hill Companies, Inc. USA. 5. 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