CHAPTER 45 DRUGS FOR HYPERTENSION

It is important to appreciate that we cannot cure HTN, we can only reduce symptoms - treatment must continue lifelong, making noncompliance a significant problem

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CLASSIFICATION OF BLOOD PRESSURE

NORMAL - systolic BP <120 mm Hg and diastolic BP <80 mm Hg PREHYPERTENSION - indicates increased risk of cardiovascular disease even though outright HTN has not yet developed - those with pressure in the prehypertension range have a 2- to 3-fold increased risk of cardiovascular events - to reduce risk, people should adopt certain health promoting lifestyle changes HYPERTENSION - systolic BP >140 mm Hg or diastolic BP >90 mm Hg isolated systolic hypertension (ISH) systolic BP >140 mm Hg and diastolic BP <90 mm Hg - should be based on several BP readings, not just one - if initial screen shows that BP is elevated (but does not represent an immediate danger), measurement should be repeated on two subsequent visits - at each visit, two measurements should be made, at least 5 minutes apart - patient should be seated in a chair not an examination table with his or her feet on the floor - if the mean of all readings shows that systolic BP is indeed >140 mm Hg or diastolic BP is >90 mm Hg, HTN should be diagnosed

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TYPES OF HYPERTENSION
PRIMARY (ESSENTIAL) HYPERTENSION - HTN that has no identifiable cause - diagnosis is made by ruling out probable specific causes of BP elevation - chronic, progressive disorder - at risk: older people are at higher risk than younger people African Americans and Mexican Americans are at higher risk than white Americans postmenopausal women are at higher risk than premenopausal women obese people are at higher risk than lean people - although the cause of primary HTN is unknown, the condition can be successfully treated - treatment is not curative; drugs can lower BP, but they do not eliminate the underlying pathology - treatment must continue lifelong - also referred to as essential HTN

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SECONDARY HYPERTENSION - elevation of BP brought on by an identifiable primary cause - it may be possible to treat that cause directly rather than relying on drugs for symptomatic relief - some individuals can actually be cured - when cure is not possible, secondary HTN can be managed with the same drugs used for primary HTN

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CONSEQUENCES OF HYPERTENSION
- left untreated, prolonged elevation of BP can lead to heart disease (myocardial infarction [MI], heart failure, angina pectoris), kidney disease, and stroke - degree of injury is directly related to the degree of pressure elevation: the higher the pressure, the greater the risk - HTN-related deaths result largely from cerebral hemorrhage, renal failure, heart failure, and MI

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MANAGEMENT OF CHRONIC HYPERTENSION

BASIC CONSIDERATIONS 1. Benefits of Lowering Blood Pressure - when the BP of hypertensive individuals is lowered, morbidity is decreased and life is prolonged 2. Patient Evaluation a. Hypertension with a Treatable Cause some forms of HTN result from treatable causes, such as Cushings syndrome, pheochromocytoma, and oral contraceptive use - patients should be evaluated for these causes and managed appropriately - direct treatment of the underlying cause can control BP, eliminating the need for further antihypertensive therapy b. Factors that Increase Cardiovascular Risk When the following factors are present, aggressive therapy is indicated: i. target-organ damage: heart disease retinopathy stroke / transient ischemic attack chronic kidney disease peripheral arterial disease ii. major cardiovascular risk factors: cigarette smoking obesity diabetes inadequate exercise dyslipidemia microalbuminuria advancing age (>55 for men, >65 for women) family history of premature cardiovascular disease

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Diagnostic Tests should be done in all patients: - electrocardiogram - complete urinalysis - hemoglobin and hematocrit - blood levels of sodium, potassium, calcium, creatinine, glucose, uric acid, triglycerides, and cholesterol (total, LDL, and HDL)

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Treatment Goals - ultimate goal is to reduce cardiovascular and renal morbidity and mortality - hopefully, this can be accomplished without decreasing quality of life with the drugs employed Stage 1 or 2 HTN maintain systolic BP<140 mm Hg and diastolic BP<90 mm Hg Diabetes or Chronic Kidney Disease target BP <130/<80 mm Hg Over 50 reducing systolic pressure Therapeutic Interventions Blood Pressure Reductions: - patients with prehypertension = implement healthy lifestyle changes - patients with HTN = treat with antihypertensive drugs combined with healthy lifestyle changes

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LIFESTYLE MODIFICATIONS - when implemented before HTN develops, healthy lifestyle changes may actually prevent HTN - when implemented after HTN develops, healthy lifestyles changes can lower BP, decreasing or eliminating the need for drugs - can decrease other cardiovascular risk factors 1. 2. Weight Loss can reduce BP and can enhance responses to antihypertensive drugs - goal is to achieve a body mass index in the normal range (18.5 24.9) Sodium Restriction can lower BP and can enhance hypotensive effects of drugs - restriction benefits are short lasting: over time, BP returns to its original level, despite continued salt restriction - patients should be given information on salt content of foods DASH Eating Plan diet rich in fruits, vegetables, and low-fat dairy products, and low in total fat, saturated fats, and cholesterol - encourages intake of whole grain products, fish, poultry, and nuts - recommends minimal intake of red meat and sweets Alcohol Restriction excessive alcohol consumption can raise BP and create resistance to antihypertensive drugs - most men should consume no more than 1 ounce/day - most women should consume no more than 0.5 ounce/day Aerobic Exercise regular exercise can reduce BP - facilitates weight loss, reduces the risk of cardiovascular disease, and reduces all cause mortality

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Smoking Cessation smoking is a major factor for cardiovascular disease and may reduce the effects of antihypertensive drugs - cardiovascular benefits of quitting become evident within a year Maintenance of Potassium and Calcium Intake in hypertensive patients, potassium can lower BP - preferred sources are fresh fruits and vegetables - in hypokalemic patients, potassium supplement, potassium-sparing diuretic or a potassium containing salt substitute may be necessary

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MANAGEMENT OF CHRONIC HYPERTENSION: PHARMACOLOGIC THERAPY

PHARMACOLOGIC THERAPY - many medications are used to treat chronic HTN - all can lower BP, however, the difference is the site of the drug action CLASS OF ANTIHYPERTENSIVE DRUGS 1. Diuretics mainstay of antihypertensive therapy - reduce BP when used alone, and can enhance the effects of other hypotensive drugs a. Thiazide Diuretics hydrochorothiazide - reduce BP by: reduction of blood volume = responsible for initial antihypertensive effects reduction of arterial resistance = develops over time and is responsible for long-term antihypertensive effects - principal adverse effect is hypokalemia which can be minimized by consuming potassium rich foods and using potassium supplements or potassium sparing diuretic - other adverse effects include dehydration, hyperglycemia, and hyperuricemia High-Ceiling (Loop) Diuretics greater diuresis than thiazides - possible amount of fluid loss that can be produced is greater than needed or desirable - - are not routinely used - reserved for: patients who need greater diuresis than can be achieved with thiazides patients with a low GFR (thiazides do not work when GFR is low) - lower BP by reducing blood volume and promoting vasodilation - adverse effects: hypokalemia, dehydration, hyperglycemia, and hyperuricemia - can cause hearing loss Potassium Sparing Diuretics degree of diuresis is small - have only modest hypotensive effects - can play an important role in an antihypertensive regimen - role is to balance potassium loss caused by thiazides or loop diuretics

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- most significant adverse effect is hyperkalemia - must not be used in combination with one another or with potassium supplements - should not be used routinely with ACE inhibitors or angiotensin II receptor blockers, both of which promote hyperkalemia 2. Sympatholytics (Adrenergic Antagonists) - suppress the influence of the sympathetic nervous system on the heart, blood vessels, and other structures a. Beta-Adrenergic Blockers among the most widely used antihypertensive drugs - less effective in African American patients than in white patients - adverse effects: bradycardia, decreased atrioventricular (AV) conduction, and reduced contractility, bronchoconstriction, can mask signs of hypoglycemia, depression, insomnia, bizarre dreams and sexual dysfunction Useful Actions: blockade of cardiac beta1 receptors decreases heart rate and contractility, decreasing cardiac output beta blockers can suppress reflex tachycardia caused by vasodilators in the regimen blockade of beta1 receptors on juxtaglomerular cells of the kidney reduces release of rennin, reducing angiotensin II-mediated vasoconstriction and aldosterone-mediated volume expansion long-term use of beta blockers reduces peripheral vascular resistance - intrinsic symathomimetic activity can produce mild stimulation of beta receptors while blocking receptor stimulation by strong agonists (norepinephrine) - heart rate at rest is slowed less than with other beta blockers - if symptomatic bradycardia with another beta blocker develops, switching to one of these may help b. Alpha1 Blockers doxazosin, terazosin - prevent stimulation of alpha1 receptors on arterioles and veins, preventing sympathetically mediated vasoconstriction - resultant vasodilation reduces both peripheral resistance and venous return to the heart - most disturbing side effect is orthostatic hypotension - not used as first line therapy for HTN - - diuretic is clearly preferred to the alpha blocker Alpha/Beta Blockers: Carvedilol and Labetalol can block alpha1 receptors as well as beta receptors Useful actions: alpha blockade promotes dilation of arterioles and veins blockade of cardiac beta1 receptors reduces heart rate and

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contractility blockade of beta1 receptors on juxtaglomerular cells suppresses release of rennin - share the ability of other beta blockers to reduce peripheral vascular resistance - can exacerbate bradycardia, AV heart block, and asthma - can produce postural hypotension d. Centrally Acting Alpha2 Agonists clonidine, methyldopa - act within the brainstem to suppress sympathetic outflow to the heart and blood vessels - result is vasodilation and reduced cardiac output, both of which help lower BP - can dry mouth, sedation, severe rebound HTN if treatment is abruptly discontinued, hemolytic anemia, and liver disorders Adrenergic Neuron Blockers guanethidine, guanadrel, reserpine - decrease BP through actions in the terminals of postganglionic sympathetic neurons - guanethidine and guanadrel inhibit release of norepinephrine - reserpine causes norepinephrine depletion - both actions result in decreased sympathetic stimulation of the heart and blood vessels - major adverse effect of guanethidine and guanadrel = severe orthostatic hypotension, resulting from decreased sympathetic tone to veins - last choice agents for chronic HTN - major adverse effect of reserpine = depression

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Direct Acting Vasodilators: Hydralazine and Minoxidil - both reduce BP by promoting arteriolar dilation - both have little or no effect on veins, producing very little orthostatic hypotension - with both drugs, lowering BP may be followed by reflex tachycardia, rennin release, and fluid retention - reflex tachycardia can rennin release can be prevented with a beta blocker - fluid retention can be prevented with a diuretic Adverse Effects: hydralazine syndrome resembling systemic lupus erythematosus (SLE) - rare at recommended doses - if SLE-like reaction occurs, hydralazine should be withdrawn - 3rd drug of choice for HTN treatment minoxidil substantially more toxic than hydralazine - by causing fluid retention, can promote pericardial effusion (accumulation of fluid beneath the myocardium) that can progress to cardiac tamponade (compression of the heart) - less serious effect is Hypertrichosis (excessive hair growth) - not routinely used in chronic HTN

- reserved for patients with severe HTN 4. Calcium Channel Blockers - dihydropyridines (nifedipine) and nondihydropyridines (verapamil and diltiazem) - promote dilation of arterioles - verapamil and diltiazem have direct suppressant effects on the heart - can cause reflex tachycardia (greater risk from dihydropyridine and minimal with verapamil and diltiazem) - verapamil and diltiazem must be used with caution in patients with bradycardia, heart failure, or AV heart block - rapid-acting formulation of nifedipine has been associated with increased mortality in patients with MI and unstable angina ACE Inhibitors - lower BP by preventing formation of angiotensin II, preventing angiotensin II-mediated vasoconstriction and aldosterone-mediated volume expansion - in diabetic patients with renal damage, these actions slow progression of kidney injury - less effective in African Americans than in white patients - principal adverse effects are persistent cough, first dose hypotension, angioedema, and hyperkalemia (secondary to suppression of aldosterone release) - combined use with potassium supplements or potassium sparing diuretics is generally avoided - can cause fetal harm during 2nd and 3rd trimester Angiotensin II Receptor Blockers - lower BP in much the same way as ACE inhibitors, except ARBs do their work by blocking the actions of angiotensin II (ACE inhibitors block the formation) - can cause fetal harm and must not be used during pregnancy - do not induce cough or significant hyperkalemia - causes angioedema Aldosterone Receptor Blockers - eplerenone and spirolactone (also potassium sparing diuretic) - lower BP by promoting renal excretion of sodium and water - promote renal retention of potassium, posing a risk of hyperkalemia - combined use with ACE inhibitors and ARBs is permissible, but must be done with caution

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FUNDAMENTALS OF HYPERTENSION DRUG THERAPY - lifestyle changes should be instituted first - drug therapy should be initiated and lifestyle changes should continue - treatment often begins with a single dose and, if needed, another drug may be added or substituted - possible reasons for failure of initial drug should be assessed - insufficient dosage, poor compliance, excessive salt intake, and the presence of secondary hypertension may be among the reasons 1. Initial Drug Selection determined by the presence or absence of a compelling indication (comorbid condition for which a specific class of antihypertensive drugs has been shown to improve) a. Patients WITHOUT Compelling Indications for initial therapy in the absence of a compelling indication, thiazide diuretic is recommended - can reduce morbidity and mortality

- well tolerated and inexpensive - beta blockers reduce morbidity and mortality as a good alternative - ACE inhibitors, ARBs, CCBs, and alpha/beta blockers = diuretics and beta blockers in the ability to lower BP - may not be as effective at reducing morbidity and mortality - reserved for special indications and for patients who have not responded to thiazide diuretics and beta blockers - centrally acting sympatholytics, adrenergic neuron blockers, and direct acting vasodilators are not well suited for initial monotherapy 2. Individualizing Therapy a. Patients with Comorbid Conditions comorbid conditions complicate treatment of HTN - renal disease and diabetes are two especially problematic conditions i. renal disease nephrosclerosis (hardening of the kidney) secondary to HTN is among the most common causes of progressive renal disease - renal insufficiency causes water retention, causing BP to rise higher, promoting even more renal injury, etc. - ACE inhibitors and ARBs work best for these patients - as a rule, diuretics are used also - advanced renal insufficiency, thiazide diuretics are ineffective, hence a loop diuretic should be employed - potassium sparing diuretics should be avoided diabetes in patients with diabetic nephropathy, ACE inhibitors and ARBs can slow progression of renal damage and reduce albuminuria - in diabetic patients, beta blockers and diuretics can decrease morbidity and mortality - beta blockers can suppress glycogenolysis and mask early signs of hypoglycemia, therefore must be used with caution - thiazides and high-ceiling diuretics promote hyperglycemia, therefore should be used with caution

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Patients in Special Populations a. African Americans HTN is a major health problem - develops earlier in blacks than in whites - much higher incidence and more likely to be more severe - greater risk of heart disease, end-stage renal disease and stroke b. Elderly incidence of HTN in people over 60 is about 65% - since cardiovascular reflexes are blunted, treatment carries a significant risk of orthostatic hypotension

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MINIMIZING ADVERSE EFFECTS - antihypertensive drugs can produce many unwanted effects, including hypotension, sedation, and sexual dysfunction - adverse effects caused by exacerbation of comorbid diseases are both predictable and avoidable

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Why Compliance can be Difficult to Achieve - antihypertensive regimens can be complex and expensive - treatment must continue lifelong - antihypertensive drugs can cause a number of adverse effects, ranging from sedation to hypotension to disruption of sexual function - difficult to convince people who are feeling good to take drugs that may make them feel worse - people may decide that exposing themselves to the negative effects of therapy today is paying too high a price to avoid the adverse consequences of HTN at some indefinite time in the future a. Ways to Promote Compliance i. Educate the Patient compliance requires motivation, patient education can help provide it - patients should be taught about the consequences of HTN and benefits of treatment - patients must understand that, left untreated, HTN can cause heart disease, kidney, and stroke - patients should appreciate that, with proper therapy, the risks of long-term complications can be minimized, resulting in a longer and healthier life - patients must understand that drugs do not cure HTN they only control symptoms - patients must understand that for treatment to be effective, medication must be taken lifelong ii. Teach Self-Monitoring patients should be taught the goal of treatment (usually maintenance of BP) - they should also be taught to monitor and record their BP daily - this increases patient involvement and provides positive feedback that can help promote compliance Minimize Side Effects adverse side effects can be minimized by: encouraging patients to report side effects discontinuing objectionable drugs and substituting more acceptable ones avoiding drugs that can exacerbate comorbid conditions using doses that are low initially and then gradually increased Establish a Collaborative Relationship patient who feels like a collaborative partner in the treatment program is more likely to comply than is the patient who feels that treatment is being imposed - collaboration allows the patient to help set treatment goals, create the treatment program, and evaluate progress - facilitates communication about side effects, especially with respect to druginduced sexual dysfunction Simplify the Regimen in order to promote compliance, steps should be taken to make the dosing schedule as simple as possible - once effective regimen is established, an attempt should be made to switch to once-a-day or twice-a-day dosing

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- if appropriate combination product is available, substitute it for components Other Measures positive reinforcement = therapeutic goals achieved - family member involvement - schedule office visits at convenient times and following missed appointments - KEEP COSTS LOW

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DRUGS FOR HYPERTENSIVE DISORDERS OF PREGNANCY

PREECLAMPSIA AND ECLAMPSIA preeclampsia = elevated BP and proteinuria that develops after the 20 th week of gestation - risks factors include obesity, black race, chronic HTN, diabetes, collagen vascular disorders, and previous preeclampsia - management is based on the severity of the disease, the status of the mother and fetus, and the length of gestation - objective is to preserve the health of the mother and deliver an infant that will not require intensive and prolonged neonatal care - requires close maternal and fetal monitoring - delivery is the only cure - drug of choice for lowering BP is hydralazine - vitamins C and E may prevent development because both are antioxidants and scavenge free radicals that are believed to trigger this condition eclampsia = elevated BP and proteinuria that develops after the 20 th week of gestation that leads to the development of seizures - seizure drug of choice is magnesium sulfate (anticonvulsant) - magnesium blood levels should be monitored (target range is 4 7 mEq/L)