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.
Correct answers 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. 4. E is correct. All four may be associated with untreated hypertension. 8. E is correct. Choices A and C are the indication that the limit of therapeutic effectiveness had been reached. 9. B is correct. Thiazides (A), angiotensin receptor blockers, ACE inhibitors and calcium-channel blockers (D) can be effective as monotherapy for mild hypotension. Centrally acting α2-agonists (B) should reserved for use in refractory cases. When your group has finished discussing the pretest, read "Instructions for the Clinical Problem" on the next page of your booklet.
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. The group member whose booklet contains Episode 1 should begin the discussion.
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 25-50 TPR, hypovolemia, Hypokalemia, hyperuricemia, (HCTZ) secondary sodium hyponatremia, insulin sensitivity, hyperglycemia, hyperlipoproteinemia, digitalis intoxication Chlorthalidone 25-100 Same as HCTZ Same as HCTZ Indapamide 1.25-5 Same as HCTZ Same as HCTZ Metolazone 2.5-5 Same as HCTZ Same as HCTZ 2. Calcium-Channel Blockers Nifedipine 30-120 Direct vasodilation Constipation, tachycardia, headaches, edema Nicardipine 20-60 Same as nifedipine Same as nifedipine Amlodipine 5-10 Same as nifedipine Same as nifedipine Diltiazem 120-540 Same as nifedipine Bradycardia, edema, but less vasodilation heart block Verapamil 80-480 Same as nifedipine Constipation, heart block but less vasodilation 3. ACE Inhibitors Captopril 25-450 Total peripheral Cough, hyperkalemia, resistance, with BP, angioedema, rash, proteinuria, and renal flow teratogenic Enalapril 5-40 Same as captopril Same as captopril Lisinopril 10-80 Same as captopril Same as captopril
Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects 4. ARBs Losartan 50-100 Total peripheral Same as ACE inhibitors resistance, with BP, with less cough and renal flow Candesartan 16-32 Same as losartan Same as losartan Eprosartan 400-800 Same as losartan Same as losartan Irbesartan 150-300 Same as losartan Same as losartan Olmesartan 20-40 Same as losartan Same as losartan Valsartan 80-320 Same as losartan Same as losartan 5. Other diuretics a. Loop diuretics Furosemide 80-160 hypovolemia Same as HCTZ secondary to Na+ b. Aldosterone antagonist diuretics Spironolactone 50-400 Mineralocorticoid Gynecomastia, libido, antagonist menstrual disorders c. Potassium-sparing diuretics Triamterene 50-100 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 40-640 cardiac output, Bronchoconstriction, renin release, heart failure, fatigue, reflex inhibition of sympathetic peripheral vasoconstriction, neurotransmission bradyarrhythmias, prolonged insulin reactions, libido
Antihypertensive Physiologic Side Category Dose (mg/day) Effect Effects a. β-blockers (cont.) Nadolol 40-320 Same as propranolol Same as propranolol but more but longer effect accumulation, renal failure Timolol 20-60 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 100-2400 Same as propranolol Same as propranolol plus α 1 -receptor blocking activity Metoprolol 25-400 Same as propranolol, Same as propranolol, with less ß 1 -receptor selective bronchoconstriction, effect on insulin-induced hypoglycemia and peripheral vasoconstriction Betaxolol 10-40 Same as metoprolol Same as metoprolol Atenolol 50-100 Same as metoprolol Same as metoprolol but longer effect but accumulation with renal failure Acebutolol 400-1200 Same as metoprolol Same as metoprolol and pindolol and pindolol Carvedilol 6.25-25 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 250-3000 Decreased central Somnolence, orthostatic sympathetic outflow, hypotension, fever, hepatitis renin hemolytic anemia, libido Clonidine 0.1-0.6 Same as methyldopa Sedation, dry mouth, withdrawal hypertension, libido
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 0.1-0.25 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 50-300 Direct artery Tachycardia, myocardial vasodilation ischemia, systemic lupus erythematosus Minoxidil 5-100 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.
Therapy Sheet D: Captopril (ACE inhibitors) When prompted during Episode 1, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of captopril? Answer 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? Answer Advantages: Captopril is effective in both mild and severe forms of renin-dependent hypertension. Absence of side effects in most patients makes Captopril a choice for first-drug therapy of hypertension. It may be combined with other antihypertensive drugs to produce additive effects. Newer ACE inhibitors (e.g., enalapril, lisinopril, and ramipril) may have longer durations of action and fewer adverse effects. Disadvantages and complications: Captopril 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.
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:10.1001/jama.2013.284427
Therapy Sheet H: Hydralazine/Sodium Nitroprusside (vasodilators) When prompted during Episode 2, study this page and then ask your colleagues the following questions: 1. What is the mechanism of action of hydralazine? Answer Hydralazine acts directly on arteriolar smooth muscle. The resultant vasodilation precipitates a baroreceptor reflex that increases heart rate and contractility. These cardiac effects, which then promote the release of renin and lead to sodium and water retention, tend to reverse the antihypertensive effects of hydralazine. As a consequence, it is only used in combination with β-blockers and a diuretic or in hypertensive emergencies. 2. What are the advantages, disadvantages, and complications associated with the use of hydralazine? Answer Advantages: Can be used alone in hypertensive crises and eclampsia not complicated by ischemic heart disease. Disadvantages and Complications: a. Angina and tachycardia b. Headache c. Diarrhea and constipation d. Nasal congestion e. Flushing, rashes 3. What is the mechanism of action of nitroprusside? Answer Sodium nitroprusside is an IV drug and acts to dilate both arteries and veins. It is metabolized to thiocyanate and nitric oxide. Nitric oxide stimulates soluble guanylate cyclase, which increases cyclic guanosine monophosphate levels leading to smooth muscle relaxation. Because both resistance and capacitance vessels are dilated; the cardiac effects are a modest increase in heart rate, decreased myocardial workload, and a normal coronary blood flow. Renal blood flow is also maintained, but markedly increases plasma renin activity.
4. What are the advantages, disadvantages, and complications associated with the use of nitroprusside? Answer Advantages: Nitroprusside has a rapid onset of action and can be carefully titrated to avoid rapid hypotension with its attendant adverse effects. Disadvantages and Complications: a. Hypotension with nausea, vomiting, headache, sweating, restlessness, chest pain, confusion and palpitations b. Thiocyanate toxicity with CNS symptoms, if used for days c. Rebound hypertension if drug is withdrawn without coverage by β-blocker or ACE inhibitor d. Hypothyroidism e. Reduced platelets
Episode 4 Harry hasn't been to see his physician in more than 1 year. While working as the pharmacist in the emergency department at a hospital, a resident tells you that a patient named Harry Hypertensive has just arrived and is complaining of blurred vision, headaches, and nausea. Physical findings include a blood pressure of 220/145 mm Hg in the supine position and evidence of papilledema. The resident has made a diagnosis of hypertensive crisis with evidence of encephalopathy. Upon questioning Harry's wife, you find out that Harry has not been taking his drugs regularly. When his prescription ran out, he did not have time to come to you to get new prescriptions, so he just stopped taking his medicine. Use the following questions and the Discussion Notes to guide the group discussion. Each member of the group should take the lead in answering at least one of the questions. 4.1 What is the best approach to lower Harry's blood pressure, and why? (Because of the seriousness of Harry's situation, you should lead the discussion toward consideration of drugs and routes of administration that have a rapid onset of action.) 4.2 What are the potential consequences if Harry isn't treated quickly? 4.3 What can be done to encourage compliance after Harry goes home?
Discussions Notes for Questions in Episode 4 4.1 The most effective and, if properly used, safest drug in this case is IV sodium nitroprusside. It lowers blood pressure almost instantaneously. Because the duration of action of the drug is so short, it must be given by constant IV infusion and the patient's BP must be continuously monitored. However, because the duration of action of the drug is short, it is possible to have minute-to-minute control over the BP. Nitroprusside dilates both arterioles and venules. The venodilation results in a reduction in cardiac preload. 4.2 Harrry s BP is so high that he is in an emergent situation and must be treated immediately. The most rational choice of therapy is a parenteral drug that acts almost immediately to reduce Harry's diastolic pressure slowly to less than 100 mm Hg. Harry is at risk for a life-threatening stroke if a vascular hemorrhage occurs in the brain. 4.3 Harry's compliance for drug therapy can be enhanced by involving him in the monitoring of his own blood pressure. Also his family can be supportive and reinforce his desire to participate in his therapy. Since cost is a problem, you should know that some drugs are available in generic dosage form and can be supplied, if requested. When you have finished discussing this episode, you have completed the clinical problem. Now, please have each group member, individually, answer the questions on the posttest.