NURS 251 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 first 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 patient’s blood pressure. The provider continues to let air out of the cuff and eventually the sounds disappear, representing that the brachial artery is now completely open. When this occurs, the numerical value on the sphygmomanometer is known as the diastolic value (bottom number) in a patient’s blood pressure. Hypertension is defined as the persistent systolic blood pressure of greater than 150mm/Hg and/or a diastolic blood pressure greater than 90mm/Hg in patients 60 years of age and older. For patients younger than 60 or those with kidney disease or diabetes, it is defined as a systolic reading greater than 140mm/Hg and diastolic greater than 90mmHg. Hypertension is often an asymptomatic disease and is also considered the most common disease state worldwide. Table 3.1 below breaks down different classifications of hypertension. Table 3.1 Classification of Hypertension Classification 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 Essential hypertension, also known as primary hypertension, is when the cause of the increased blood pressure is unknown. Secondary hypertension is when a patient’s elevated blood pressure is caused by another disease. Orthostatic hypotension, which is when a patient experiences a sudden drop in blood pressure when they change positions (i.e. when going from a seated position to standing). Physiologic Factors that Determine Blood Pressure Blood Pressure is determined by cardiac output, the amount of blood ejected from the heart’s left ventricle multiplied 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, avoiding smoking, proper exercise, and minimizing stress. If these contributing 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 antihypertensive medications work. Figure 3.1. Normal Regulation of Blood Pressure and corresponding medications. 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 mention 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. Ultimately, renin leads to further vasoconstriction, water and sodium retention, and an increase in blood pressure. 3.2: Antihypertensives The goal of antihypertensive therapy is the reduction of cardiovascular and renal morbidity and mortality. According to guidelines, drug therapy should be started in patients over the age of 60 if their blood pressure is greater than 150/90mm/Hg. In younger patients 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 time where there are many drug therapy options available for patients and often their treatment needs to be individualized to meet their specific needs. There are essentially seven main classes of antihypertensives that can be used or more commonly are used in combination with one another in order to get the patient’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 exerting their effect. Table 3.2 Antihypertensive Drug Classes and Mechanism of actions. Class Example Mechanism of Action Special Considerations Adrenergic Agents · Centrally acting o Alpha Agonists · Peripherally acting Clonidine- centrally acting alpha agonist Doxazosin- peripheral acting alpha blocker Centrally acting: stimulate alpha2 adrenergic receptors in the brain causing a lack of norepinephrine production. It also reduced the Centrally acting- means their site of action is in the brain. o alpha blockers o beta blockers Metoprolol- beta blocker *Carvedilol and labetalol have both alpha and beta blocking action. (generally classified as Beta Blockers still) activity of renin which is responsible for the production of the potent vasoconstrictor angiotensin II Peripherally acting: 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 reduction in heart rate. They also reduce the secretion of renin. Long term use also reduced SVR. Peripherally acting means their site of action is in the heart and blood vessels. Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) Lisinopril (Prinivil) Prevent angiotensin I from being converted to angiotensin II. Angiotensin II is a potent vasoconstrictor. It also stimulates the reabsorption of water and sodium into the body. Both of these actions raise blood pressure. Therefore by blocking, blood pressure is reduced. First line Drug of choice for hypertensive patients with Heart Failure and Diabetes due to their cardioprotective effect and protective 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 vasoconstriction and the secretion 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 preventing contraction. First line Diuretics *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 vasodilation- this results in a reduced SVR. Side Effects Direct Renin Inhibitors Aliskiren (Tekturna) Inhibits renin and decreases the formation of angiotensin I and II. Not recommended for initial treatment Figure 3.2 Sites of action of major antihypertensive medications. There are four main sites of action where antihypertensive medications exert their effect, including the brain, heart, blood vessels themselves, and kidneys. Four of the classes described above are considered first line treatment for hypertension including: (1) Thiazides Diuretics, (2) ACE-inhibitors, (3) ARBs, and (4) Calcium channel blockers. It is important to note that lifestyle modifications are always a part of the treatment of hypertension and include strategies such as smoking cessation, blood sugar control, low sodium diet, and regular physical activity. Thiazides Diuretics: It has long been known that a low sodium diet could lower blood pressure. Essentially diuretics increase the excretion of salt from the kidney leading to a decrease in blood pressure. It is important to understand that the long-term antihypertensive effect of thiazide diuretics is due to a reduction in sodium concentration in the cell leading to a reduced sensitivity to vasoconstrictors. This gradually reduces peripheral resistance and blood pressure. Notably, the reduction in blood pressure is seen at the lower end of the dosing range. Therefore, increasing the dose will not lead to a further reduction in blood pressure. Thiazides can be used alone or in combination and take about 4 weeks to see their full effect. Adverse effects: Low potassium, which can lead to dehydration, muscle weakness, and fatigue. 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 antihypertensive 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 antihypertensive effect. ACE-Inhibitors: Angiotensin Converting Enzyme inhibitors are one of the preferred therapies for the treatment of hypertension. They work by inhibiting 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 antidiuretic hormone. In turn, this causes vasodilation which leads to lower blood pressure. ACE-inhibitors are well tolerated and have been shown to have both cardio and renal protective properties making them the antihypertensives of choice in patients 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 patient 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 vasoconstriction 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 vasodilation. Calcium channel blockers are broken into two groups: non-dihydropyridines (verapamil and diltiazem) and dihydropyridines (amlodipine and nifedipine). The main difference being that the non-dihydropyridines also have direct actions to decrease heart rate, conduction in the heart, and contractility. This makes them better drug choices for patients with coronary artery disease or arrhythmias. The dihydropyridines, in contrast, have no direct actions on the heart. Calcium channel blockers will be discussed again in the section on angina. Adverse Events: Headache, facial flushing, dizziness, fluid retention, 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 tissues and organs of the body. Angina Pectoris is defined as chest pain that occurs when the heart’s supply of blood carrying oxygen is insufficient to meet the demands of the heart. Angina is often a symptom of Coronary Artery Disease (CAD). CAD is defined as a condition due to atherosclerosis and insufficient blood supply to the heart. The coronary arteries specifically are the arteries that deliver oxygen to the heart. Ischemia is when there is damage to the tissues or cells because of a lack of oxygen delivery. When the heart is the specific 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 fatty plaques that develop in the arteries known as atherosclerosis. The fatty plaques make the arteries narrower which in turn decreases the supply of oxygen rich blood to the heart. A heart attack, or myocardial infarction (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 latter two were also covered in the section 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 patients’ functional capacity and to ultimately prevent or delay a myocardial infarction (MI). Nitrates Historically, nitrates have been the main treatment for both preventing and treating angina. They are available in many different dosage forms. Nitrates currently available for use include: Nitroglycerin (rapid acting and long acting), isosorbide dinitrate (rapid acting and long acting), and isosorbide mononitrate (long acting). Mechanism of action: Nitrates work by relaxing vascular smooth muscle. This happens when the nitrate ions are converted to nitric oxide, which is a potent vasodilator. The vasodilation 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: reactively or preventively. Nitrates can be administered during an angina attack to relieve the pain. Most commonly accomplished with a sublingual tablet, the onset of action is almost immediate. The second way is to take daily to prevent an attack. Adverse Events: Main adverse events are related to the vasodilation—flushing, dizziness, headache, weakness or fainting. Patients can also experience sudden or excessive drops in blood pressure. Beta Blockers Mechanism of action: 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 contraction. These two actions lower the heart’s workload and oxygen need. Since the heart needs less oxygen, the patient 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, tiredness, nausea, and diarrhea. If the dose is too high, patients can experience an unwanted drop (too low) in blood pressure or heart rate. Calcium Channel Blockers Mechanism of Action: As previously discussed, CCB block calcium from entering the vascular smooth muscle. This leads to vasodilation and reduced blood pressure. Again, lowering the overall workload of the heart. The non-dihydropyridines (verapamil and diltiazem) 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 antianginal activity. Use: CCB are also taken on a daily basis to prevent angina attacks. Both non-dihydropyridines and dihydropyridines can have antianginal effect. CCBs typically used for angina include: verapamil, diltiazem, amlodipine, nifedipine, and nicardipine. Adverse Events: headache, facial flushing, dizziness, low blood pressure. Verapamil specifically can cause constipation. Both verapamil and diltiazem at too high of dosages can cause a dangerously low drop in heart rate. 3.4: Chronic Heart Failure Chronic heart failure (CHF) is defined as a condition in which the heart is unable to pump sufficient blood to the tissues of the body. Since the heart is unable to pump blood efficiently, 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 often the lower extremities). Symptoms of this disease include tiredness, shortness of breath, rapid heart rate and fluid build-up in both the lungs and extremities. Important terms to be familiar with when discussing CHF include: Ejection Fraction: The proportion of blood that is ejected during each contraction of the heart compared with the total volume of blood within the ventricle of the heart. Left 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 classification systems for CHF used to help clinicians and patients to assess their symptoms and better understand the severity or progression of the disease: (1) New York Heart Association’s (NYHA) and (2) American College of Cardiology Foundation/ American Heart Association’s (ACCF/AHA). New York Heart Association’s (NYHA) Functional classes are historically an older system. The focus of the NYHA functional classes is the severity of the patient’s symptoms. The specifics of the NYHA functional classes are shown in Table 3.3 below. Table 3.3 New York Heart Association (NYHA) functional classes NYHA Functional Class Classification Class I: No limitations on physical activity. Normal physical activity does not cause symptoms. Class II: Slight limitations on physical activity. Comfortable when at rest, but ordinary activity caused symptoms. Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms. Class IV: Unable to have physical activity without symptoms or symptoms at rest. American College of Cardiology Foundation/ American Heart Association’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 specifics ACCF/AHA stages are shown in Table 3.4 below. Table 3.4 Classification of Heart Failure from the American College of Cardiology Foundation/American Heart Association (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 interventions Drug Therapy The drugs of choice to treat CHF include ACE-inhibitors and ARBs, certain Beta Blockers, and diuretics (to reduce symptoms which will be discussed in the nephrology section below). As heart failure worsens, aldosterone inhibitors are often added. Only after 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 first as it is also the first time 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 positive inotrope, meaning its clinical effect is to increase the force of the heart’s contraction. However, it has not been shown to reduce mortality and so because of that, the risk of toxicity and drug interactions, it has fallen out of favor. Adverse Events: Drop or rise in heart rate, low blood pressure, headache, fatigue, confusion, convulsions, colored vision (green, yellow, or purple), anorexia, nausea, vomiting, diarrhea. Digoxin Toxicity: Digoxin has a low therapeutic index, so drug concentrations do need to be monitored especially when first initiating therapy. Signs of digoxin toxicity include low heart rate, headache, dizziness, confusion, nausea, visual disturbances (blurred vision or yellow vision). Managing toxicity can range from withholding the next dose to administering an antidote 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 efficiently. However, in CHF the heart is trying to meet the demands of the body by beating faster, often causing patients to be tachycardic (increased heart rate). Despite working so hard, the heart is unable to meet the demands of the body and beating faster only makes the problem worse. Thus, when a patient takes a beta blocker, it slows the heart rate and actually allows the heart to fill and function more efficiently. 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. Specifically, by preventing 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 defined as a condition 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 tissue, liver, kidneys, adrenal glands, and nerve fibers. Our bodies get cholesterol in two ways: the first is through the foods that we eat, the second is through the body itself. The liver is responsible for cholesterol production. 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 formation, atherosclerosis, and coronary heart disease. Plaque is defined 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 attached to a lipid carrying protein. This combination 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 fatty acids, supplies energy to muscle cells. When assessing a patient’s cholesterol levels, clinicians will order a lipid panel. Lipid panels will typically report out the patient’s LDL, HDL, and TG. To better 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 initiate drug therapy is multifactorial, and it is no longer recommend to go off of lipid panel values alone. There are four groups that have been identified as good candidates for drug therapy. These include patients with: 1. Clinical atherosclerotic cardiovascular disease 2. LDL cholesterol >190 mg/dL 3. 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 statins. Statins: HMG-CoA reductase inhibitors or “statins” are the drug of choice in treating hyperlipidemia. As the name implies, they inhibit the enzyme HMG-CoA reductase which happens to be the rate limiting enzyme in cholesterol synthesis within the liver. Table 3.5 below lists select statins and their relative intensity for lowering LDL. Table 3.5 Statin Intensity Name of Statin and Dose Range Trade Name Intensity Level Atorvastatin 40-80mg Lipitor High Simvastatin 20-40mg Zocor Moderate Pravastatin 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 attention. 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 combination with certain medications such as the calcium channel blockers, specifically diltiazem, verapamil, and amlodipine. Concomitant use with the cholesterol lowering drug gemfibrozil is also known to increase the risk. Risk factors include being over the age of 65, thyroid problems and renal insufficiency. Besides muscle pain other signs that this is happening include changes in urine color and should be reported immediately. When taken in combination with other medications, there is an increase in potentially harmful drug interactions. Gemfibrozil is another medication used to treat high cholesterol, although it has fallen out of favor. When used in combination with a statin, the risk of myopathy increases. Warfarin is a commonly used blood thinner. When used in combination with statins, warfarin metabolism is slowed which can increase the concentration of warfarin and increases the risk of a bleed. Other Medications There are several other classes of medications that can be used to treat high cholesterol. They are generally used when patients are unable to tolerate statins. Additionally, some of these medications target triglycerides specifically, so depending on a patient’s lipid profile, they may be used to lower triglycerides. See Table 3.6 for a summary of other medications that can also be used to treat high cholesterol. Table 3.6 Other medications that can be used to treat high cholesterol Drug Class How it works Ezetimibe (Zetia) Cholesterol Absorption Inhibitor Works by blocking the absorption of cholesterol at the small intestines. 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. Gemfibrozil (Lopid) Fibric Acid Derivative Works by activating the enzyme lipoprotein lipase, an enzyme responsible for cholesterol breakdown. Significant impact on triglycerides. Niacin B Vitamin Exact mechanism is not known, but it is thought to be related to cholesterol synthesis in the liver. Significant impact on triglycerides. Omega 3 Fatty Acids (Lovaza) Fish oil Works to lower triglycerides specifically although the mechanism of action 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 filter out the electrolytes still 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 diuretics work in the kidney, basic kidney physiology must be reviewed. The filtration process described above occurs in the nephron, which is the main structural component of the kidney. The glomerulus is the site of blood filtration. 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 five different diuretics (Osmotic, Carbonic anhydrase inhibitors, Loop, Thiazide, and potassium sparing) exert their effect. The glomerular filtration rate (GFR) is the rate at which the filtering occurs and is used by clinicians to estimate how well the kidneys are functioning. The proximal convoluted tubule is the part of the nephron immediately after the glomerulus and before the loop of Henle. Close to 70% of the sodium and water that are filtered here is reabsorbed back into the bloodstream. Both the osmotic diuretics 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 diuretics work here. The last 5% of sodium reabsorption occurs in the distal convoluted tubule, which is right after the loop of Henle. The thiazides and potassium sparing diuretics both have their site of action in the distal tubule. Lastly, the filtrate reaches the collecting tubule before it is excreted as urine. It is here that antidiuretic 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 filtration within the kidney and is also the site of action for diuretics. Diuretics There are five different classifications of diuretics. (1) Osmotic diuretics, (2) Carbonic Anhydrase Inhibitors, (3) Loop Diuretics, (4) Thiazide diuretic and (5) Potassium sparing diuretics. They are classified based on where in the kidney they exert their effect, their chemical structure, and how potent of a diuretic they are. See Table 3.7 for examples of the five different classes of diuretics. Osmotic Diuretics Mechanism of action: Osmotic diuretics are non-absorbable. They increase the pressure of the glomerular filtrate, which pulls fluid into the nephron preventing reabsorption 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 function Carbonic Anhydrase Inhibitors Mechanism of action: As the name implies these diuretics inhibit the enzyme carbonic anhydrase. The sodium and water reabsorption process requires hydrogen. Carbonic anhydrase makes hydrogen available, so when it is inhibited, the reabsorption of water and sodium cannot occur. Uses: Edema or fluid accumulation caused by CHF. Specifically, acetazolamide is used when other diuretics have not worked. Carbonic anhydrase inhibitors can also be used to treat high-altitude sickness. Adverse Events: anorexia, drowsiness, GI distress, headache, metabolic acidosis Loop Diuretics are very potent diuretics. They are structurally related to the sulfa class of antibiotics. Loop diuretics have a relatively fast onset of action and last for at least 2 hours. They are effective even with significant renal insufficiency. Mechanism of action: Primarily acts along the ascending limb of the loop of Henle blocking both chloride and sodium reabsorption, resulting 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 Diuretics are also related to the sulfa antibiotics like the loop diuretics. It is important to note that as kidney function declines, thiazides become less effective because the drug is no longer able to reach the site of action. Mechanism of action: Works in the distal tubule to inhibit the reabsorption of electrolytes, leading to water being excreted. They also directly relax small blood vessels which reduces SVR, making them effective 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 Diuretics are named for their ability to spare potassium meaning that less potassium is excreted in the urine. Mechanism of action: Spironolactone, specifically, binds to aldosterone receptors in the collecting duct and distal tubule. This blocks the reabsorption of sodium and water that aldosterone initiates. Amiloride and triamterene do not bind directly to aldosterone receptors, but rather inhibit sodium reabsorption induced by aldosterone within the distal tubules. Uses: Hypertension, reverse potassium loss caused by thiazide and loop diuretics, and heart failure. Adverse Events: Gynecomastia (spironolactone only), high potassium, nausea, and vomiting Table 3.7 Diuretics by Class Class Select Drug Examples Carbonic Anhydrase Inhibitor Acetazolamide Loop Diuretics Bumetanide, furosemide, torsemide Osmotic Diuretics Mannitol Potassium Sparing Diuretics Amiloride, spironolactone, triamterene Thiazide Diuretics Hydrochlorothiazide, chlorthalidone, metolazone Problem Set Question 1 Name the two factors that determine a person’s blood pressure. Cardiac Output and Systemic Vascular Resistance. Question 2 Define Cardiac Output. The amount of blood ejected from the heart’s left ventricle Question 3 List three contributing factors to a patient’s blood pressure. Any three of the following: Cardiac Factors- heart rate, contractibility, Circulating Volume- salt, aldosterone, hormones and peripheral sympathetic receptors Question 4 Define what is considered hypertension (classify: normotensive, prehypertensive, hypertension, stage 1 and stage 2) Classification 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 Question 5 Describe how a clinician takes a patient’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 first 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 patient’s blood pressure. The provider continues to let air out of the cuff and eventually the sounds disappear, representing that the brachial artery is now completely open. This is known as the diastolic value or bottom number in a patient’s blood pressure. Question 6 Differentiate essential hypertension and secondary hypertension. Essential 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 patient’s elevated blood pressure is caused by another disease. Question 7 Briefly describe the mechanism of action of the four first line antihypertensives. Thiazide diuretics: 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 stimulates the reabsorption of water and sodium into the body. Both of these actions 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 vasoconstriction and the secretion 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 preventing contraction. Question 8 Define key terms related to angina: coronary artery disease, ischemia, and myocardial infarction. CAD is defined as any one of the abnormal conditions 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 tissues or cells because of lack of oxygen delivery. Myocardial infarction occurs when blood flow to the heart is completely blocked causing part of the heart muscle to receive no oxygen. Question 9 Briefly describe the mechanism of action of nitrates in treating 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 vasodilation 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. Question 10 Define key terms related to heart failure- ejection fraction, left ventricular end-diastolic volume. Ejection Fraction: The proportion of blood that is ejected during each contraction of the heart compared with the total volume of blood within the ventricle of the heart. Left ventricular end diastolic volume: The total amount of blood in the ventricle right before it contracts (also known as the preload). Question 11 Explain the basic difference between NYHA functional classes and ACCF/AHA stages of HF. The NYHA classes focus on the symptomatic status of the disease. The ACCF/AHA stages focus more on the progression of the disease. Question 12 Explain 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 patients are often tachycardic (increased heart rate). Despite working so hard, the heart is unable to meet the demands of the body and beating faster is just making it worse. So, when they take a beta blocker, that slows the heart rate, it actually allows the heart to fill and function more efficiently. ACE-inhibitors/ARBs- Work in CHF by preventing 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. Question 13 Describe digoxin current place in treating heart failure. The drugs of choice to treat CHF include ACE-inhibitors and ARBs, certain Beta Blockers, and diuretics. As the heart failure worsens aldosterone inhibitors are added. Only after 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 interactions it has fallen out of favor. Question 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). Question 15 Define 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 tissue, liver, kidneys, adrenal glands, and nerve fibers. 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 fatty acids that supplies energy to muscle cells. Plaque is defined 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. Question 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/dL Triglycerides >200 mg/dL Total Cholesterol >240mg/dL Question 17 Describe the mechanism of action for the statins. They inhibit the enzyme HMG-CoA reductase which is the rate limiting enzyme in cholesterol synthesis within the liver. Question 18 Explain the renal physiology and the role of the kidneys in water excretion. As blood passes through the kidney it works to filter out the electrolytes still 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 formation of urine and is eliminated from the body as waste. Question 19 Define key terms such as: distal and proximal convoluted tubule, GFR, glomerulus, loop of Henle. Proximal convoluted tubule- is the part of the nephron immediately after the glomerulus and before the loop of Henle. Distal convoluted tubule- is right after the loop of Henle. Glomerular filtration rate (GFR)- is the rate at which the filtering occurs and is used by clinicians to estimate how well the kidneys are functioning. 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. Question 20 Where in the kidney do the following diuretics work: thiazide, loop and potassium sparing. Thiazide- distal tubule Loop- ascending loop of Henle Potassium Sparing- distal tubule and collecting duct. Question 21 Identify the primary indications for the different types of diuretics including: Loop, thiazide, potassium sparing, osmotic, and carbonic anhydrase inhibitors. Loop- edema Thiazide- hypertension Potassium sparing- hypertension (especially in combination with thiazide to offset the potassium loss), heart failure Osmotic- acute renal failure Carbonic anhydrase- refractory edema Question 22 List some of the common side effects with loop diuretics. Decreased potassium, urinary frequency, low blood pressure, high blood sugar.