Treatment of Essential Hypertension

Transcription

1 2016 edition by Mark A. Simmons, PhD Department of Pharmaceutical Sciences School of Pharmacy University of Maryland Eastern Shore Originally developed by Hugh J. Burford, PhD, FCP Department of Pharmacology Schools of Medicine and Pharmacy University of North Carolina Chapel Hill and Patricia B. Williams, PhD, FCP Department of Pharmacology Eastern Virginia Medical School Norfolk Note to Students The fundamental purposes of all activities in the health-care professions are to help other people. Like all behavior, helping behavior becomes more effective and natural with practice. This exercise enables you to practice by helping your fellow students to learn basic science. Your skill at helping your fellow students should relate to your ability to help your patients in the future. This is a Patient-Oriented Problem-Solving (POPS) exercise designed for four students. Before beginning this session, you should have (a) studied the objectives designed to prepare you for it, (b) taken the pretest, and (c) reviewed the topics listed at the end of the pretest. Now, each of you should take one of the four color-coded parts and follow the directions in it. If your group has only three students, one of you should take two parts. If your group has more than four students, two should take turns with a part. Please begin by discussing the answers to the pretest.

2 Correct s to Pretest Questions In the discussion to follow, you are given the correct answers to some of the 10 pretest questions, along with explanations. Other students in your group have been given the answers to other questions. This allocation of answers and explanations is designed to encourage all members of your group to actively exchange ideas and concepts. First, study the answers in your part and then EXPLAIN them to your group. Don't simply read the answers to your classmates, and don't let your classmates read their answers to you. In explaining something to another person, most people gain and often transmit a better understanding of the subject. The pretest discussion and patient-oriented problem-solving parts of this activity are "open book"; be sure to refer to textbooks, notes, and other written resources whenever questions arise. To help you review any questions that you may have missed, you probably will want to make notes on your pretest answer sheets. However, avoid "collecting pages" for later study and understanding." Learn the concepts now so that later you will only need to review them. 1. You should have selected D because nitroprusside has a rapid predictable antihypertensive effect and decreases venous return and cardiac work. B, promotion of fluid and sodium retention, is an undesirable characteristic. This side effect is not produced by nitroprusside. 5. B is correct. Losartan is an angiotensin II receptor blocker (ARB). ARBs may induce a more complete inhibition of the renin-angiotensin system than the ACE inhibitors, such as captopril. Hydrochlorothiazide is a diuretic, which inhibits sodium reabsorption in the distal tubule. Clonidine is an α 2 -adrenergic-receptor antagonist. Nifedipine is a calcium channel blocker. When your group has finished discussing all of the pretest questions, read Instructions for the Clinical Problem" on the next page. 2

3 Instructions for the Clinical Problem In the remainder of this exercise, you are to use your knowledge of the pharmacology of antihypertensive drugs to decide appropriate therapy for Harry Hypertensive. Each of the four members of your group has information about one episode in Mr. Hypertensive's medical history and part of the drug data necessary to find the best therapy for him. Thus, you must share information and work together to treat his hypertension. When the episode for which you are responsible comes up, read it to the group and lead a discussion of the questions included with the episode. Pose each question to a different member of the group. Use the Discussion Notes provided as a guide for the discussion. DO NOT SIMPLY READ THE NOTES to the group. Learning is facilitated by active processes such as thinking about the questions and their possible solutions. Do not stop discussing a question until every member of the group is completely satisfied with the answer. During the discussion, members of the group may consult textbooks, notes, and any other reference material. This is a group effort. Work together and teach one another. As the group member whose part contains Episode 1, you should begin the discussion. 3

4 Episode 1 Harry Hypertensive, is a 40-year-old white male stockbroker with type A behavior. Harry is slightly overweight (BMI = 25.1) and is not very athletic. He has recently visited his physician for a physical examination. It had been 2 to 3 years since his last physical. His blood pressure (BP) was 170/110 mm Hg and his heart rate (HR) was 80 beats per minute (bpm). All other physical findings were within normal limits; there were normal fundi, no cardiomegaly, and no evidence of abdominal bruits. Harry has a strong family history of hypertension. Serum electrolytes, creatinine, cholesterol, and urinalysis are within normal limits. Harry has no physical complaints. Ask one of your classmates if drug therapy should be considered for Harry. Should therapy be started now? Why or why not? (: Don't begin therapy now. You would first confirm that his BP was elevated at a second visit. With this degree of hypertension, the patient should be reevaluated and within 1 month, but it can be done in one week or even few days. If there is any evidence of end organ damage, if initial BP is greater than 180/110, or if there are any symptoms of hypertensive emergency present, diagnosis of hypertension can be made on the first visit.) Now, ask a different classmate if drug therapy should be initiated. (: For Stage 1 hypertension [diastolic 90 to 99 mm Hg] drug therapy is needed. However, lifestyle changes are important and should be taught to the patient to enhance drug efficacy and reduce the dose of antihypertensives used.) At follow-up, Harry's average supine BP is 162/112 mm Hg with a HR of 76 bpm, and his standing BP is 155/112 mm Hg with a HR of 82 bpm. You decide that drug therapy is required. Now you must recall the physiological regulation of BP and how the different categories of antihypertensive drugs work. To accomplish this, ask your colleagues to review Handout 1. Allow 5 minutes for each member of the group, including yourself, to review the information. 4

5 HANDOUT 1 for use with Episode 1 ANTIHYPERTENSIVE DRUG CATEGORIES AND AGENTS Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects 1. Thiazide and Related Diuretics Hydrochlorothiazide TPR, hypovolemia, Hypokalemia, hyperuricemia, (HCTZ) secondary sodium hyponatremia, insulin sensitivity, hyperglycemia, hyperlipoproteinemia, digitalis intoxication Chlorthalidone Same as HCTZ Same as HCTZ Indapamide Same as HCTZ Same as HCTZ Metolazone Same as HCTZ Same as HCTZ 2. Calcium-Channel Blockers Nifedipine Direct vasodilation Constipation, tachycardia, headaches, edema Nicardipine Same as nifedipine Same as nifedipine Amlodipine 5-10 Same as nifedipine Same as nifedipine Diltiazem Same as nifedipine Bradycardia, edema, but less vasodilation heart block Verapamil Same as nifedipine Constipation, heart block but less vasodilation 3. ACE Inhibitors Captopril Total peripheral Cough, hyperkalemia, resistance, with BP, angioedema, rash, proteinuria, and renal flow teratogenic Enalapril 5-40 Same as captopril Same as captopril Lisinopril Same as captopril Same as captopril

6 Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects 4. ARBs Losartan Total peripheral Same as ACE inhibitors resistance, with BP, with less cough and renal flow Candesartan Same as losartan Same as losartan Eprosartan Same as losartan Same as losartan Irbesartan Same as losartan Same as losartan Olmesartan Same as losartan Same as losartan Valsartan Same as losartan Same as losartan 5. Other diuretics a. Loop diuretics Furosemide hypovolemia Same as HCTZ secondary to Na+ b. Aldosterone antagonist diuretics Spironolactone Mineralocorticoid Gynecomastia, libido, antagonist menstrual disorders c. Potassium-sparing diuretics Triamterene Na/K exchange Nausea, hyperkalemia at distal tubule renal function Amiloride 5-20 Same as triamterene Nausea, hyperkalemia 6. Sympatholytic Drugs a. β-blockers Propranolol cardiac output, Bronchoconstriction, renin release, heart failure, fatigue, reflex inhibition of sympathetic peripheral vasoconstriction, neurotransmission bradyarrhythmias, prolonged insulin reactions, libido

7 Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects a. β-blockers (cont.) Nadolol Same as propranolol Same as propranolol but more but longer effect accumulation, renal failure Timolol Same as propranolol Same as propranolol Pindolol 5-60 Same as propranolol Same as propranolol but less plus intrinsic bradycardia and less sympathomimetic activity peripheral vasoconstriction Labetalol Same as propranolol Same as propranolol plus α 1 -receptor blocking activity Metoprolol Same as propranolol, Same as propranolol, with less ß 1 -receptor selective bronchoconstriction, effect on insulin-induced hypoglycemia and peripheral vasoconstriction Betaxolol Same as metoprolol Same as metoprolol Atenolol Same as metoprolol Same as metoprolol but longer effect but accumulation with renal failure Acebutolol Same as metoprolol Same as metoprolol and pindolol and pindolol Carvedilol Same as labetalol Same as metoprolol plus α 1 -receptor blocking Nebivolol 5-40 Same as metoprolol Same as metoprolol b. Central α-agonists Methyldopa Decreased central Somnolence, orthostatic sympathetic outflow, hypotension, fever, hepatitis renin hemolytic anemia, libido Clonidine Same as methyldopa Sedation, dry mouth, withdrawal hypertension, libido

8 Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects b. Central α-agonists (cont.) Guanfacine 1-3 Same as methyldopa Same as clonidine c. Depletor of Norepinephrine Stores Reserpine Central/peripheral Depression, peptic ulcer, catecholamine depletion libido, nasal congestion d. α 1 -Blockers Prazosin 1-20 Peripheral α 1 - Postural hypotension, blockade leading to syncope, favorable plasma TPR, venous lipid shifts capacitance Doxazosin 1-16 Same as prazosin Same as prazosin Terazosin 1-40 Same as prazosin Same as prazosin 7. Vasodilators Hydralazine Direct artery Tachycardia, myocardial vasodilation ischemia, systemic lupus erythematosus Minoxidil Same as hydralazine Tachycardia, myocardial ischemia, edema, hypertrichosis, pericardial effusion Sodium nitroprusside IV Arterial and venous Hypotension, dilation reflex tachycardia cyanide buildup Additional agents in the above classes are available commercially. When the group members have reviewed the regulation of blood pressure and Antihypertensive Drug Categories, make sure that everyone understands the mechanism of BP lowering for each category of drugs before you proceed. Also make sure everyone understands the physiological regulation of BP. Use your slides or any other material and make notes as needed.

9 Therapy Sheets A through D. Ask each person to study their own Therapy Sheet. You start with Therapy Sheet A. Then have the group members take turns asking the rest of the group about the drugs on their own Therapy Sheet. 1. What is the mechanism of action of the drug? 2. What are the advantages, disadvantages, and/or complications associated with the use of the drug? 5

10 Therapy Sheet A: Hydrochlorothiazide (diuretic) - Student 1 Study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of diuretics, in general, and hydrochlorothiazide, in particular? Diuretics block sodium, potassium, and chloride cotransport in the ascending limb of the loop of Henle (e.g., furosemide) or sodium chloride reabsorption in the distal tubule (e.g., hydrochlorothiazide). The net effect is sustained salt and water loss, contraction of extracellular fluid volume (ECFV) with consequent reduction in cardiac output. Decreased cardiac output contributes to reduced glomerular filtration rate and renal blood flow during diuretic therapy. The thiazides have an additional vasodilator effect through activation of adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle. For diuretics the reduced ECFV is most significant in chronic therapy. This is shown by the ability of salt to reverse the antihypertensive effect of diuretics and by the increased plasma renin activity and aldosterone excretion from the decreased ECFV during diuretic therapy. 2. What are the advantages, disadvantages, and complications associated with the use of diuretics and hydrochlorothiazide? Advantages: are synergistic antihypertensive effects with most other drugs used. Also, diuretics are able to lower body sodium chloride load and thus enhance the antihypertensive effect. Disadvantages and complications: center on the metabolic actions of hydrochlorothiazide. This diuretic class increases blood sugar, calcium, uric acid, and cholesterol and reduces serum potassium. In addition, increases in dietary sodium will antagonize the antihypertensive effect of all diuretics.

11 Therapy Sheet B: Losartan (angiotensin II receptor blocker) - Student 2 When prompted during Episode 1, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of losartan? Angiotensin II receptor blockers (ARBs) are antagonists of angiotensin II at the AT1 receptor. ARBs reduce blood pressure by blocking the effects of angiotensin II, a vasoconstrictor. Angiotensin II receptor blockade produces vasodilatation with reduction of total peripheral resistance and a decrease in blood pressure. ARBs also increase urinary sodium and water excretion and reduce plasma volume. 2. What are the advantages, disadvantages, and complications associated with the use of ARBs? Advantages: ARBs provide a more direct inhibition of angiotensin II action, by acting directly at the angiotensin II (type AT1) receptor. In addition to ACE, there are other enzymes that can produce angiotensin II that are not blocked by ACE inhibitors. ARBs appear to be just as effective as ACE inhibitors in treating hypertension. Cough is less frequent with ARBs than with ACE inhibitors. Angioedema is a rare severe reaction, seen less frequently than with ACE inhibitors. Disadvantages and complications: Like ACE inhibitors, ARBs increase serum potassium due to blockade of angiotensin-stimulated aldosterone. ARBs also can cause complications in special patients and with high doses. Since these drugs decrease glomerular filtration, they must be used with caution in patients with renal artery stenosis. ARBs, like ACE inhibitors, can cause fetal abnormalities and should not be used in pregnancy.

12 Therapy Sheet C: Amlodipine (calcium-channel blockers) - Student 3 When prompted during Episode 1, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of nifedipine? Block L-type calcium channels in vascular smooth muscle cells. Depolarization and contraction of vascular smooth muscle depends mainly on the influx of Ca 2+ ; thus, Ca 2+ channel blockade leads to vasodilation. Nifedipine is more potent as an arteriolar vasodilator and has less effect on S-A and A-V node conduction than verapamil. The result is usually a slight increase in heart rate that offsets the negative inotropic effect of calcium antagonism. 2. What are the advantages, disadvantages, and complications associated with the use of calcium-channel blockers? Advantages: Nifedipine may be used to treat all degrees of hypertension but is used most for moderate to severe hypertension. It may be combined with β-blockers to reduce side effects and to enhance antihypertensive and antianginal effects. Also, it may be given sublingually for rapid onset of action. Disadvantages and complications: Disadvantages include tachycardia, headaches, edema, and constipation. Interactions can occur with other medications (e.g., hypotension with quinidine, increased levels of digoxin, and increased levels of nifedipine with cimetidine).

13 Therapy Sheet D: Lisinopril (ACE inhibitors) - Student 4 When prompted during Episode 1, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of lisinopril? ACE inhibitors block the conversion of angiotensin I to the vasoactive angiotensin II. ACE inhibitors reduce blood pressure by several mechanisms, but the most important is believed to be reduction of angiotensin II levels. The result is arteriolar dilatation with reduction of total peripheral resistance and increased urinary sodium and water excretion. 2. What are the advantages, disadvantages, and complications associated with the use of ACE inhibitors? Advantages: Lisinopril is effective in both mild and severe forms of renin-dependent hypertension. Absence of side effects in most patients makes lisinopril a choice for first-drug therapy of hypertension. It may be combined with other antihypertensive drugs to produce additive effects. The newer ACE inhibitors, enalapril, lisinopril, and ramipril, have longer durations of action and fewer adverse effects. Disadvantages and complications: Lisinopril is generally well tolerated in adequate doses, but causes a chronic cough in many patients, especially women. It does raise serum potassium due to blockade of angiotensin-stimulated aldosterone. Other common side effects include macropapular rash, angioneurotic edema, and a decreased sense of taste. Elderly white patients respond better to monotherapy than black patients. Finally, captopril's antihypertensive effect is antagonized by indomethacin and aspirin. ACE inhibitors should not be used in pregnancy. Since these drugs decrease glomerular filtration, they must be used with caution in patients with bilateral renal artery stenosis, but are the drug of choice for therapy of renovascular hypertension due to unilateral renal artery stenosis. In high doses (e.g., 150 mg/day, captopril) leukopenia and rash are often seen.

14 After you have reviewed the pharmacology of the antihypertensive drugs, use the following questions and the Discussion Notes to guide the discussion. Each member of the group should take the lead in answering at least one of the questions. 1.1 Do you choose to start Mr. Hypertensive on single-drug or multiple-drug therapy? Give the reasons for your choice. 1.2 What class of antihypertensive drug would be most appropriate for the initial treatment of Mr. Hypertensive? Give reasons for this choice. Give three advantages and three disadvantages. Make sure the group comes to a consensus and picks a single drug and class. 1.3 What advice should be given to Mr. Hypertensive to emphasize compliance and adjunctive treatments? 1.4 How would the following factors alter the choice? The patient is black, elderly, diabetic, asthmatic, or has congestive heart failure. 1.5 What is the therapeutic goal? 6

15 Discussion Notes for Questions in Episode The JNC 8 evidence-based guidelines (JAMA. 2014;311(5): doi: /jama ) call for initiation of therapy with a thiazide-type diuretic, an angiotensin-converting enzyme inhibitor (ACEI), an angiotensin II receptor blocker (ARB) or a calcium-channel blocker (CCB), alone or in combination. Some clinicians prefer to start with a low dose of one drug and adjust the amount toward the upper limit of the dose-therapeutic response curve, while carefully observing the patient for unwanted side effects, before adding a second drug. Other practitioners consider the addition of a second medication with a different mechanism of action before complete upward titration of the first medication. Still others will initiate treatment with a combination of drugs from two of the above-mentioned classes. In patients without coexisting disease, any of these choices will result in comparable effects on overall mortality. 1.2 Thiazides, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or calcium-channel blockers would be appropriate choices. Harry is asymptomatic, feels well, and has no known cardiac irregularities. The degree of his hypertension is Stage 1. He has not been previously treated and therefore his responsiveness to drug therapy should be good. Because the thiazide-type diuretics are (1) effective in most patients with mild to moderate hypertension and (2) have minimal side effects, they may be the best choice for initial therapy in a previously untreated patient; in addition, (3) diuretics usually increase the effects of other antihypertensive drugs. Therefore, if a second drug must be added to the regimen, lower doses of the second drug may be adequate to achieve your therapeutic goal. This effect of the diuretic drugs is probably related to the prevention of salt and water retention that frequently accompanies the use of other antihypertensive drugs. Some clinicians favor the use of calcium-channel blockers, ARBs, or ACEIs as initial therapy in hypertension. ARBs or ACEIs may be logical first-choice drugs in patients who have heart disease or chronic kidney disease. ACEIs do synergize with diuretics but raise serum potassium due to blockade of angiotensin-stimulated aldosterone. Finally, calcium-channel blockers also may be used as first-choice drugs for mild essential hypertension; especially verapamil in the patient who may have angina pectoris or other disease indication for verapamil. However, amlodipine is thought to be a more effective drug for moderate to severe hypertension. 7

16 1.3 Advise Harry to a. take his medicine regularly (patient compliance) although he feels well. b. reduce his sodium intake. c. cut down on cigarette smoking and alcohol intake. d. start a moderate exercise program (e.g., walk one mile a day) e. lose 10 pounds and maintain his weight at that level. Discuss the consequences of hypertension with Harry, emphasizing the need to control his blood pressure for good health. Also, discuss the ease of controlling blood pressure with simple drugs added to the nonpharmacologic factors above. 1.4 Patient factors such as race, age, and the presence of complicating diseases such as asthma, diabetes, dyslipidemias, or heart failure always complicate therapy. African Americans have a general insensitivity to ARBs, ACEIs, and β-blockers. Elderly patients may respond better to thiazides and CCBs than to ACEIs and ARBs. β-blockers may worsen the symptoms of asthmatic patients and prolong hypoglycemia of diabetic patients by retarding the blood glucose rebound following insulin. β-blockers and thiazides can also affect blood lipids, while ACE inhibitors, ARBs and CCBs are lipid neutral. Blood pressure and blood volume control with either an ACEI or ARB and a thiazide diuretic is typical in heart failure patients with reduced left ventricular function. 1.5 The therapeutic goal is to prevent end-organ damage to the kidneys, heart, vasculature, and central nervous system (CNS). In the young patient with no other disease, the goal is obviously maintenance of normal blood pressure at an affordable cost. In elderly patients with complicating disease, the goal is to keep them as comfortable as possible while normalizing their blood pressure as much as possible. Most experts agree that regular administration of antihypertensive agents may be necessary for the control of blood pressure. However, adjuncts to drug therapy may obviate the need for initial therapy or, in Harry's case, to add additional drugs to his regimen. Most clinicians agree that exercise, reduced salt intake, and maintenance of weight in the normal range (BMI = ) are beneficial adjuncts to therapy. High alcohol intake (4 to 6 drinks/day) results in a significant increase in the incidence of hypertension. Low to moderate alcohol intake increases levels of high-density lipoprotein (HDL) cholesterol and may decrease the incidence of atherosclerosis. It is clear that smoking causes oral and lung cancers and is a major cause of cardiovascular mortality and obstructive lung disease. All these conditions complicate the therapy of hypertension. After the initial drug for Harry has been selected, the group member whose part contains Episode 2 should now take over as discussion leader. 8

17 HANDOUT 2 for use in Episode 2 GUIDELINES FOR TREATMENT OF ESSENTIAL HYPERTENSION Step 0. Nonpharmacologic Approaches (Lifestyle Interventions): sodium and alcohol restriction, weight control, and control of other cardiovascular risk factors. Step 1. In nonblack patients, begin with a low dose of either 1) a thiazide diuretic, 2) calcium channel blocker, or 3) angiotensin inhibitor (angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB)). These 3 classes of drugs can be administered alone or in combination. Avoid combined use of ACE inhibitors and ARBs.In black patients, initiate therapy with either 1) a thiazide diuretic or 2) a calcium channel blocker, alone or in combination. Step 2. Select a drug treatment titration strategy. Decide to either A) maximize a first medication before adding a second, B) add a second medication before reaching the maximum tolerable dose of the first, or C) start with 2 medication classes. Step 3. If blood pressure control is not achieved, for strategy A increase dose of the first drug. For strategy B, add a second drug of a different class. For strategy C, increase doses of initial medications. Step 4. If blood pressure control is not achieved, for strategy A, add a second drug of a different class and titrate doses of both drugs up to maximums. For strategies B and C, titrate doses of both drugs to maximums. Step 5. If blood pressure control is not achieved, add a third drug class from above. Step 6. If blood pressure control is not achieved, add a drug from one of the other medication classes and/or refer to an expert in hypertension management. See Handout 1 for drug choices. Summary of 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). doi: /jama

18 Therapy Sheet E: Propranolol (β-blocker) - Student 1 When prompted during Episode 2, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of propranolol? There are several mechanisms of action β-blockers use to decrease blood pressure. They decrease cardiac output secondary to a decrease in heart rate, inhibit the release of renin, and to a modest extent suppress CNS preganglionic nerve impulses. Those β-blockers with intrinsic sympathomimetic action (e.g., pindolol) also may cause a modest decrease in peripheral vascular resistance via partial agonist action at β-receptors. Those with an additional α-blocking activity may do so by blocking peripheral α receptors and carvedilol and nebivolol have an additional direct vasodilating activity. 2. What are the advantages, disadvantages, and complications associated with the use of β-blockers? Advantages: β-blockers may be used in any hypertensive disease category. Also they do not contribute to sodium and water retention. Their most frequent use combines the need for antihypertensive therapy and another indication for a β-blockers (e.g., coronary artery disease). They have few serious side effects in otherwise healthy patients. Disadvantages and complications: Bradycardia is a common side effect. They may exacerbate asthma, due to β 2 -blockade, and peripheral vascular disease, due to unopposed α-receptor stimulation. Sudden withdrawal of these drugs can cause anginal attacks, ventricular arrhythmias, and sudden death. Metabolic effects, such as blockade of the adrenergic response to hypoglycemia (tachycardia, nervousness) may leave diabetics without the usual warning signs of a decrease in blood sugar. Lipid soluble drugs may produce CNS effects; sexual impotence has also been reported. These drugs also decrease high-density lipoproteins and increase triglycerides.