PHARMACOLO NURS 251 Pharmacology Module 3.

Module 3 3.1: Introduction to Cardiology Taking a Blood Pressure Blood pressure is the pressure exerted against the walls of blood vessels as blood circulates through the body. Blood pressure is measured using an instrument called a sphygmomanometer, perhaps more commonly known as the blood pressure cuff. The pressures associated are measured in units of millimeters of mercury (mm/Hg). The health care provider inflates a blood pressure cuff in order to cut off the blood flow from the brachial artery. As they release the pressure in the cuff, they are listening with a stethoscope, for the frst sound, called the Korotkoff sound, meaning there is no longer enough pressure to keep all the blood from flowing. The Korotkoff sound corresponds to a numerical gauge on the sphygmomanometer and is called the systolic value (top number) of the patent’s blood pressure. The provider contnues to let air out of the cuff and eventually the sounds disappear, representng that the brachial artery is now completely open. When this occurs, the numerical value on the sphygmomanometer is known as the diastolic value (botom number) in a patent’s blood pressure. Hypertension is defned as the persistent systolic blood pressure of greater than 150mm/Hg and/or a diastolic blood pressure greater than 90mm/Hg in patents 60 years of age and older. For patents younger than 60 or those with kidney disease or diabetes, it is defned as a systolic reading greater than 140mm/Hg and diastolic greater than 90mmHg. Hypertension is ofen an asymptomatc disease and is also considered the most common disease state worldwide. Table 3.1 below breaks down different classifcatons of hypertension. Table 3.1 Classifcaton of Hypertension Classifcaton Blood Pressure (mm/Hg) Normotensive 120/80 Prehypertensive 120-139/80-89 Hypertensive 140/90 Stage 1 140-159/90-99 Stage 2 160/100 Essental hypertension, also known as primary hypertension, is when the cause of the increased blood pressure is unknown. Secondary hypertension is when a patent’s elevated blood pressure is caused by another disease. Orthostatc hypotension, which is when a patent experiences a sudden drop in blood pressure when they change positons (i.e. when going from a seated positon to standing). Physiologic Factors that Determine Blood Pressure Blood Pressure is determined by cardiac output, the amount of blood ejected from the heart’s lef ventricle multplied by the Systemic Vascular Resistance (SVR), the resistance to blood flow. Cardiac output is determined by two factors: heart rate (beats per minute) and stroke volume (volume of blood pumped per minute). SVR is determined by the diameter of the blood vessel as well as the musculature nature of the blood vessel. An increase in any of the above factors: heart rate, stroke volume or SVR will result in a rise in blood pressure. There are also several factors commonly associated with high blood pressure even though they alone do not cause high blood pressure. Associated factors of blood pressure include: sodium intake, maintaining a healthy weight, avoidingsmoking, proper exercise, and minimizing stress. If these contributng factors can be carefully regulated, then the blood pressure can be reduced. Figure 3.1 below shows the factors that regulate blood pressure within the body and where certain anthypertensive medicatons work. Figure 3.1. Normal Regulaton of Blood Pressure and corresponding medicatons. Blue boxes represent align with Cardiac Output. Yellow boxed align with Systemic Vascular Resistance. The kidney’s role will be discussed in more detail later in this module, but it is important to menton that with high blood pressure there is an increased peripheral resistance which in turn decreases the blood supply to the kidney. Peripheral resistance is the resistance generated by the flow of blood through the arteries. When this happens, the kidney releases an enzyme called renin. Ultmately, renin leads to further vasoconstricton, water and sodium retenton, and an increase in blood pressure. 3.2: Antihypertensives The goal of anthypertensive therapy is the reducton of cardiovascular and renal morbidity and mortality. According to guidelines, drug therapy should be started in patents over the age of 60 if their blood pressure is greater than 150/90mm/Hg. In younger patents or those with chronic kidney disease or diabetes, it should be started when the blood pressure is greater than 140/90mm/Hg. Fortunately, we are now living in a tme where there are many drug therapy optons available for patents and ofen their treatment needs to be individualized to meet their specifc needs. There are essentally seven main classes of anthypertensives that can be used or more commonly are used in combinaton with one another in order to get the patent’s blood pressure to goal. Table 3.2 summarizes the different drug classes available to treat high blood pressure and highlights how they work to reduce blood pressure. Refer to Figure 3.2 to place where in the body each of these major drug classes is exertng their effect. Table 3.2 Anthypertensive Drug Classes and Mechanism of actons. Class Example Mechanism of Acton Special Consideratons Adrenergic Agents · Centrally actng o Alpha Agonists · Peripherally actng Clonidine- centrally actng alpha agonist Doxazosin- peripheral actng alpha blocker Centrally actng: stmulate alpha2 adrenergic receptors in the brain causing a lack of norepinephrine producton. It also reduced the Centrally actng- means their site of acton is in the brain.o alpha blockers o beta blockers Metoprolol- beta blocker *Carvedilol and labetalol have both alpha and beta blocking acton. (generally classifed as Beta Blockers stll) actvity of renin which is responsible for the producton of the potent vasoconstrictor angiotensin II Peripherally actng: Alpha-block norepinephrine’s effect on alpha1 adrenergic receptors. Primarily this dilates arteries and veins reducing SVR and blood pressure. Beta- Block beta receptors causing a reducton in heart rate. They also reduce the secreton of renin. Long term use also reduced SVR. Peripherally actng means their site of acton is in the heart and blood vessels. Angiotensin Convertng Enzyme Inhibitors (ACE Inhibitors) Lisinopril (Prinivil) Prevent angiotensin I from being converted to angiotensin II. Angiotensin II is a potent vasoconstrictor. It also stmulates the reabsorpton of water and sodium into the body. Both of these actons raise blood pressure. Therefore by blocking, blood pressure is reduced. First line Drug of choice for hypertensive patents with Heart Failure and Diabetes due to their cardioprotectve effect and protectve effects on the kidney. Angiotensin II Receptor Blockers (ARBs) Losartan (Cozzar) Block the binding of Angiotensin II to type 1 Angiotensin II receptors. This blocks vasoconstricton and the secreton of aldosterone. Aldosterone causes sodium and water to be reabsorbed into the body, which can raise BP. Therefore, by blocking, blood pressure is reduced. First line Calcium Channel Blockers Amlodipine (Norvasc) Blocks Calcium from binding to receptors which causes smooth muscles to relax, thereby preventng contracton. First line Diuretcs *Thiazide Hydrochlorothiazide Work by decreasing plasma and extracellular fluid volumes- this decreases the preload, which leads to a decrease in cardiac output and total peripheral resistance. First line Vasodilators Hydralazine Directly cause peripheral vasodilaton- this results in a reduced SVR. Side Effects Direct Renin Inhibitors Aliskiren (Tekturna) Inhibits renin and decreases the formaton of angiotensin I and II. Not recommended for inital treatmentFigure 3.2 Sites of acton of major anthypertensive medicatons. There are four main sites of acton where anthypertensive medicatons exert their effect, including the brain, heart, blood vessels themselves, and kidneys. Four of the classes described above are considered frst line treatment for hypertension including: (1) Thiazides Diuretcs, (2) ACE-inhibitors, (3) ARBs, and (4) Calcium channel blockers. It is important to note that lifestyle modifcatons are always a part of the treatment of hypertension and include strategies such as smoking cessaton, blood sugar control, low sodium diet, and regular physical actvity. Thiazides Diuretcs: It has long been known that a low sodium diet could lower blood pressure. Essentally diuretcs increase the excreton of salt from the kidney leading to a decrease in blood pressure. It is important to understand that the long-term anthypertensive effect of thiazide diuretcs is due to a reducton in sodium concentraton in the cell leading to a reduced sensitvity to vasoconstrictors. This gradually reduces peripheral resistance and blood pressure. Notably, the reducton in blood pressure is seen at the lower end of the dosing range. Therefore, increasing the dose will not lead to a further reducton in blood pressure. Thiazides can be used alone or in combinaton and take about 4 weeks to see their full effect. Adverse effects: Low potassium, which can lead to dehydraton, muscle weakness, and fatgue. Drugs that Reduce the Activity of Angiotensin II Figure 3.3 depicts the progression of Angiotensin to Angiotensin II. This pathway is known as the renin-angiotensinaldosterone mechanism (RAA). All three of the classes of drugs (ACE-inhibitors, ARBs, and direct renin inhibitors) that work in this pathway exert their anthypertensive effect reducing the amount of angiotensin II produced, which is a potent vasoconstrictor.Figure 3.3 The renin angiotensin system is the pathway where ACE-inhibitors, ARBs, and direct renin inhibitors act to produce their anthypertensive effect. ACE-Inhibitors: Angiotensin Convertng Enzyme inhibitors are one of the preferred therapies for the treatment of hypertension. They work by inhibitng the enzyme that converts angiotensin I to angiotensin II. When angiotensin II is reduced, this leads to a decrease in the release of aldosterone and antdiuretc hormone. In turn, this causes vasodilaton which leads to lower blood pressure. ACE-inhibitors are well tolerated and have been shown to have both cardio and renal protectve propertes making them the anthypertensives of choice in patents with heart failure and kidney disease. Adverse Events: Common adverse events include headache, dizziness, GI disturbances, and rash. They can also cause an increase in potassium levels in the body. Two unique adverse events associated with ACE-inhibitors is a dry cough and angioedema (swelling of the face and oral cavity). The cough is not harmful but generally is managed by changing the patent to an ARB, which is not known to have the same side effect. As the angioedema can be life threatening, the use of an ACE-inhibitor would need to be stopped. Angiotensin II Receptor Blockers (ARBs): Angiotensin II acts on the angiotensin-1 receptor. As the name suggests, the receptor is where angiotensin receptor blockers exert their effect. ARBs bind to this receptor and prevent the angiotensin II from being able to bind. This inhibits the vasoconstricton effects of angiotensin II leading to a decrease in blood pressure. Adverse Events: Similar to ACE-inhibitors, ARBs can cause headache, dizziness, GI disturbance, and increased potassium levels. However, they are not associated with a dry cough or angioedema. Calcium Channel Blockers: When used for hypertension, the primary mechanism is their ability to block calcium channels in cardiac and vascular smooth muscles leading to arteriolar vasodilaton. Calcium channel blockers are broken into two groups: non-dihydropyridines (verapamil and diltazem) and dihydropyridines (amlodipine and nifedipine). The main difference being that the non-dihydropyridines also have direct actons to decrease heart rate, conducton in the heart, and contractlity. This makes them beter drug choices for patents with coronary artery disease or arrhythmias. The dihydropyridines, in contrast, have no direct actons on the heart. Calcium channel blockers will be discussed again in the secton on angina. Adverse Events: Headache, facial flushing, dizziness, fluid retenton, the non-dihydropyridines can cause a drop-in heart rate. 3.3: Angina The heart requires a large amount of oxygen in order to pump blood to all the tssues and organs of the body. Angina Pectoris is defned as chest pain that occurs when the heart’s supply of blood carrying oxygen is insufcient to meet the demands of the heart. Angina is ofen a symptom of Coronary Artery Disease (CAD). CAD is defned as a conditon due to atherosclerosis and insufcient blood supply to the heart. The coronary arteries specifcally are the arteries that deliver oxygen to the heart. Ischemia is when there is damage to the tssues or cells because of a lack of oxygen delivery. When the heart is the specifc organ damaged by ischemia, it is termed ischemic heart disease. Ischemic heart disease is actually the number 1 killer in the US today. The primary cause of the disease is faty plaques that develop in the arteries known as atherosclerosis. The faty plaques make the arteries narrower which in turn decreases the supply of oxygen rich blood to the heart. A heart atack, or myocardial infarcton (MI) occurs when blood flow in one or more of the coronary arteries leading to the heart is completely blocked causing part of the heart muscle to receive no oxygen.There are three main classes of drugs that treat angina (chest pain) caused by this lack of oxygen delivery to the heart. They include: (1) Nitrates and Nitrites, (2) Beta Blockers, and (3) Calcium Channel Blockers. Nitrates will be covered in most detail, as the later two were also covered in the secton on hypertension. The goals of these drug therapies when used to treat angina are to decrease the frequency and intensity of the chest pain, to improve the patents’ functonal capacity and to ultmately prevent or delay a myocardial infarcton (MI). Nitrates Historically, nitrates have been the main treatment for both preventng and treatng angina. They are available in many different dosage forms. Nitrates currently available for use include: Nitroglycerin (rapid actng and long actng), isosorbide dinitrate (rapid actng and long actng), and isosorbide mononitrate (long actng). Mechanism of acton: Nitrates work by relaxing vascular smooth muscle. This happens when the nitrate ions are converted to nitric oxide, which is a potent vasodilator. The vasodilaton leads to a decrease in blood volume returning to the heart, which in turn reduces the workload of the heart. As the workload on the heart decreases, the heart requires less oxygen and there is relief from the pain. Use: Nitrates are used in two ways: reactvely or preventvely. Nitrates can be administered during an angina atack to relieve the pain. Most commonly accomplished with a sublingual tablet, the onset of acton is almost immediate. The second way is to take daily to prevent an atack. Adverse Events: Main adverse events are related to the vasodilaton—flushing, dizziness, headache, weakness or faintng. Patents can also experience sudden or excessive drops in blood pressure. Beta Blockers Mechanism of acton: Beta blockers work by blocking beta-1 receptors in the heart. This blockage leads to a decrease in the heart rate as well as the force of the heart’s contracton. These two actons lower the heart’s workload and oxygen need. Since the heart needs less oxygen, the patent experiences less chest pain. Use: Beta blockers are used on a daily basis when used for angina. They have been shown to prevent or at least delay the onset of chest pain. The preferred beta blockers for angina pain include: nadolol, propranolol, atenolol, and metoprolol. Adverse Events: Drowsiness, tredness, nausea, and diarrhea. If the dose is too high, patents can experience an unwanted drop (too low) in blood pressure or heart rate. Calcium Channel Blockers Mechanism of Acton: As previously discussed, CCB block calcium from entering the vascular smooth muscle. This leads to vasodilaton and reduced blood pressure. Again, lowering the overall workload of the heart. The non-dihydropyridines (verapamil and diltazem) also directly work on the heart, blocking calcium in the heart muscle itself. This can also decrease the heart rate leading to lower workload for the heart and antanginal actvity. Use: CCB are also taken on a daily basis to prevent angina atacks. Both non-dihydropyridines and dihydropyridines can have antanginal effect. CCBs typically used for angina include: verapamil, diltazem, amlodipine, nifedipine, and nicardipine. Adverse Events: headache, facial flushing, dizziness, low blood pressure. Verapamil specifcally can cause constpaton. Both verapamil and diltazem at too high of dosages can cause a dangerously low drop in heart rate. 3.4: Chronic Heart Failure Chronic heart failure (CHF) is defned as a conditon in which the heart is unable to pump sufcient blood to the tssues of the body. Since the heart is unable to pump blood efciently, it begins to build up in the heart and then overflow into the lungs, leading to both pulmonary edema (fluid in the lungs) and peripheral edema (fluid in the body ofen the lower extremites). Symptoms of this disease include tredness, shortness of breath, rapid heart rate and fluid build-up in both the lungs and extremites.Important terms to be familiar with when discussing CHF include: Ejecton Fracton: The proporton of blood that is ejected during each contracton of the heart compared with the total volume of blood within the ventricle of the heart. Lef ventricular end diastolic volume: The total amount of blood in the ventricle right before it contracts (also known as the preload). There are two common classifcaton systems for CHF used to help clinicians and patents to assess their symptoms and beter understand the severity or progression of the disease: (1) New York Heart Associaton’s (NYHA) and (2) American College of Cardiology Foundaton/ American Heart Associaton’s (ACCF/AHA). New York Heart Associaton’s (NYHA) Functonal classes are historically an older system. The focus of the NYHA functonal classes is the severity of the patent’s symptoms. The specifcs of the NYHA functonal classes are shown in Table 3.3 below. Table 3.3 New York Heart Associaton (NYHA) functonal classes NYHA Functonal Class Classifcaton Class I: No limitatons on physical actvity. Normal physical actvity does not cause symptoms. Class II: Slight limitatons on physical actvity. Comfortable when at rest, but ordinary actvity caused symptoms. Class III: Marked limitaton of physical actvity. Comfortable at rest, but less than ordinary actvity causes symptoms. Class IV: Unable to have physical actvity without symptoms or symptoms at rest. American College of Cardiology Foundaton/ American Heart Associaton’s (ACCF/AHA) was more recently developed to assess the stages of heart failure. The focus of this staging is on disease progression displaying as structural changes to the heart. The specifcs ACCF/AHA stages are shown in Table 3.4 below. Table 3.4 Classifcaton of Heart Failure from the American College of Cardiology Foundaton/American Heart Associaton (ACCF/AHA) Stages of Heart Failure ACCF/AHA Stages of Heart Failure Stage A: At high risk but no symptoms or structural heart disease Stage B: Structural heart disease present but no signs or symptoms Stage C: Structural heart disease with past or current symptoms Stage D: Refractory heart failure requiring interventons Drug Therapy The drugs of choice to treat CHF include ACE-inhibitors and ARBs, certain Beta Blockers, and diuretcs (to reduce symptoms which will be discussed in the nephrology secton below). As heart failure worsens, aldosterone inhibitors are ofen added. Only afer this point in the treatment regimen is digoxin added. However, digoxin had been the mainstay of therapy for hundreds of years and so we will discuss it frst as it is also the frst tme we have covered this drug. Digoxin: is in a class of its own known as the cardiac glycosides. It was originally obtained from the digitalis plant (or foxglove). It is a positve inotrope, meaning its clinical effect is to increase the force of the heart’s contracton. However, it has not been shown to reduce mortality and so because of that, the risk of toxicity and drug interactons, it has fallen out of favor. Adverse Events: Drop or rise in heart rate, low blood pressure, headache, fatgue, confusion, convulsions, colored vision (green, yellow, or purple), anorexia, nausea, vomitng, diarrhea. Digoxin Toxicity: Digoxin has a low therapeutc index, so drug concentratons do need to be monitored especially when frst initatng therapy. Signs of digoxin toxicity include low heart rate, headache, dizziness, confusion, nausea, visualdisturbances (blurred vision or yellow vision). Managing toxicity can range from withholding the next dose to administering an antdote type therapy in more severe cases. Beta Blockers: It may be surprising that beta blockers, which are known for decreasing the workload of the heart, are used in heart failure when the heart is already not working efciently. However, in CHF the heart is trying to meet the demands of the body by beatng faster, ofen causing patents to be tachycardic (increased heart rate). Despite working so hard, the heart is unable to meet the demands of the body and beatng faster only makes the problem worse. Thus, when a patent takes a beta blocker, it slows the heart rate and actually allows the heart to fll and functon more efciently. Preferred Beta blockers for CHF: Metoprolol, bisoprolol, nebivolol, and carvedilol. Of note, the dosages of beta blockers for CHF are on the lower range. ACE-Inhibitors/ARBs: Both drug classes have become the preferred therapy for CHF. They work in heart failure by the same mechanism previously learned. Specifcally, by preventng sodium and water from being reabsorbed into the body, they decrease blood volume and blood return to the heart. This decreases the preload and work load required of the heart. 3.5: Hyperlipidemia Hypercholesterolemia is defned as a conditon in which higher than normal amounts of cholesterol are present in the blood. This may lead to the development of atherosclerosis and coronary heart disease. Cholesterol is a fat-soluble steroid found in animal fats, oils, egg yolks, as well as widely distributed in the body, especially in the bile, blood, brain tssue, liver, kidneys, adrenal glands, and nerve fbers. Our bodies get cholesterol in two ways: the frst is through the foods that we eat, the second is through the body itself. The liver is responsible for cholesterol producton. Cholesterol is necessary to make steroid hormones, cell membranes, and bile acid. However, when the body has too much cholesterol, it can lead to plaque formaton, atherosclerosis, and coronary heart disease. Plaque is defned as a substance containing cholesterol, dead cell products, and calcium that accumulates in the innermost layer of the arteries. Lipids are fat soluble, so in order to move throughout the body, they must be atached to a lipid carrying protein. This combinaton is called a lipoprotein that can transport lipids via the blood. Lipoproteins are what we are actually referring to when we use the term cholesterol in most cases. Examples include: Low density lipoprotein (LDL)- known as “bad cholesterol”, High Density Lipoprotein (HDL) known as the “good cholesterol” because it works to remove cholesterol from the blood and return it to the liver to be metabolized. Triglycerides, a fat formed by three faty acids, supplies energy to muscle cells. When assessing a patent’s cholesterol levels, clinicians will order a lipid panel. Lipid panels will typically report out the patent’s LDL, HDL, and TG. To beter understand the lipid panel and goal cholesterol levels, see Table 3.5 below. Table 3.5 Lipid Panel Components Lipoprotein type Typical Recommended Level High or Abnormal level HDL 40 mg/dL 40 mg/dL LDL 100 mg/dL 160 mg/dL Triglycerides (TG) 150 mg/dL 200 mg/dL Total Cholesterol (TC) 200 mg/dL 240mg/dL Drug Therapy The decision to initate drug therapy is multfactorial, and it is no longer recommend to go off of lipid panel values alone. There are four groups that have been identfed as good candidates for drug therapy. These include patents with: 1. Clinical atherosclerotc cardiovascular disease 2. LDL cholesterol 190 mg/dL3. Diabetes between the ages of 40-75 and an LDL 70-189 mg/dL and no evidence of CVD. 4. No evidence of CVD or diabetes but have an LDL 70-189 mg/dL and are at risk for developing CVD. When drug therapy is necessary, the mainstay of treatment is a class of drugs commonly known as the statns. Statns: HMG-CoA reductase inhibitors or “statns” are the drug of choice in treatng hyperlipidemia. As the name implies, they inhibit the enzyme HMG-CoA reductase which happens to be the rate limitng enzyme in cholesterol synthesis within the liver. Table 3.5 below lists select statns and their relatve intensity for lowering LDL. Table 3.5 Statn Intensity Name of Statn and Dose Range Trade Name Intensity Level Atorvastatn 40-80mg Lipitor High Simvastatn 20-40mg Zocor Moderate Pravastatn 10-20mg Pravachol Low Adverse Events: Generally, these drugs are well tolerated when taken alone. However, abdominal pain, rash, and headache are most common. An important adverse effect to note is myopathy (muscle pain) as this can be severe and would warrant seeking medical atenton. Rhabdomyolysis is the rapid breakdown of skeletal muscle due to muscle injury, in this case, caused by the drug. It is thought to be dose-dependent. There is greater risk when used in combinaton with certain medicatons such as the calcium channel blockers, specifcally diltazem, verapamil, and amlodipine. Concomitant use with the cholesterol lowering drug gemfbrozil is also known to increase the risk. Risk factors include being over the age of 65, thyroid problems and renal insufciency. Besides muscle pain other signs that this is happening include changes in urine color and should be reported immediately. When taken in combinaton with other medicatons, there is an increase in potentally harmful drug interactons. Gemfbrozil is another medicaton used to treat high cholesterol, although it has fallen out of favor. When used in combinaton with a statn, the risk of myopathy increases. Warfarin is a commonly used blood thinner. When used in combinaton with statns, warfarin metabolism is slowed which can increase the concentraton of warfarin and increases the risk of a bleed. Other Medications There are several other classes of medicatons that can be used to treat high cholesterol. They are generally used when patents are unable to tolerate statns. Additonally, some of these medicatons target triglycerides specifcally, so depending on a patent’s lipid profle, they may be used to lower triglycerides. See Table 3.6 for a summary of other medicatons that can also be used to treat high cholesterol. Table 3.6 Other medicatons that can be used to treat high cholesterol Drug Class How it works Ezetmibe (Zeta) Cholesterol Absorpton Inhibitor Works by blocking the absorpton of cholesterol at the small intestnes. Cholestyramine (Questran) Bile Acid sequestrant Bind to bile causing it to be excreted this in turn causes the liver to convert cholesterol into bile acids, reducing the level of cholesterol. Gemfbrozil (Lopid) Fibric Acid Derivatve Works by actvatng the enzyme lipoprotein lipase, an enzyme responsible for cholesterol breakdown. Signifcant impact on triglycerides. Niacin B Vitamin Exact mechanism is not known, but it is thought to be related to cholesterol synthesis in the liver.Signifcant impact on triglycerides. Omega 3 Faty Acids (Lovaza) Fish oil Works to lower triglycerides specifcally although the mechanism of acton is not fully understood. 3.6: Introduction to Nephrology The kidney’s main role within the body is to maintain water and electrolyte balance. As blood passes through the kidney, it works to flter out the electrolytes stll needed by the body and reabsorb them back into the body. The main electrolytes involved are sodium, potassium, and chloride. Whatever is not reabsorbed is eliminated from the body as waste in the form of urine. In order to understand how diuretcs work in the kidney, basic kidney physiology must be reviewed. The fltraton process described above occurs in the nephron, which is the main structural component of the kidney. The glomerulus is the site of blood fltraton. The glomerulus marks the beginning of the nephron and is proximal to the proximal convoluted tubule. Figure 3.4 depicts the anatomy of a nephron within the kidney and where in the nephron each of the fve different diuretcs (Osmotc, Carbonic anhydrase inhibitors, Loop, Thiazide, and potassium sparing) exert their effect. The glomerular fltraton rate (GFR) is the rate at which the fltering occurs and is used by clinicians to estmate how well the kidneys are functoning. The proximal convoluted tubule is the part of the nephron immediately afer the glomerulus and before the loop of Henle. Close to 70% of the sodium and water that are fltered here is reabsorbed back into the bloodstream. Both the osmotc diuretcs and carbonic anhydrase inhibitors work here. Next is the loop of Henle, the part of the nephron between the proximal and distal tubules. Another 25% of the sodium is reabsorbed back into the bloodstream. As the name implies, loop diuretcs work here. The last 5% of sodium reabsorpton occurs in the distal convoluted tubule, which is right afer the loop of Henle. The thiazides and potassium sparing diuretcs both have their site of acton in the distal tubule. Lastly, the fltrate reaches the collectng tubule before it is excreted as urine. It is here that antdiuretc hormone (ADH) acts to reabsorb water back into the bloodstream. ADH is a hormone released within the brain that works to regulate water balance in the body. Figure 3.4 The Anatomy of the Nephron The nephron is the site of fltraton within the kidney and is also the site of acton for diuretcs. Diuretics There are fve different classifcatons of diuretcs. (1) Osmotc diuretcs, (2) Carbonic Anhydrase Inhibitors, (3) Loop Diuretcs, (4) Thiazide diuretc and (5) Potassium sparing diuretcs. They are classifed based on where in the kidney theyexert their effect, their chemical structure, and how potent of a diuretc they are. See Table 3.7 for examples of the fve different classes of diuretcs. Osmotc Diuretcs Mechanism of acton: Osmotc diuretcs are non-absorbable. They increase the pressure of the glomerular fltrate, which pulls fluid into the nephron preventng reabsorpton and leading to diuresis. There is minimal electrolyte loss in this process and therefore they are not used for peripheral edema. Uses: Acute Renal Failure Adverse Events: Chills, dizziness, headache, nausea, strain on cardiac functon Carbonic Anhydrase Inhibitors Mechanism of acton: As the name implies these diuretcs inhibit the enzyme carbonic anhydrase. The sodium and water reabsorpton process requires hydrogen. Carbonic anhydrase makes hydrogen available, so when it is inhibited, the reabsorpton of water and sodium cannot occur. Uses: Edema or fluid accumulaton caused by CHF. Specifcally, acetazolamide is used when other diuretcs have not worked. Carbonic anhydrase inhibitors can also be used to treat high-alttude sickness. Adverse Events: anorexia, drowsiness, GI distress, headache, metabolic acidosis Loop Diuretcs are very potent diuretcs. They are structurally related to the sulfa class of antbiotcs. Loop diuretcs have a relatvely fast onset of acton and last for at least 2 hours. They are effectve even with signifcant renal insufciency. Mechanism of acton: Primarily acts along the ascending limb of the loop of Henle blocking both chloride and sodium reabsorpton, resultng in decreased fluid volume. Uses: Edema associated with Heart failure, liver or kidney disease, and hypertension management. Adverse Events: High blood sugar, low potassium, low blood pressure, and urinary frequency Thiazide Diuretcs are also related to the sulfa antbiotcs like the loop diuretcs. It is important to note that as kidney functon declines, thiazides become less effectve because the drug is no longer able to reach the site of acton. Mechanism of acton: Works in the distal tubule to inhibit the reabsorpton of electrolytes, leading to water being excreted. They also directly relax small blood vessels which reduces SVR, making them effectve for both hypertension and heart failure. Uses: Hypertension, adjunct for heart failure, and some edema Adverse Events: Dizziness, headache, high blood sugar, low potassium, low blood pressure, and lightheadedness Potassium Sparing Diuretcs are named for their ability to spare potassium meaning that less potassium is excreted in the urine. Mechanism of acton: Spironolactone, specifcally, binds to aldosterone receptors in the collectng duct and distal tubule. This blocks the reabsorpton of sodium and water that aldosterone initates. Amiloride and triamterene do not bind directly to aldosterone receptors, but rather inhibit sodium reabsorpton induced by aldosterone within the distal tubules. Uses: Hypertension, reverse potassium loss caused by thiazide and loop diuretcs, and heart failure. Adverse Events: Gynecomasta (spironolactone only), high potassium, nausea, and vomitng Table 3.7 Diuretcs by ClassClass Select Drug Examples Carbonic Anhydrase Inhibitor Acetazolamide Loop Diuretcs Bumetanide, furosemide, torsemide Osmotc Diuretcs Mannitol Potassium Sparing Diuretcs Amiloride, spironolactone, triamterene Thiazide Diuretcs Hydrochlorothiazide, chlorthalidone, metolazone Problem Set Queston 1 Name the two factors that determine a person’s blood pressure. Cardiac Output and Systemic Vascular Resistance. Queston 2 Defne Cardiac Output. The amount of blood ejected from the heart’s lef ventricle Queston 3 List three contributng factors to a patent’s blood pressure. Any three of the following: Cardiac Factors- heart rate, contractbility, Circulatng Volume- salt, aldosterone, hormones and peripheral sympathetc receptors Queston 4 Defne what is considered hypertension (classify: normotensive, prehypertensive, hypertension, stage 1 and stage 2) Classifcaton Blood Pressure (mm/Hg) Normotensive 120/80 Prehypertensive 120-139/80-89 Hypertensive 140/90 Stage 1 140-159/90-99 Stage 2 160/100 Queston 5 Describe how a clinician takes a patent’s blood pressure. Blood pressure is measured using the instrument called sphygmomanometer which is also called blood pressure cuff. The instrument used is called a sphygmomanometer. The health care provider uses a blood pressure cuff to cut off the blood flow from the brachial artery. As they release the pressure in the cuff, using a stethoscope, they are listening for the frst sound, called the Korotkoff sound, meaning there is no longer enough pressure to keep all the blood from flowing. This is the top number or systolic value of the patent’s blood pressure. The provider contnues to let air out of the cuff and eventually the sounds disappear, representng that the brachial artery is now completely open. This is known as the diastolic value or botom number in a patent’s blood pressure. Queston 6 Differentate essental hypertension and secondary hypertension.Essental hypertension is also known as primary hypertension and is when the cause of the increased blood pressure is unknown. In contrast to, secondary hypertension which is when a patent’s elevated blood pressure is caused by another disease. Queston 7 Briefly describe the mechanism of acton of the four frst line anthypertensives. Thiazide diuretcs: Work by decreasing plasma and extracellular fluid volumes- this decreases the preload, which leads to a decrease in cardiac output and total peripheral resistance. ACE-Inhibitors: Prevent angiotensin I from being converted to angiotensin II. Angiotensin II is a potent vasoconstrictor. It also stmulates the reabsorpton of water and sodium into the body. Both of these actons raise blood pressure. Therefore, by blocking, blood pressure is reduced. ARBs: Block the binding of Angiotensin II to type 1 Angiotensin II receptors. This blocks vasoconstricton and the secreton of aldosterone. Aldosterone causes sodium and water to be reabsorbed into the body, which can raise BP. Therefore, by blocking this receptor, blood pressure is reduced. CCBs: Blocks Calcium from binding to receptors which causes smooth muscles to relax, thereby preventng contracton. Queston 8 Defne key terms related to angina: coronary artery disease, ischemia, and myocardial infarcton. CAD is defned as any one of the abnormal conditons that can affect the arteries of the heart and produce various pathologic effects especially a reduced supply of oxygen and nutrients to the heart. Ischemia is when there is damage to the tssues or cells because of lack of oxygen delivery. Myocardial infarcton occurs when blood flow to the heart is completely blocked causing part of the heart muscle to receive no oxygen. Queston 9 Briefly describe the mechanism of acton of nitrates in treatng angina. They work by relaxing the vascular smooth muscle. This happens when the nitrate ions are converted to nitric oxide, which is a potent vasodilator. The vasodilaton leads to a decrease in blood volume returned to the heart which reduced the workload of the heart. Meaning that less oxygen is required by the heart leading to a relief from the pain. Queston 10 Defne key terms related to heart failure- ejecton fracton, lef ventricular end-diastolic volume. Ejecton Fracton: The proporton of blood that is ejected during each contracton of the heart compared with the total volume of blood within the ventricle of the heart. Lef ventricular end diastolic volume: The total amount of blood in the ventricle right before it contracts (also known as the preload). Queston 11 Explain the basic difference between NYHA functonal classes and ACCF/AHA stages of HF. The NYHA classes focus on the symptomatc status of the disease. The ACCF/AHA stages focus more on the progression of the disease. Queston 12Explain how beta blockers and ACE-inhibitors/ARBs work in CHF. Beta blockers: In CHF the heart is trying to meet the demands of the body patents are ofen tachycardic (increased heart rate). Despite working so hard, the heart is unable to meet the demands of the body and beatng faster is just making it worse. So, when they take a beta blocker, that slows the heart rate, it actually allows the heart to fll and functon more efciently. ACE-inhibitors/ARBs- Work in CHF by preventng sodium and water reabsorbing into the body they decrease blood volume and blood return to the heart. This decreased the preload and work load required of the heart. Queston 13 Describe digoxin current place in treatng heart failure. The drugs of choice to treat CHF include ACE-inhibitors and ARBs, certain Beta Blockers, and diuretcs. As the heart failure worsens aldosterone inhibitors are added. Only afer this point is digoxin added. It has not been shown to reduce mortality and so because of that and the risk of toxicity and drug interactons it has fallen out of favor. Queston 14 List signs of digoxin toxicity. Signs of digoxin toxicity include: low heart rate, headache, dizziness, confusion, nausea, visual disturbances (blurred vision or yellow vison). Queston 15 Defne key terms related to hyperlipidemia: cholesterol (LDL, HDL, TG), plaque, rhabdomyolysis. Cholesterol is a fat-soluble steroid found in animal fats, oils, egg yolk, as well as widely distributed in the body, especially in the bile, blood, brain tssue, liver, kidneys, adrenal glands, and nerve fbers. Low density lipoprotein (LDL)- known as “bad cholesterol” High Density Lipoprotein (HDL) known as the “good cholesterol” because it actually works to remove cholesterol to the blood and return it to the liver to be metabolized. Triglycerides a fat formed by three faty acids that supplies energy to muscle cells. Plaque is defned as a substance containing cholesterol, dead cell products, and calcium that accumulates in the innermost layer of the arteries. Rhabdomyolysis is the rapid breakdown of skeletal muscle due to muscle injury. Queston 16 List the components of a lipid panel and what would be considered abnormal values. Lipoprotein type Abnormal level 1. 2. 3. 4. 5. 6. 7. 8. Lipoprotein type Abnormal level HDL 40 mg/dL LDL 160 mg/dLTriglycerides 200 mg/dL Total Cholesterol 240mg/dL Queston 17 Describe the mechanism of acton for the statns. They inhibit the enzyme HMG-CoA reductase which is the rate limitng enzyme in cholesterol synthesis within the liver. Queston 18 Explain the renal physiology and the role of the kidneys in water excreton. As blood passes through the kidney it works to flter out the electrolytes stll needed by the body and reabsorb them back into the body. The main electrolytes involved are sodium, potassium and chloride. What is not reabsorbed results in the formaton of urine and is eliminated from the body as waste. Queston 19 Defne key terms such as: distal and proximal convoluted tubule, GFR, glomerulus, loop of Henle. Proximal convoluted tubule- is the part of the nephron immediately afer the glomerulus and before the loop of Henle. Distal convoluted tubule- is right afer the loop of Henle. Glomerular fltraton rate (GFR)- is the rate at which the fltering occurs and is used by clinicians to estmate how well the kidneys are functoning. Glomerulus- marks the beginning of the nephron and is proximal to the proximal convoluted tubule. Loop of Henle- the part of the nephron between the proximal and distal tubules. Queston 20 Where in the kidney do the following diuretcs work: thiazide, loop and potassium sparing. Thiazide- distal tubule Loop- ascending loop of Henle Potassium Sparing- distal tubule and collectng duct. Queston 21 Identfy the primary indicatons for the different types of diuretcs including: Loop, thiazide, potassium sparing, osmotc, and carbonic anhydrase inhibitors. Loop- edema Thiazide- hypertension Potassium sparing- hypertension (especially in combinaton with thiazide to offset the potassium loss), heart failure Osmotc- acute renal failure Carbonic anhydrase- refractory edema Queston 22 List some of the common side effects with loop diuretcs.Decreased potassium, urinary frequency, low blood pressure, high blood sugar.