Ch 32-Treatment of Hypertension PDF

32 Chapter EPIDEMIOLOGY AND TREATMENT ALGORITHMS Principles of Antihypertensive Therapy Treatment of Hypertension Thomas Eschenhagen...

32 Chapter EPIDEMIOLOGY AND TREATMENT ALGORITHMS Principles of Antihypertensive Therapy Treatment of Hypertension Thomas Eschenhagen α1 Blockers Combined α1 and β Blockers Centrally Acting Sympatholytic Drugs INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM VASODILATORS Angiotensin-Converting Enzyme Inhibitors AT1 Receptor Blockers Hydralazine Direct Renin Inhibitors KATP Channel Openers: Minoxidil Sodium Nitroprusside Ca2+ CHANNEL BLOCKERS Diazoxide DIURETICS NONPHARMACOLOGICAL THERAPY OF HYPERTENSION Benzothiadiazines and Related Compounds SELECTION OF ANTIHYPERTENSIVE DRUGS IN INDIVIDUAL Other Diuretic Antihypertensive Agents K+-Sparing Diuretics PATIENTS Diuretic-Associated Drug Interactions ACUTE ANTIHYPERTENSIVE TREATMENT SYMPATHOLYTIC AGENTS β Blockers RESISTANT HYPERTENSION in the intensified treatment group, but this did not translate to a signal for Epidemiology and Treatment Algorithms real harm. The consequences of these results on the recent American Heart Hypertension is the most common cardiovascular disease. Elevated arte- Association (AHA)/American College of Cardiology (ACC) (Whelton et rial pressure causes hypertrophy of the left ventricle and pathological al., 2018) and European Society of Cardiology (ESC) guidelines (Williams changes in the vasculature. As a consequence, hypertension is the princi- et al., 2018) slightly differ (Bakris et al., 2019; Table 32–1). In the U.S., pal cause of stroke; a major risk factor for coronary artery disease (CAD) hypertension is now defined as a blood pressure of 130/80 mmHg or and its associated complications, myocardial infarction (MI) and sudden higher, and in Europe, it is defined as a blood pressure of 140/90 mmHg cardiac death; and a major contributor to heart failure, renal insufficiency, or higher. These criteria characterize a group of patients whose risk of and dissecting aneurysm of the aorta. The prevalence of hypertension hypertension-related cardiovascular disease is high enough to merit med- increases with age; for example, about 50% of people between the ages ical attention. The risk of both fatal and nonfatal cardiovascular disease in of 60 and 69 years old have hypertension, and the prevalence further adults is lowest with systolic blood pressures of less than 120 mmHg and increases beyond age 70. According to a survey in the U.S., 81.5% of those diastolic blood pressures less than 80 mmHg; these risks increase incre- with hypertension are aware they have it, 74.9% are being treated, yet mentally as systolic and diastolic blood pressures rise. Recognition of this only 52.5% are considered controlled (Go et al., 2014). The success of continuously increasing risk prevents a simple definition of hypertension hypertension treatment programs, such as one organized in a large inte- (Table 32–1). Although many early clinical trials classified the severity grated healthcare delivery system in the U.S. (Jaffe et al., 2013), shows that of hypertension by diastolic pressure, progressive elevations of systolic these figures can be substantially improved by electronic hypertension pressure are similarly predictive of adverse cardiovascular events; at every registries tracking hypertension control rates, regular feedback to provid- level of diastolic pressure, risks are greater with higher levels of systolic ers, development and frequent updating of an evidence-based treatment blood pressure. Indeed, in patients more than 50 years old, systolic blood guideline, promotion of single-pill combination therapies, and follow-up pressures predict adverse outcomes better than diastolic pressures. Pulse blood pressure checks. Between 2001 and 2009, this program increased pressure, defined as the difference between systolic and diastolic pressure, the number of patients with a diagnosis of hypertension by 78%, as well as may add additional predictive value (Franklin et al., 2009; Pastor-Barriuso the proportion of subjects meeting target blood pressure goals from 44% et al., 2003). This may be at least in part due to higher-than-normal pulse to more than 84% (Jaffe et al., 2013). pressure indicating adverse remodeling of blood vessels, representing an The definition of hypertension and treatment goals have evolved over accelerated decrease in blood vessel compliance (“stiffening”) normally the years according to results of intervention studies. The SPRINT study associated with aging and atherosclerosis. Isolated systolic hypertension in nondiabetics with increased cardiovascular risk was prematurely (increased systolic and normal diastolic blood pressure) in younger peo- stopped because the group of patients treated with antihypertensives to ple (particularly men) is strongly associated with smoking. In elderly a systolic blood pressure target of 120 mmHg experienced a 25% lower people, it indicates stiffening of the large arteries. rate of cardiovascular end points and total mortality than the group tar- High blood pressure in the presence of pathological changes in cer- geted to 140 mmHg (SPRINT Research Group, 2015). The rate of adverse tain target organs heralds a worse prognosis than the same level of effects such as hypotension and worsening of renal function were higher blood pressure in a patient lacking these findings. For instance, retinal https://ebooksmedicine.net/  626 Abbreviations TABLE 32–1 COMPARISON OF DEFINITIONS AND TREATMENT GOALS OF HYPERTENSION IN THE U.S. AND ACC: American College of Cardiology EUROPE ACE: angiotensin-converting enzyme GUIDELINE BLOOD PRESSURE (BP; mmHg) AHA: American Heart Association DEFINITIONS OF Aldo: aldosterone HYPERTENSION U.S. EUROPE AngII: angiotensin II Office/clinic BP ≥130 systolic and/or ≥140 systolic and/or ARB: angiotensin receptor blocker ≥80 diastolic ≥90 diastolic AT1: type 1 receptor for angiotensin II Daytime mean ≥130 systolic and/or ≥135 systolic and/or AV: atrioventricular ≥80 diastolic ≥85 diastolic β blocker: β adrenergic receptor antagonist BP: blood pressure Nighttime mean ≥110 systolic and/or ≥120 systolic and/or CAD: coronary artery disease ≥65 diastolic ≥70 diastolic COX-2: cyclooxygenase 2 24-h mean ≥125 systolic and/or ≥130 systolic and/or DOPA: 3,4-dihydroxyphenylalanine ≥75 diastolic ≥80 diastolic ENaC: epithelial Na+ channel Home BP mean ≥130 systolic and/or ≥135 systolic and/or ESC: European Society of Cardiology ≥80 diastolic ≥85 diastolic GI: gastrointestinal BP targets for 130/80 mmHg ≥140/90 mmHg SA: sinoatrial intervention Importance Take BP at home, twice in the morning and of home BP twice in the evening, in the week before clinic monitoring Check BP machine annually hemorrhages, exudates, and papilledema in the eyes indicate a far worse Therapy Restrict β blockers to patients with short-term prognosis for a given level of blood pressure. Left ventricular comorbidities or other indications hypertrophy defined by electrocardiogram, or more sensitively by echoc- Single-pill combinations as initial therapy ardiography or cardiac magnetic resonance imaging, is associated with Follow-up Detect poor adherence and focus on a substantially worse long-term outcome that includes a higher risk of improvement sudden cardiac death. The risk of cardiovascular disease, disability, and BP telemonitoring and digital health solutions death in hypertensive patients also is increased markedly by concomitant recommended cigarette smoking, diabetes, or elevated low-density lipoprotein (LDL); Source: Adapted with permission from Bakris G, Ali W, Parati G. ACC/AHA the coexistence of hypertension with these risk factors increases cardio- versus ESC/ESH on hypertension guidelines: JACC guideline comparison. J Am vascular morbidity and mortality to a degree that is compounded by each Coll Cardiol, 2019, 73:3018–3026. Copyright © 2019 by the American College of additional risk factor. Cardiology Foundation. Published by Elsevier. The purpose of treating hypertension is to decrease cardiovascular risk and to improve life expectancy. Effective pharmacological treatment of patients with hypertension decreases morbidity and mortality from Arterial pressure is the product of cardiac output and peripheral vas- cardiovascular disease, particularly the risk of stroke, heart failure, and cular resistance (Figure 32–3). Drugs lower blood pressure by actions on CAD (Rosendorff et al., 2015). The reduction in risk of MI may be less peripheral resistance, cardiac output, or both. Drugs may decrease the significant. cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may Principles of Antihypertensive Therapy be achieved by actions on the venous tone or on blood volume via renal Nonpharmacological therapy (lifestyle-related changes) is an important effects. Drugs can decrease peripheral resistance by acting on smooth component of treatment of all patients with hypertension (Whelton et al., muscle to cause relaxation of resistance vessels or by interfering with the 2018; Williams et al., 2018). In some grade 1 hypertensives (Figure 32–1), activity of systems that produce constriction of resistance vessels (e.g., the blood pressure may be adequately controlled by a combination of weight sympathetic nervous system, the renin-angiotensin system [RAS]). Low- loss (in overweight individuals), restricting sodium intake (to 30 min/d), moderating consumption of lower peripheral resistance, possibly by reducing the response to vaso- alcohol (ethanol/day ≤20–30 g in men [two drinks], ≤10–20 g in women constrictors and/or by reducing T-cell–mediated inflammation (Titze, [one drink]), smoking cessation, and increased consumption of fruits, 2015). In patients with isolated systolic hypertension, complex hemody- vegetables, and low-fat dairy products. namics in a rigid arterial system contribute to increased blood pressure; The majority of patients require drug therapy for adequate blood drug effects may be mediated not only by changes in peripheral resistance pressure control (Figure 32–1). Current guidelines from cardiovascular but also via effects on large artery stiffness. societies differ slightly in their definitions and treatment targets, but Antihypertensive drugs can be classified according to their sites or the principles are the same (Bakris et al., 2019; Table 32–1). One of the mechanisms of action (Table 32–2, Figure 32–3). The hemodynamic important common recommendations is early use of single-pill combina- consequences of long-term treatment with antihypertensive agents tion therapy (Figure 32–2). (Table 32–3) provide a rationale for potential complementary effects of  627 BP thresholds and recommendations for treatment and follow-up Normal BP Elevated BP Stage 1 hypertension Stage 2 hypertension diltiazem) and are therefore not first- other classes of drugs (Table 30–2). Nevertheless, the aldosterone escape line antihypertensives. known from ACE inhibitors and ARBs has also been observed under Compared with other classes of antihypertensive agents, there may be continuous treatment with aliskiren (Bomback et al., 2012). a greater frequency of achieving blood pressure control with Ca2+ channel blockers as monotherapy in elderly subjects and in African Americans, ADME population groups in which the low renin status is more prevalent. How- Aliskiren is poorly absorbed, with an oral bioavailability of less than 3%. ever, intrasubject variability is more important than relatively small dif- Taking the drug with a high-fat meal may substantially decrease plasma ferences between population groups. Ca2+ channel blockers are effective concentrations. Aliskiren has an elimination t1/2 of at least 24 h. Elimina- in lowering blood pressure and decreasing cardiovascular events in the tion of the drug may be primarily through hepatobiliary excretion with elderly with isolated systolic hypertension (Staessen et al., 1997) and may limited metabolism via CYP3A4. be a preferred treatment in these patients. Therapeutic Uses Given the unclear effectiveness and safety of aliskiren monotherapy, the Diuretics place of this drug in the treatment of hypertension remains clouded. The combination of aliskiren with other RAS inhibitors is contraindicated. An early strategy for the management of hypertension was to alter Na+ balance by restriction of salt in the diet. Pharmacological alteration of Toxicity and Precautions Na+ balance became practical with the development of the orally active SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Aliskiren is generally well tolerated. Diarrhea may occur, especially at thiazide diuretics (see Chapter 29). These and related diuretic agents have higher-than-recommended doses. The incidence of cough may be higher antihypertensive effects when used alone, and they enhance the efficacy than for placebo but substantially less than found with ACE inhibitors. of virtually all other antihypertensive drugs. Thus, this class of drugs Aliskiren has been associated with several cases of angioedema in clinical remains important in the treatment of hypertension. trials (Frampton and Curran, 2007). Drugs acting on the RAS may dam- The exact mechanism for reduction of arterial blood pressure by age the fetus and should not be used in pregnant women. diuretics is not certain. The initial action of thiazide diuretics decreases extracellular volume by interacting with a thiazide-sensitive NaCl cotrans- porter (SLC12A3) expressed in the distal convoluted tubule in the kidney, Ca2+ Channel Blockers enhancing Na+ and water excretion in the urine, which leads to a decrease The Ca2+ channel–blocking agents are an important group of drugs in cardiac output. However, cardiac output returns to pretreatment values, for the treatment of hypertension. The general pharmacology of these and extracellular volume returns to almost normal due to compensatory drugs is presented in Chapter 31. The basis for their use in hypertension responses such as activation of the RAS, while the hypotensive effect is comes from the understanding that hypertension generally is the result of maintained during long-term therapy due to decreased vascular resis- increased peripheral vascular resistance. Because contraction of vascular tance. The long-term vasodilation induced by thiazide diuretics must smooth muscle is dependent on the free intracellular concentration of be secondary to their effect on the kidney, because no blood pressure– Ca2+, inhibition of transmembrane movement of Ca2+ through voltage- lowering effect of chlorothiazide was seen in nephrectomized dogs (Orbi- sensitive Ca2+ channels can decrease the total amount of Ca2+ that reaches son, 1962). The fact that SLC12A3, the major drug target of thiazides, is intracellular sites. Indeed, all of the Ca2+ channel blockers lower blood expressed predominantly in the distal convoluted tubules and not in vascu- pressure by relaxing arteriolar smooth muscle and decreasing peripheral lar smooth muscle or the heart further suggests that these drugs decrease vascular resistance. As a consequence of a decrease in peripheral vas- peripheral resistance as an indirect effect of negative Na+ balance. Accord- cular resistance, the Ca2+ channel blockers evoke a baroreceptor reflex– ingly, the hypotensive effect of a chronic treatment with thiazides has been mediated sympathetic discharge. In the case of the dihydropyridines, reversed by a high-salt diet (Winer, 1961). That thiazides lose efficacy in tachycardia may occur from the adrenergic stimulation of the sinoatrial treating hypertension in patients with coexisting renal insufficiency is (SA) node; this response is generally quite modest except when the drug compatible with this hypothesis. Moreover, carriers of rare functional is administered rapidly. Tachycardia is typically minimal or absent with mutations in SLC12A3 that decrease renal Na+ reabsorption have lower verapamil and diltiazem because of the direct negative chronotropic effect blood pressure than appropriate controls (Ji et al., 2008); in a sense, this of these two drugs. Indeed, the concurrent use of a β blocker may mag- is an experiment of nature that may mimic the therapeutic effect of thiaz- nify negative chronotropic effects of these drugs or cause heart block in ides. Newer data suggest that large amounts of Na+ can be stored in the susceptible patients. Consequently, the concurrent use of β blockers with body independently of changes in water content (challenging the dogma either verapamil or diltiazem should be avoided. of strict coupling between Na+ and water). High concentrations of Na+ The Ca2+ channel blockers are among the preferred drugs for the have been visualized in human skeletal muscle and skin of patients with treatment of hypertension, both as monotherapy and in combination Conn syndrome and were sensitive to adrenalectomy or spironolactone with other antihypertensives, because they have a well-documented effect (Titze, 2015). Not all details are clear, but Na+ accumulation in T cells and on cardiovascular end points and total mortality. The combination of macrophages goes along with a proinflammatory state likely important in amlodipine and the ACE inhibitor perindopril proved superior to the hypertension. It is well established that even small increases in intracellu- combination of the β blocker atenolol and hydrochlorothiazide (Dahlof lar Na+ concentrations in cardiomyocytes have major effects on contrac- et al., 2005). Amlodipine was superior to hydrochlorothiazide as the com- tility (see Chapter 33; positive inotropic mechanism of digoxin). Similar bination partner for the ACE inhibitor benazepril (Jamerson et al., 2008). mechanisms in smooth muscle cells could explain why chronic treatment The Ca2+ channel blockers most studied and used for the treatment with a thiazide markedly lowered the sensitivity to vasoconstrictors such of hypertension are long-acting dihydropyridines with sufficient 24-h as phenylephrine and AngII (Noveck, 1983). efficacy at once-daily dosing (e.g., amlodipine, felodipine, lercanidip- ine [no longer available in the U.S.], and sustained-release formula- Benzothiadiazines and Related Compounds tions of others). Peripheral edema (ankle edema) is the main unwanted Benzothiadiazines (“thiazides”) and related diuretics are the most fre- effect. Fewer patients appear to experience this harmless, but possibly quently used class of antihypertensive agents in the U.S. Following the distracting, side effect with newer compounds such as lercanidipine discovery of chlorothiazide, a number of oral diuretics were developed (Makarounas-Kirchmann et al., 2009), but the commonly used combi- that have an arylsulfonamide structure and block the NaCl cotransporter. nation with RAS inhibitors has the same effect (Messerli et al., 2000). Some of these are not benzothiadiazines but have structural features and https://ebooksmedicine.net/  632 molecular functions that are similar to the original benzothiadiazine three or more drugs fails to yield adequate control of the blood pressure. compounds; consequently, they are designated as members of the thiaz- Alternatively, there may be a need to use higher-capacity diuretics such as ide class of diuretics. For example, chlorthalidone (also written as chlortal- furosemide, especially if renal function is not normal. idone), one of the nonbenzothiadiazines, is widely used in the treatment The effectiveness of thiazides as diuretics or antihypertensive agents is of hypertension, as is indapamide. progressively diminished when the glomerular filtration rate falls below 30 mL/min. Exceptions are the thiazide-like diuretics metolazone and Regimen for Administration of the Thiazide-Class xipamide, which retain efficacy in patients with this degree of renal insuf- Diuretics in Hypertension ficiency. In the case of xipamide, this is explained by its access to the NaCl Because members of the thiazide class have similar pharmacological cotransporter from the blood side, which contrasts with classical thiaz- effects, they generally have been viewed as interchangeable with appro- ides reaching it via the tubular side. priate adjustment of dosage (see Chapter 29). However, the pharmacok- Most patients will respond to thiazide diuretics with a reduction in inetics and pharmacodynamics of these drugs differ, so they may not blood pressure within about 4 to 6 weeks. Therefore, doses should not be necessarily have the same clinical efficacy in treating hypertension. In increased more often than every 4 to 6 weeks. There is no way to predict a direct comparison, the antihypertensive efficacy of chlorthalidone was the antihypertensive response from the duration or severity of the hyper- greater than that of hydrochlorothiazide, particularly during the night tension in a given patient, although diuretics are unlikely to be effective as (Ernst et al., 2006), suggesting the much longer t1/2 of chlorthalidone sole therapy in patients with stage 2 hypertension (Table 32–1). Because (>24 h) compared to hydrochlorothiazide (several hours) gave more sta- the effect of thiazide diuretics is additive with that of other antihyper- ble blood pressure reductions. Meta-analyses confirmed the superiority tensive drugs, combination regimens that include these diuretics are of chlorthalidone over hydrochlorothiazide in long-term studies (Roush common and rational. A wide range of fixed-dose combination products and Messerli, 2021). Chlorthalidone appears to be an underutilized drug containing a thiazide are marketed for this purpose. Diuretics also have CHAPTER 32 TREATMENT OF HYPERTENSION in hypertensive patients requiring a diuretic. the advantage of minimizing the retention of salt and water that is com- Antihypertensive effects can be achieved in many patients with as monly caused by vasodilators and some sympatholytic drugs. Omitting little as 12.5 mg daily of chlorthalidone or hydrochlorothiazide. Further- or underutilizing a diuretic is a frequent cause of “resistant hypertension.” more, when used as monotherapy, the maximal daily dose of thiazide- class diuretics usually should not exceed 25 mg of hydrochlorothiazide Adverse Effects and Precautions or chlorthalidone (or equivalent). Even though more diuresis can be The adverse effects of diuretics are discussed in Chapter 29. Some of achieved with higher doses, some evidence suggests that doses higher these determine whether a patient can tolerate and adhere to diuretic than this are not generally more efficacious in lowering blood pressure in treatment. patients with normal renal function. Low doses of either thiazide reduce The K+ depletion produced by thiazide-class diuretics is dose depen- the risk of adverse effects such as K+ wasting and inhibition of uric acid dent and variable among individuals, such that a subset of patients may excretion, indicating an improved risk-to-benefit ratio at low doses of a become substantially K+ depleted on diuretic drugs. Given chronically, thiazide. However, other studies suggested that low doses of hydrochloro- even small doses lead to some K+ depletion, which is a well-known risk thiazide have inadequate effects on blood pressure when monitored in a factor for ventricular arrhythmias by reducing cardiac repolarization detailed manner (Lacourciere et al., 1995). reserve. A reduction in the cardiac repolarization reserve has recently Clinical trials of antihypertensive therapy in the elderly demonstrated been used to explain that insults in a particular repolarization current the best outcomes for cardiovascular morbidity and mortality when do not necessarily result in QT interval prolongation, the principal clin- 25 mg of hydrochlorothiazide or chlorthalidone was the maximum dose ical measure of repolarization (see Chapter 34). Hypokalemia directly given; if this dose did not achieve the target blood pressure reduction, reduces repolarization reserve by decreasing several K+ conductances a second drug was initiated (Dahlof et al., 1991). A case-control study (inward rectifier IK1, delayed rectifier IKr, and the transient outward cur- found a dose-dependent increase in the occurrence of sudden death at rent Ito) and increasing the binding activity of IKr-inhibiting drugs such as doses of hydrochlorothiazide greater than 25 mg daily (Siscovick et al., dofetilide (Yang and Roden, 1996). Hypokalemia also reduces the activ- 1994), supporting the hypothesis that higher diuretic doses are associ- ity of the Na+,K+-ATPase (adenosine triphosphatase) (the Na+ pump), ated with increased cardiovascular mortality as long as hypokalemia is causing intracellular accumulation of Na+ and Ca2+, further increasing not corrected. Thus, if adequate blood pressure reduction is not achieved the risk of afterdepolarizations (Pezhouman et al., 2015). Consequently, with the 25 mg daily dose of hydrochlorothiazide or chlorthalidone, the hypokalemia increases the risk of drug-induced polymorphic ventricular addition of a second drug is indicated rather than an increase in the dose tachycardia (torsade de pointes; see Chapter 34) and the risk for ischemic of diuretic. ventricular fibrillation, the leading cause of sudden cardiac death and Urinary K+ loss can be a problem with thiazides. ACE inhibitors and a major contributor to cardiovascular mortality in treated hypertensive ARBs will attenuate diuretic-induced loss of K+ to some degree, and this patients. There is a positive correlation between diuretic dose and sudden is a consideration if a second drug is required to achieve further blood cardiac death and an inverse correlation between the use of adjunctive pressure reduction beyond that attained with the diuretic alone. Because K+-sparing agents and sudden cardiac death (Siscovick et al., 1994). Thus, the diuretic and hypotensive effects of these drugs are greatly enhanced hypokalemia needs to be avoided by, for example, combining a thiazide when they are given in combination, care should be taken to initiate com- with inhibitors of the RAS or with a K+-sparing diuretic. bination therapy with low doses of each of these drugs (Vlasses et al., Thiazides have residual carbonic anhydrase–inhibiting activity, 1983). Administration of ACE inhibitors or ARBs together with other thereby reducing Na+ reabsorption in the proximal tubule. The increased K+-sparing agents or with K+ supplements requires great caution; com- presentation of Na+ at the macula densa leads to a reduced glomerular bining K+-sparing agents with each other or with K+ supplementation can filtration rate via tubuloglomerular feedback. While this effect is clini- cause potentially dangerous hyperkalemia in some patients. cally not meaningful in patients with normal renal function, it reduces In contrast to the limitation on the dose of thiazide-class diuretics diuretic effectiveness and may gain importance in patients with reduced used as monotherapy, the treatment of severe hypertension that is unre- kidney function. RAS inhibitors and Ca2+ channel blockers interfere with sponsive to three or more drugs may require larger doses of the thiazide- tubuloglomerular feedback, providing one explanation for the synergistic class diuretics. Indeed, hypertensive patients may become refractory to effect on blood pressure. drugs that block the sympathetic nervous system or to vasodilator drugs, Erectile dysfunction is a troublesome adverse effect of the thiazide- because these drugs engender a state in which the blood pressure is very class diuretics, and physicians should inquire specifically regarding its volume dependent. Therefore, it is appropriate to consider the use of occurrence in conjunction with treatment with these drugs. Gout may thiazide-class diuretics in doses of 50 mg of daily hydrochlorothiazide be a consequence of the hyperuricemia induced by these diuretics. The equivalent when treatment with appropriate combinations and doses of occurrence of either of these adverse effects is a reason for considering alternative approaches to therapy. However, precipitation of acute gout despite triple standard antihypertensive therapy (Williams et al., 2015). 633 is relatively uncommon with low doses of diuretics. Hydrochlorothiazide Spironolactone had about a 2-fold larger blood pressure–lowering effect may cause rapidly developing, severe hyponatremia in some patients. (8.7 vs. 4.8 and 4 mmHg, respectively). The efficacy of the mineralocorti- Thiazides inhibit renal Ca2+ excretion (in contrast to loop diuretics coid receptor antagonist (MRA) spironolactone in resistant hypertension increasing it), occasionally leading to hypercalcemia; although gener- supports a primary role of Na+ retention in this condition. Some of the ally mild, this can be more severe in patients subject to hypercalcemia, effect may be related to the so-called aldosterone-escape phenomenon, such as those with primary hyperparathyroidism. The thiazide-induced or a return to pre-RAS-inhibitor plasma aldosterone levels with extended decreased Ca2+ excretion may be used therapeutically in patients with time of treatment, observed under treatment with RAS inhibitors. Pri- osteoporosis or hypercalciuria. mary hyperaldosteronism occurs in a significant fraction of patients with Thiazide diuretics have also been associated with changes in plasma resistant hypertension (Calhoun et al., 2002). The addition of spirono- lipids and glucose tolerance that have led to some concern. The clinical lactone at low dose is currently recommended as the third step in the ESC significance of the changes has been disputed because the clinical studies treatment algorithms (Figure 32–2). demonstrated comparable efficacy of the thiazide diuretic chlortalidone Spironolactone has some significant adverse effects, especially in men in reducing cardiovascular risk (ALLHAT Officers, 2002). (e.g., erectile dysfunction, gynecomastia, benign prostatic hyperplasia). All thiazide-like drugs cross the placenta. While they have no direct Eplerenone is a more specific, though less-potent, MRA with reduced side adverse effects on the fetus, administration of a thiazide during preg- effects. nancy increases a risk of transient volume depletion that may result in All K+-sparing diuretics should be used cautiously, with frequent mea- placental hypoperfusion. Because the thiazides appear in breast milk, surements of plasma K+ concentrations in patients predisposed to hyper- they should be avoided by nursing mothers. kalemia (e.g., type 2 diabetics). Patients should be cautioned regarding SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Recent registry data from Denmark revealed an increased risk the possibility that concurrent use of K+-containing salt substitutes could (10%–70%) of certain types of skin cancers (squamous skin cell carci- produce hyperkalemia. Renal insufficiency is a relative contraindication noma, nonmelanoma basal cell carcinoma) associated with the use of to the use of K+-sparing diuretics. Concomitant use of an ACE inhibitor hydrochlorothiazide (Pedersen et al., 2018). The effect may be due to a or an ARB magnifies the risk of hyperkalemia with these agents. photosensitizing effect and has led the FDA to require inclusion of that information on the label of all hydrochlorothiazide-containing drug for- Diuretic-Associated Drug Interactions mulations. It is not clear whether the risk extends to other thiazides. Because the antihypertensive effects of diuretics are additive with those of other antihypertensive agents, a diuretic commonly is used in combination Other Diuretic Antihypertensive Agents with other drugs. The K+- and Mg2+-depleting effects of the thiazides and The thiazide diuretics are more effective antihypertensive agents than loop diuretics can potentiate arrhythmias that arise from digitalis toxic- are the loop diuretics, such as furosemide and bumetanide, in patients ity. Corticosteroids can amplify the hypokalemia produced by the diuret- who have normal renal function. This differential effect is most likely ics. NSAIDs (see Chapter 43) that inhibit the synthesis of prostaglandins related to the short duration of action of loop diuretics. In fact, a single reduce the antihypertensive effects of diuretics and all other antihyperten- daily dose of loop diuretics does not cause a significant net loss of Na+ sives. The renal effects of selective cyclooxygenase 2 (COX-2) inhibitors for an entire 24-h period because the strong initial diuretic effect is fol- are similar to those of the traditional NSAIDs. NSAIDs and RAS inhib- lowed by a rebound mediated by activation of the RAS. Unfortunately, itors reduce plasma concentrations of aldosterone and can potentiate the loop diuretics are frequently and inappropriately prescribed as a once- hyperkalemic effects of a K+-sparing diuretic. All diuretics can decrease a-day medication in the treatment not only of hypertension, but also of the clearance of Li+, resulting in increased plasma concentrations of Li+ congestive heart failure and ascites. The high efficacy of loop diuretics and potential toxicity. to produce a rapid and profound natriuresis can be detrimental for the treatment of hypertension. When a loop diuretic is given twice daily, the acute diuresis can be excessive and lead to more side effects than occur Sympatholytic Agents with a slower-acting, milder thiazide diuretic. Loop diuretics may be par- ticularly useful in patients with azotemia or with severe edema associated With the demonstration in 1940 that bilateral excision of the thoracic with a vasodilator such as minoxidil. sympathetic chain could lower blood pressure, there was a search for effective chemical sympatholytic agents. Many of the early sympatholytic drugs were poorly tolerated and had limiting adverse side effects, par- K+-Sparing Diuretics ticularly on mood. A number of sympatholytic agents are currently in Amiloride and triamterene are K+-sparing diuretics that have little value use (Table 32–2). Antagonists of α and β adrenergic receptors have been as antihypertensive monotherapy but are important in combination with mainstays of antihypertensive therapy but have recently lost their place thiazides to antagonize urinary K+ loss and the concomitant risk of ven- as first-line therapy. tricular arrhythmias. They act by reversibly inhibiting the epithelial Na+ channel (ENaC) in the distal tubule membrane, the transporter responsible β Blockers for the reabsorption of Na+ in exchange for K+. The importance of ENaC in β Adrenergic receptor antagonists (β blockers) were not expected to have hypertension is illustrated by the fact that an inherited form of hyperten- antihypertensive effects when they were first investigated in patients with sion, Liddle syndrome, is due to hyperactivity of ENaC. Gene expression angina, their primary indication. However, pronethalol, a drug that was of ENaC is mineralocorticoid sensitive, explaining the antihypertensive never marketed, was found to reduce arterial blood pressure in hyperten- and K+-sparing effect of another class of K+-sparing diuretics, the MRAs sive patients with angina pectoris. This antihypertensive effect was subse- spironolactone and eplerenone. In contrast to the immediate and short-term quently demonstrated for propranolol and all other β blockers. The basic inhibition of ENaC by amiloride and triamterene, the action of MRAs is pharmacology of these drugs is discussed in Chapter 14; characteristics delayed for about 3 days and is long lasting because MRAs regulate the relevant to their use in hypertension are described here. density of the channel protein in the tubule membrane. The MRAs have a particular role in hypertension and heart failure (see Locus and Mechanism of Action Chapter 23) because small doses of spironolactone are often highly effec- Antagonism of β adrenergic receptors affects the regulation of the circu- tive in patients with “resistant hypertension.” First described decades ago lation through a number of mechanisms, including a reduction in myo- (Ramsay et al., 1980), the concept was recently validated in a prospective, cardial contractility and heart rate (i.e., cardiac output; see Figure 32–3). placebo-controlled trial comparing spironolactone (25–50 mg) with biso- Antagonism of β1 receptors of the juxtaglomerular complex reduces prolol or doxazosin as add-ons in patients with uncontrolled hypertension renin secretion and RAS activity. This action likely contributes to the https://ebooksmedicine.net/  634 antihypertensive action. Some members of this large, heterogeneous patients with a specific indication for their use (e.g., heart failure; Table class of drugs have additional effects unrelated to their capacity to bind 32–1) or in the third step of the treatment algorithm (Figure 32–2). to β adrenergic receptors. For example, labetalol and carvedilol are also α1 blockers, and nebivolol promotes endothelial cell–dependent vasodilation Adverse Effects and Precautions via activation of nitric oxide (NO) production (Pedersen and Cockcroft, The adverse effects of β blockers are discussed in Chapter 14. These drugs 2006) (see Figure 14–4). should be avoided in patients with reactive airway disease (e.g., asthma) or with SA or atrioventricular (AV) nodal dysfunction or in combination Pharmacodynamic Differences with other drugs that inhibit AV conduction, such as verapamil. The risk The β blockers vary in their selectivity for the β1 receptor subtype, of hypoglycemic reactions may be increased in diabetics taking insulin, presence of partial agonist or intrinsic sympathomimetic activity, and but type 2 diabetes is not a contraindication. β Blockers increase con- vasodilating capacity. While all of the β blockers are effective as antihy- centrations of triglycerides in plasma and lower those of high-density pertensive agents, these differences influence the clinical pharmacology lipoprotein (HDL) cholesterol without changing total cholesterol con- and spectrum of adverse effects of the various drugs. The antihyperten- centrations. The long-term consequences of these effects are unknown. sive effect resides in antagonism of the β1 receptor, while major unwanted β Blockers may aggravate depression and psoriasis. effects result from antagonism of β2 receptors (e.g., peripheral vasocon- Sudden discontinuation of β blockers can produce a withdrawal syn- striction, bronchoconstriction, hypoglycemia). Standard therapies are drome, likely due to upregulation of β receptors during blockade, causing β1 blockers without intrinsic sympathomimetic activity (e.g., atenolol, enhanced tissue sensitivity to endogenous catecholamines—potentially bisoprolol, metoprolol). They produce an initial reduction in cardiac out- exacerbating the symptoms of CAD. The result, especially in active put (mainly β1) and a reflex-induced rise in peripheral resistance, with patients, can be rebound hypertension. Thus, β blockers should not be little or no acute change in arterial pressure. In patients who respond with discontinued abruptly, except under close observation; dosage should be CHAPTER 32 TREATMENT OF HYPERTENSION a reduction in blood pressure, peripheral resistance gradually returns to tapered gradually over 10 to 14 days prior to discontinuation. pretreatment values or less. Generally, persistently reduced cardiac out- Epinephrine can produce severe hypertension and bradycardia when put and possibly decreased peripheral resistance account for the reduc- a nonselective β blocker is present. The hypertension is due to the unop- tion in arterial pressure. Nonselective β blockers (e.g., propranolol) have posed stimulation of α adrenergic receptors when vascular β2 receptors stronger adverse effects on peripheral vascular resistance by also blocking are blocked. The bradycardia is the result of reflex vagal stimulation. Such β2 receptors that normally mediate vasodilation. Vasodilating β blockers paradoxical hypertensive responses to β blockers have been observed in (e.g., carvedilol, nebivolol) may be preferred in patients with peripheral patients with hypoglycemia or pheochromocytoma, during withdrawal artery disease. Drugs with intrinsic sympathomimetic activity (e.g., from clonidine, following administration of epinephrine as a therapeutic pindolol, xamoterol) are not recommended for the treatment of hyperten- agent, or in association with the illicit use of cocaine. sion or any other cardiovascular disease because they increase nighttime Therapeutic Uses mean heart rate due to their direct partial agonistic activity. The β blockers provide effective therapy for all grades of hypertension. Pharmacokinetic Differences Marked differences in their pharmacokinetic properties should be con- Lipophilic β blockers (metoprolol, bisoprolol, carvedilol, propranolol) sidered; once-daily dosing is preferred for better compliance. Populations appear to have more antiarrhythmic efficacy than the hydrophilic com- that tend to have a lesser antihypertensive response to β blockers include pounds (atenolol, nadolol, labetalol), possibly related to a central mode the elderly and African Americans. However, intraindividual differences of action. Many β blockers have relatively short plasma half-lives and in antihypertensive efficacy are generally much larger than statistical evi- require more than once-daily dosing (metoprolol, propranolol, carvedilol), dence of differences between racial or age-related groups. Consequently, a significant disadvantage in the treatment of hypertension. They should these observations should not discourage the use of these drugs in indi- generally be prescribed in sustained-release forms. Bisoprolol and vidual patients in groups reported to be less responsive. nebivolol have t1/2 values of 10 to 12 h and thus achieve sufficient trough The β blockers usually do not cause retention of salt and water, and levels at once-daily dosing. Hepatic metabolism of metoprolol, carvedilol, administration of a diuretic is not necessary to avoid edema or the devel- and nebivolol is CYP2D6 dependent. The relevance is probably greatest opment of tolerance. However, diuretics do have additive antihyperten- in case of metoprolol, for which CYP2D6 poor metabolizers (~7% of the sive effects when combined with β blockers. The addition of a β blocker Caucasian population) show 5-fold higher drug exposure and 2-fold to first-line treatment with an ACE inhibitor/ARB or calcium channel higher heart rate decreases than the majority of extensive metabolizers blocker and diuretic is effective for patients who require a third anti- (Rau et al., 2009). hypertensive drug (Figure 32–2). β Blockers (i.e., bisoprolol, carvedilol, metoprolol, or nebivolol) remain preferred drugs for hypertensive patients Effectiveness in Hypertension with conditions such as MI, ischemic heart disease, atrial fibrillation, or Meta-analyses have suggested that β blockers reduce the incidence of congestive heart failure and may be preferred for younger patients with MI similar to other antihypertensives but are only about half as effective signs of increased sympathetic drive. in preventing stroke (Lindholm et al., 2005). This has led to downgrad- ing of this class of drugs in important guidelines (Whelton et al., 2018; α1 Blockers Williams et al., 2018; Table 32–1, Figure 32–2). It has been argued that The availability of drugs that selectively block α1 adrenergic receptors many of the studies supporting this conclusion were conducted with without affecting α2 adrenergic receptors adds another group of antihy- atenolol, which may not be the ideal β blocker. Atenolol, in contrast to pertensive agents. The pharmacology of these drugs is discussed in detail bisoprolol, carvedilol, metoprolol, or nebivolol, has not been positively in Chapter 14. Prazosin, terazosin, and doxazosin are the agents available tested in heart failure trials. Atenolol may not lower central (aortic) blood for the treatment of hypertension. Phenoxybenzamine, an irreversible pressure as effectively as it appears when conventionally measured in the α blocker (α1 > α2), is only used in the bridging treatment of catechola- brachial artery using a standard arm cuff (Williams et al., 2006), but it is mine-producing tumors (pheochromocytoma). not clear whether other β blockers have more favorable effects on central blood pressure, arterial stiffness, and endothelial dysfunction. Prospec- Pharmacological Effects tive studies of hypertensive agents have not compared different β block- Initially, α1 blockers reduce arteriolar resistance and increase venous ers head-to-head; therefore, the clinical relevance of pharmacological capacitance; this causes a sympathetically mediated reflex increase in differences in this heterogeneous drug class remains unclear. Regardless, heart rate and plasma renin activity. During long-term therapy, vaso- β blockers as a class are associated with more side effects than ACE inhib- dilation persists, but cardiac output, heart rate, and plasma renin activ- itors/ARBs or calcium channel blockers, including increased incidence of ity return to normal. Renal blood flow is unchanged during therapy diabetes and weight gain. Therefore, β blockers are only recommended in with an α1 blocker. The α1 blockers cause a variable amount of postural hypotension, depending on the plasma volume. Retention of salt and effect profile limits its current use largely to treatment of hypertension in 635 water occurs in many patients during continued administration, and this pregnancy, where it has a record for safety. attenuates the postural hypotension. The α1 blockers reduce plasma con- Methyldopa (α-methyl-3,4-dihydroxy-l-phenylalanine), an analogue centrations of triglycerides and total LDL cholesterol and increase HDL of 3,4-dihydroxyphenylalanine (DOPA), is metabolized by the l-aromatic cholesterol. These potentially favorable effects on lipids persist when a amino acid decarboxylase in adrenergic neurons to α-methyldopamine, thiazide-type diuretic is given concurrently. The long-term consequences which then is converted to α-methylnorepinephrine, the pharmacologi- of these small, drug-induced changes in lipids are unknown. cally active metabolite. α-Methylnorepinephrine is stored in the secretory vesicles of adrenergic neurons, substituting for norepinephrine (NE), Therapeutic Uses such that the stimulated adrenergic neuron now discharges α-methylnor- α1 Blockers are not recommended as monotherapy for hypertensive epinephrine instead of NE. α-Methylnorepinephrine acts in the CNS to patients, primarily as a consequence of the ALLHAT study (see further inhibit adrenergic neuronal outflow from the brainstem, probably by act- discussion). They are used primarily in conjunction with diuretics, β ing as an agonist at presynaptic α2 adrenergic receptors in the brainstem, blockers, and other antihypertensive agents. β Blockers enhance the effi- attenuating NE release and thereby reducing the output of vasoconstric- cacy of α1 blockers. α1 Blockers are not the drugs of choice in patients with tor adrenergic signals to the peripheral sympathetic nervous system. pheochromocytoma because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular α2 adrenergic recep- ADME. Because methyldopa is a prodrug that is metabolized in the brain tors. α1 Blockers are attractive drugs for hypertensive patients with benign to the active form, its Cp has less relevance for its effects than that for prostatic hyperplasia because they also improve urinary symptoms. many other drugs. Cpmax occurs 2 to 3 h following an oral dose. The drug is eliminated with a t1/2 of about 2 h. Methyldopa is excreted in the urine Adverse Effects primarily as the sulfate conjugate (50%–70%) and as the parent drug SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR The use of doxazosin as monotherapy for hypertension increases the (25%). Other minor metabolites include methyldopamine, methylnor- risk for developing congestive heart failure (ALLHAT Officers, 2002). epinephrine, and their O-methylated products. The t1/2 of methyldopa is This may be a class effect that represents an adverse effect of all of the α1 prolonged to 4 to 6 h in patients with renal failure. blockers and has led to recommendations not to use this class of drugs in Despite its rapid absorption and short t1/2, the peak effect of methyldopa patients with heart failure. Interpretation of the outcome of the ALLHAT is delayed for 6 to 8 h, even after intravenous administration, and the study is controversial, but the commonly held belief that the higher rate duration of action of a single dose is usually about 24 h; this permits once- of apparent heart failure development in the groups of patients treated or twice-daily dosing. The discrepancy between the effects of methyldopa with a nondiuretic was caused by withdrawal of prestudy diuretics has and the measured concentrations of the drug in plasma is most likely not been substantiated (Davis et al., 2006). related to the time required for transport into the CNS, conversion to A major precaution regarding the use of the α1 blockers for hyper- the active metabolite storage of α-methyl NE, and its subsequent release tension is the so-called first-dose phenomenon, in which symptomatic in the vicinity of relevant α2 receptors in the CNS. Methyldopa is a good orthostatic hypotension occurs within 30 to 90 min (or longer) of the example of a complex relationship between a drug’s pharmacokinetics initial dose of the drug or after a dosage increase. This effect may occur and its pharmacodynamics. Patients with renal failure are more sensitive in up to 50% of patients, especially in patients who are already receiving to the antihypertensive effect of methyldopa, but it is not known if this is a diuretic. After the first few doses, patients develop a tolerance to this due to alteration in excretion of the drug or to an increase in transport marked hypotensive response. into the CNS. Combined α1 and β Blockers Therapeutic Uses. Methyldopa is a preferred drug for treatment of hypertension during pregnancy based on its effectiveness and safety for Carvedilol (see Chapter 14) is a nonselective β blocker with α1-antagonist both mother and fetus (Magee et al., 2016). The usual initial dose of meth- activity. Carvedilol is approved for the treatment of hypertension and yldopa is 250 mg twice daily; there is little additional effect with doses symptomatic heart failure. The ratio of α1- to β-antagonist potency for greater than 2 g/d. Administration of a single daily dose of methyldopa carvedilol is approximately 1:10. The drug dissociates slowly from its at bedtime minimizes sedative effects, but administration twice daily is receptor, explaining why the duration of action is longer than the short required for some patients. t1/2 (2.2 h) and why its effect can hardly be overcome by catecholamines. Carvedilol undergoes oxidative metabolism and glucuronidation in the Adverse Effects and Precautions. Methyldopa produces sedation that liver; the oxidative metabolism occurs via CYP2D6. As with labetalol, the is largely transient. A diminution in psychic energy may persist in some long-term efficacy and side effects of carvedilol in hypertension are pre- patients, and depression occurs occasionally. Methyldopa may produce dictable based on its properties as a β and α1 blocker. Carvedilol reduces dryness of the mouth. Other adverse effects include diminished libido, mortality in patients with congestive heart failure (see Chapter 33). parkinsonian signs, and hyperprolactinemia that may become suffi- Due to the vasodilating effect, it is a β blocker of choice in patients with ciently pronounced to cause gynecomastia and galactorrhea. Methyldopa peripheral artery disease. may precipitate severe bradycardia and sinus arrest. Labetalol (see Chapter 14) is an equimolar mixture of four stereoiso- Methyldopa also produces some adverse effects that are not related mers. One isomer is an α1 blocker, another is a nonselective β blocker with to its therapeutic action in the CNS. Hepatotoxicity, sometimes associ- partial agonist activity, and the other two isomers are inactive. Labetalol has ated with fever, is an uncommon but potentially serious toxic effect of efficacy and adverse effects that would be expected with any combination methyldopa. At least 20% of patients who receive methyldopa for a year of an α1 and a β blocker. It has the disadvantages that are inherent in fixed- develop a positive Coombs test (antiglobulin test) that is due to autoanti- dose combination products: The extent of α1 to β blockade is somewhat bodies directed against the Rh antigen on erythrocytes. The development unpredictable and varies from patient to patient. Labetalol is FDA approved of a positive Coombs test is not necessarily an indication to stop treat- for eclampsia, preeclampsia, hypertension, and hypertensive emergencies. ment with methyldopa; however, 1% to 5% of these patients will develop a The main indication for labetalol is hypertension in pregnancy, for which it hemolytic anemia that requires prompt discontinuation of the drug. The is one of the few compounds known to be safe (Magee et al., 2016). Coombs test may remain positive for as long as a year after discontinu- ation of methyldopa, but the hemolytic anemia usually resolves within a Centrally Acting Sympatholytic Drugs matter of weeks. Severe hemolysis may be attenuated by treatment with Methyldopa glucocorticoids. Adverse effects that are even rarer include leukopenia, Methyldopa, a centrally acting antihypertensive agent, is a prodrug that thrombocytopenia, red cell aplasia, lupus erythematosus–like syndrome, exerts its antihypertensive action via an active metabolite. Although used lichenoid and granulomatous skin eruptions, myocarditis, retroperito- frequently as an antihypertensive agent in the past, methyldopa’s adverse neal fibrosis, pancreatitis, diarrhea, and malabsorption. https://ebooksmedicine.net/  636 Clonidine and Moxonidine tremors, abdominal pain, sweating, and tachycardia. Arterial blood The detailed pharmacology of the α2 adrenergic agonists clonidine and pressure may rise to levels above those present prior to treatment, but moxonidine (no longer available in the U.S.) is discussed in Chapter 14. the withdrawal syndrome may occur in the absence of an overshoot in These drugs stimulate α2A adrenergic receptors in the brainstem, resulting pressure. Symptoms typically occur 18 to 36 h after the drug is stopped in a reduction in sympathetic outflow from the CNS (MacMillan et al., and are associated with increased sympathetic discharge, as evidenced 1996). The hypotensive effect correlates directly with the decrease in by elevated plasma and urine concentrations of catecholamines and plasma concentrations of NE. Patients who have had a spinal cord tran- metabolites. The frequency of occurrence of the withdrawal syndrome section above the level of the sympathetic outflow tracts do not display is not known, but withdrawal symptoms are likely dose related and more a hypotensive response to clonidine. At doses higher than those required dangerous in patients with poorly controlled hypertension. Rebound to stimulate central α2A receptors, these drugs can activate α2B receptors hypertension also has been seen after discontinuation of transdermal on vascular smooth muscle cells (MacMillan et al., 1996). This effect administration of clonidine (Metz et al., 1987). accounts for the initial vasoconstriction that is seen when given intra- Treatment of the withdrawal syndrome depends on the urgency of venously or overdoses of these drugs are taken. It may also be responsi- reducing the arterial blood pressure. In the absence of life-threatening ble for the loss of therapeutic effect that is observed with high doses. A target organ damage, patients can be treated by restoring the use of major limitation in the use of these drugs is the paucity of information clonidine. If a more rapid effect is required, sodium nitroprusside or a about their efficacy in reducing the risk of cardiovascular consequences combination of an α and β blocker is appropriate. β Blockers should not of hypertension. be used alone in this setting because they may accentuate the hyperten- sion by allowing unopposed α adrenergic vasoconstriction caused by Pharmacological Effects. The α2 adrenergic agonists lower arterial activation of the sympathetic nervous system and elevated circulating pressure by effects on both cardiac output and peripheral resistance. In catecholamines. CHAPTER 32 TREATMENT OF HYPERTENSION the supine position, when the sympathetic tone to the vasculature is low, Because perioperative hypertension has been described in patients the major effect is a reduction in heart rate and stroke volume; however, in whom clonidine was withdrawn the night before surgery, surgical in the upright position, when sympathetic outflow to the vasculature is patients who are being treated with an α2 adrenergic agonist either should normally increased, these drugs reduce vascular resistance. This action be switched to another drug prior to elective surgery or should receive may lead to postural hypotension. The decrease in cardiac sympathetic their morning dose or transdermal clonidine prior to the procedure. All tone leads to a reduction in myocardial contractility and heart rate that patients who receive one of these drugs should be warned of the poten- could promote congestive heart failure in susceptible patients. tial danger of discontinuing the drug abruptly, and patients suspected of Therapeutic Uses. The CNS effects are such that this class of drugs is being noncompliant with medications should not be given α2 adrenergic not a leading option for monotherapy of hypertension. Indeed, there is no agonists for hypertension. fixed place for these drugs in the treatment of hypertension. They effec- Adverse drug interactions with α2 adrenergic agonists are rare. Diuret- tively lower blood pressure in some patients who have not responded ics predictably potentiate the hypotensive effect of these drugs. Tricyclic adequately to combinations of other agents. The greater clinical expe- antidepressants may inhibit the antihypertensive effect of clonidine, but rience exists with clonidine. A study with moxonidine in patients with the mechanism of this interaction is not known. hypertension and paroxysmal atrial fibrillation indicated that the drug reduced the incidence of atrial fibrillation (Giannopoulos et al., 2014). Reserpine Clonidine may be effective in reducing early morning hypertension in Reserpine is an alkaloid extracted from the root of Rauwolfia serpentina, patients treated with standard antihypertensives. Overall, enthusiasm for a climbing shrub indigenous to India. Ancient Hindu Ayurvedic writings α2 receptor antagonists is diminished by the relative absence of evidence describe medicinal uses of the plant; Sen and Bose described its use in the demonstrating reduction in risk of adverse cardiovascular events. Indian biomedical literature. However, rauwolfia alkaloids were not used Clonidine has been used in hypertensive patients for the diagnosis of in Western medicine until the mid-1950s. Reserpine was the first drug pheochromocytoma. The failure of clonidine to suppress the plasma con- found to interfere with the function of the sympathetic nervous system in centration of NE to less than 500 pg/mL 3 h after an oral dose of 0.3 mg humans, and its use began the modern era of effective pharmacotherapy of clonidine suggests the presence of such a tumor. A modification of this of hypertension. Reserpine is no longer marketed in the U.S. test, wherein overnight urinary excretion of NE and epinephrine is mea- Mechanism of Action. Reserpine binds tightly to adrenergic storage sured after administration of a 0.3-mg dose of clonidine at bedtime, may vesicles in central and peripheral adrenergic neurons and remains bound be useful when results based on plasma NE concentrations are equivocal. for prolonged periods of time. The interaction inhibits the vesicular cate- Adverse Effects and Precautions. Many patients experience persis- cholamine transporter VMAT2, so that nerve endings lose their capacity tent and sometimes intolerable adverse effects with these drugs. Sedation to concentrate and store NE and dopamine. Catecholamines leak into the and xerostomia are prominent adverse effects. The xerostomia may be cytoplasm, where they are metabolized. Consequently, little or no active accompanied by dry nasal mucosa, dry eyes, and swelling and pain of transmitter is released from nerve endings, resulting in a pharmacologi- the parotid gland. Postural hypotension and erectile dysfunction may be cal sympathectomy. Recovery of sympathetic function requires synthesis prominent in some patients. Clonidine may produce a lower incidence of new storage vesicles, which takes days to weeks after discontinuation of dry mouth and sedation when given transdermally, perhaps because of the drug. Because reserpine depletes amines in the CNS as well as in high peak concentrations are avoided. Moxonidine has additional activ- the peripheral adrenergic neuron, it is probable that its antihypertensive ity at central imidazoline receptors and may produce less sedation than effects are related to both central and peripheral actions. clonidine, but direct comparisons are lacking. Less-common CNS side Pharmacological Effects. Both cardiac output and peripheral vascular effects include sleep disturbances with vivid dreams or nightmares, rest- resistance are reduced during long-term therapy with reserpine. lessness, and depression (note the use of α2 adrenergic antagonists such ADME. Few data are available on the pharmacokinetic properties of as mirtazapine to treat depression). Cardiac effects related to the sym- reserpine because of the lack of an assay capable of detecting low concen- patholytic action of these drugs include symptomatic bradycardia and trations of the drug or its metabolites. Reserpine that is bound to isolated sinus arrest in patients with dysfunction of the SA node and AV block storage vesicles cannot be removed by dialysis, indicating that the bind- in patients with AV nodal disease or in patients taking other drugs that ing is not in equilibrium with the surrounding medium. Because of the depress AV conduction. Some 15% to 20% of patients who receive trans- irreversible nature of reserpine binding, the amount of drug in plasma is dermal clonidine may develop contact dermatitis. unlikely to bear any consistent relationship to drug concentration at the Sudden discontinuation of clonidine and related α2 adrenergic agonists site of action. Free reserpine is entirely metabolized; therefore, none of the may cause a withdrawal syndrome consisting of headache, apprehension, parent drug is excreted unchanged. Toxicity and Precautions. Most adverse effects of reserpine are due the liver, contributing to the drug’s low bioavailability (16% in fast acety- 637 to its effect on the CNS. Sedation and inability to concentrate or per- lators and 35% in slow acetylators). The rate of acetylation is genetically form complex tasks are the most common adverse effects. More serious determined; about half of the U.S. population acetylates rapidly, and half is the occasional psychotic depression that can lead to suicide. Depres- does so slowly. The acetylated compound is inactive; thus, the dose nec- sion usually appears insidiously over many weeks or months and may essary to produce a systemic effect is larger in fast acetylators. Because the not be attributed to the drug because of the delayed and gradual onset of systemic clearance exceeds hepatic blood flow, extrahepatic metabolism symptoms. Reserpine must be discontinued at the first sign of depression. must occur. Indeed, hydralazine rapidly combines with circulating α-keto Reserpine-induced depression may last several months after the drug is acids to form hydrazones, and the major metabolite recovered from the discontinued. The risk of depression is likely dose related. Depression plasma is hydralazine pyruvic acid hydrazone. This metabolite has a lon- is uncommon, but not unknown, with doses of 0.25 mg/d or less. The ger t1/2 than hydralazine but appears to be relatively inactive. Although the drug should never be given to patients with a history of depression. Other rate of acetylation is an important determinant of the bioavailability of adverse effects include nasal stuffiness and exacerbation of peptic ulcer hydralazine, it does not play a role in the systemic elimination of the drug, disease, which is uncommon with small oral doses. probably because hepatic clearance is so high that systemic elimination is Therapeutic Uses. Reserpine at low doses, in combination with diuret- principally a function of hepatic blood flow. The peak concentration of ics, is effective in the treatment of hypertension, especially in the elderly. hydralazine in plasma and the peak hypotensive effect of the drug occurs Several weeks are necessary to achieve maximum effect. In elderly within 30 to 120 min of ingestion. Although its t1/2 in plasma is about 1 h, patients with isolated systolic hypertension, reserpine (at 0.05 mg/d) was the hypotensive effect of hydralazine can last as long as 12 h. There is no used as an alternative to atenolol together with a diuretic (Perry et al., 2000; clear explanation for this discrepancy. SHEP Cooperative Research Group, 1991). However, with the availabil- Therapeutic Uses SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR ity of newer drugs that have proven life-prolonging effects and are well Hydralazine is no longer a first-line drug in the treatment of hypertension tolerated, the use of reserpine has largely diminished, and it is no longer on account of its relatively unfavorable adverse effect profile. The drug recommended for the treatment of hypertension. has a role as a combination pill containing isosorbide dinitrate (BiDil) in the treatment of heart failure (see Chapter 33). Hydralazine may have utility in the treatment of some patients with severe hypertension, can Vasodilators be part of evidence-based therapy in patients with congestive heart fail- ure (in combination with nitrates for patients who cannot tolerate ACE Hydralazine inhibitors or ARBs), and may be useful in the treatment of hypertensive Hydralazine (1-hydrazinophthalazine) was one of the first orally active emergencies, especially preeclampsia, in pregnant women. Hydralazine antihypertensive drugs to be marketed in the U.S.; however, the drug should be used with great caution in elderly patients and in hypertensive initially was used infrequently because of tachycardia and tachyphy- patients with CAD because of the possibility of precipitating myocardial laxis. With a better understanding of the compensatory cardiovascular ischemia due to reflex tachycardia. The usual oral dosage of hydralazine responses that accompany use of arteriolar vasodilators, hydralazine was is 25 to 100 mg twice daily. Off-label twice-daily administration is as combined with sympatholytic agents and diuretics with greater thera- effective as administration four times a day for control of blood pressure, peutic success. Nonetheless, its role in the treatment of hypertension has regardless of acetylator phenotype. The maximum recommended dose markedly diminished with the introduction of new classes of antihyper- of hydralazine is 200 mg/d to minimize the risk of drug-induced lupus tensive agents. syndrome. Mechanism of Action Toxicity and Precautions Hydralazine directly relaxes arteriolar smooth muscle with little effect on Two types of adverse effects occur after the use of hydralazine. The first, venous smooth muscle. The molecular mechanisms mediating this action which are extensions of the pharmacological effects of the drug, include are not clear but may ultimately involve a reduction in intracellular Ca2+ headache, nausea, flushing, hypotension, palpitations, tachycardia, diz- concentrations. While a variety of changes in cellular signaling pathways ziness, and angina pectoris. Myocardial ischemia can occur on account are influenced by hydralazine, precise molecular targets that explain of increased O2 demand induced by the baroreceptor reflex–induced its capacity to dilate arteries remain uncertain. Potential mechanisms stimulation of the sympathetic nervous system. Following parenteral include inhibition of inositol trisphosphate–induced release of Ca2+ from administration to patients with CAD, the myocardial ischemia may be intracellular storage sites, opening of high-conductance Ca2+-activated K+ sufficiently severe and protracted to cause frank MI. For this reason, channels in smooth muscle cells, and activation of an arachidonic acid, parenteral administration of hydralazine is not advisable in hypertensive COX, and prostacyclin pathway that would explain sensitivity to NSAIDs patients with CAD, hypertensive patients with multiple cardiovascular (Maille et al., 2016). risk factors, or older patients. In addition, if the drug is used alone, there Hydralazine-induced vasodilation is associated with powerful may be salt retention with development of high-output congestive heart stimulation of the sympathetic nervous system, likely due to failure. When combined with a β blocker and a diuretic, hydralazine is baroreceptor-mediated reflexes, resulting in increased heart rate and better tolerated, although adverse effects such as headache are still com- contractility, increased plasma renin activity, and fluid retention. These monly described and may necessitate discontinuation of the drug. effects tend to counteract the antihypertensive effect of hydralazine. The second type of adverse effect is caused by immunological reactions, of which the drug-induced lupus syndrome is the most common. Admin- Pharmacological Effects istration of hydralazine also can result in an illness that resembles serum Most of the effects of hydralazine are confined to the cardiovascular sys- sickness, hemolytic anemia, vasculitis, and rapidly progressive glomeru- tem. The decrease in blood pressure after administration of hydralazine is lonephritis. The mechanism of these autoimmune reactions is unknown, associated with a selective decrease in vascular resistance in the coronary, although it may involve the drug’s capacity to inhibit DNA methylation cerebral, and renal circulations, with a smaller effect in skin and muscle. (Arce et al., 2006). The drug-induced lupus syndrome usually occurs Because of preferential dilation of arterioles over veins, postural hypoten- after at least 6 months of continuous treatment with hydralazine, and sion is not a common problem; hydralazine lowers blood pressure simi- its incidence is related to dose, gender, acetylator phenotype, and race. larly in the supine and upright positions. In one study, after 3 years of treatment with hydralazine, drug-induced ADME lupus occurred in 10% of patients who received 200 mg daily, 5% who Following oral administration, hydralazine is well absorbed via the received 100 mg daily, and none who received 50 mg daily (Cameron and gastrointestinal (GI) tract. Hydralazine is N-acetylated in the bowel and Ramsay, 1984). The incidence is four times higher in women than in men, https://ebooksmedicine.net/  638 and the syndrome is seen more commonly in Caucasians than in Afri- maximal hypotensive effect of the drug occurs later, possibly because for- can Americans. The rate of conversion to a positive antinuclear antibody mation of the active metabolite is delayed. test is faster in slow acetylators than in rapid acetylators, suggesting that The bulk of the absorbed drug is eliminated as a glucuronide; about the native drug or a nonacetylated metabolite is responsible. However, 20% is excreted unchanged in the urine. The extent of biotransforma- the majority of patients with positive antinuclear antibody tests do not tion of minoxidil to its active metabolite, minoxidil N-O sulfate, has not develop the drug-induced lupus syndrome, and hydralazine need not been evaluated in humans. Minoxidil has a plasma t1/2 of 3 to 4 h, but its be discontinued unless clinical features (arthralgia, arthritis, and fever) duration of action is 24 h and occasionally even longer. It has been pro- of the syndrome appear. Discontinuation of the drug is all that is neces- posed that persistence of minoxidil in vascular smooth muscle is respon- sary for most patients with the hydralazine-induced lupus syndrome, but sible for this discrepancy, but without knowledge of the pharmacokinetic symptoms may persist in a few patients, and administration of corticos- properties of the active metabolite, an explanation for the prolonged teroids may be necessary. duration of action cannot be given. Hydralazine als