Chapter 25_ Drugs Affecting Renal Excretory Function-merged.pdf

Access Provided by: Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Chapter 25: Drugs Affecting Renal Excretory Function Edwin K. Jackson INTRODUCTION The kidney filters the extracellular fluid volume across the renal glomeruli an average of 12 times a day, and the renal nephrons precisely regulate the fluid volume of the body and its electrolyte content via processes of secretion and reabsorption. Disease states such as hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis may disrupt this balance. Diuretics increase the rate of urine flow and Na+ excretion and are used to adjust the volume or composition of body fluids in these disorders. Precise regulation of body fluid osmolality is also essential. It is controlled by a finely tuned homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solutefree water excretion by the kidneys—that is, water balance. Abnormalities in this homeostatic system can result from genetic diseases, acquired diseases, or drugs and may cause serious and potentially lifethreatening deviations in plasma osmolality. Part I of this chapter first describes renal physiology, then introduces diuretics with regard to mechanism and site of action, effects on urinary composition, and effects on renal hemodynamics, and then integrates diuretic pharmacology with a discussion of mechanisms of edema formation and the role of diuretics in clinical medicine. Specific therapeutic applications of diuretics are presented in Chapters 28 (hypertension) and 29 (heart failure). Part II of this chapter describes the vasopressin system that regulates water homeostasis and plasma osmolality and factors that perturb those mechanisms and examines pharmacological approaches for treating disorders of water balance. ABBREVIATIONS Abbreviations A A : arachidonic acid ACTH: corticotropin (previously adrenocorticotropic hormone) ADH: antidiuretic hormone AIP: aldosteroneinduced protein Aldo: aldosterone Ang: angiotensin ANP: atrial natriuretic peptide A T L : ascending thin limb AVP: arginine vasopressin BL: basolateral membrane BNP: brain natriuretic peptide CA: carbonic anhydrase cGMP: cyclic guanosine monophosphate CHF: congestive heart failure Downloaded 2024417 6:8 A Your IP is 81.198.192.190 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson CNGC:McGraw cyclic nucleotidegated cation channel ©2024 Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility CNP: Ctype natriuretic peptide Page 1 / 46 BNP: brain natriuretic peptide CA: carbonic anhydrase Access Provided by: cGMP: cyclic guanosine monophosphate CHF: congestive heart failure CNGC: cyclic nucleotidegated cation channel CNP: Ctype natriuretic peptide CNT: connecting tubule COX: cyclooxygenase DAG: diacyglycerol DCT: distal convoluted tubule DDAVP: 1deamino8DAVP (desmopressin) DI: diabetes insipidus D T L : descending thin limb ECFV: extracellular fluid volume ENaC: epithelial Na+ channel ENCC1 or TSC: the absorptive Na+Cl− symporter ENCC2, NKCC2, or BSC1: the absorptive Na+K+2Cl− ENCC3, NKCC1, or BSC2: the secretory symporter FDA: Food and Drug Administration F F : filtration fraction GFR: glomerular filtration rate GPCR: G protein–coupled receptor GTP: guanosine triphosphate HCTZ: hydrochlorothiazide HDL: highdensity lipoprotein HSD: 11βhydroxysteroid dehydrogenase IMCD: inner medullary collecting duct I P3 : inositol trisphosphate LDL: lowdensity lipoprotein L M : luminal membrane LOX: lipoxygenase L T : leukotriene M R : mineralocorticoid receptor Downloaded 2024417 6:8 A Your IP is 81.198.192.190 MRA: mineralocorticoid receptor antagonist Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024 Hill.RNA All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility mRNA:McGraw messenger NP: natriuretic peptide Page 2 / 46 LOX: lipoxygenase L T : leukotriene Access Provided by: M R : mineralocorticoid receptor MRA: mineralocorticoid receptor antagonist mRNA: messenger RNA NP: natriuretic peptide NPA: asparagineprolinealanine NPR_: natriuretic peptide receptor _ (e.g., NPRA, B, or C) NSAID: nonsteroidal antiinflammatory drug O A T : organic anion transporter P A : phosphatidic acid PG: prostaglandin PK_: protein kinase _ (e.g. PKA, PKB, PKG) PL_: phospholipase _ (e.g., PLC, PLD) PTH: parathyroid hormone PVN: paraventricular nucleus RAAS: reninangiotensinaldosterone system RAS: reninangiotensin system RBF: renal blood flow SGK1: serum and glucocorticoidstimulated kinase 1 SIADH: syndrome of inappropriate secretion of ADH SNS: sympathetic nervous system SON: supraoptic nucleus T A L : thick ascending limb TGF: tubuloglomerular feedback T X : thromboxane VP: vasopressin VRUT: vasopressinregulated urea transporter vWD: von Willebrand disease WCV: water channelcontaining vesicle PART I: RENAL PHYSIOLOGY AND DIURETIC DRUG ACTION Renal Anatomy and Physiology The basic urineforming kidney the nephron. The initial part of the nephron, the renal (Malpighian) corpuscle, consists of a capsule Downloaded 2024417unit 6:8 of A the Your IP isis81.198.192.190 Page and 3 / 46 Chapter 25:capsule) Drugs Affecting Excretory Edwin K. Jackson (Bowman’s and a tuftRenal of capillaries (theFunction, glomerulus) residing within the capsule. The glomerulus receives blood from an afferent arteriole, ©2024exits McGraw Hill. All Rights TermsUltrafiltrate of Use Privacy Policy Notice Accessibility blood the glomerulus via anReserved. efferent arteriole. produced by the glomerulus collects in the space between the glomerulus and capsule (Bowman’s space) and enters a long tubular portion of the nephron, where the ultrafiltrate is reabsorbed and conditioned. Each human kidney is composed of about 1 million nephrons. Figure 25–1 illustrates subdivisions of the nephron. PART I: RENAL PHYSIOLOGY AND DIURETIC DRUG ACTION Access Provided by: Renal Anatomy and Physiology The basic urineforming unit of the kidney is the nephron. The initial part of the nephron, the renal (Malpighian) corpuscle, consists of a capsule (Bowman’s capsule) and a tuft of capillaries (the glomerulus) residing within the capsule. The glomerulus receives blood from an afferent arteriole, and blood exits the glomerulus via an efferent arteriole. Ultrafiltrate produced by the glomerulus collects in the space between the glomerulus and capsule (Bowman’s space) and enters a long tubular portion of the nephron, where the ultrafiltrate is reabsorbed and conditioned. Each human kidney is composed of about 1 million nephrons. Figure 25–1 illustrates subdivisions of the nephron. Figure 25–1 Anatomy and nomenclature of the nephron. Glomerular Filtration In the glomerular capillaries, a portion of plasma water is forced through a filter that has three basic components: the fenestrated capillary endothelial Downloaded 2024417 6:8 A Your IP is 81.198.192.190 cells, a basement membrane just beneath the endothelial cells, and the filtration slit diaphragms formed by epithelial cells that cover the Page basement 4 / 46 Chapter 25: Drugs Affectinglying Renal Excretory Function, Edwin K. Jackson ©2024 McGraw All Rights Reserved. Terms Use Privacy Policy Notice Accessibility membrane on its Hill. urinary space side. Solutes of smallof size flow with filtered water (solvent drag) into Bowman’s space, whereas formed elements and macromolecules are retained by the filtration barrier. Glomerular Filtration Access Provided by: In the glomerular capillaries, a portion of plasma water is forced through a filter that has three basic components: the fenestrated capillary endothelial cells, a basement membrane lying just beneath the endothelial cells, and the filtration slit diaphragms formed by epithelial cells that cover the basement membrane on its urinary space side. Solutes of small size flow with filtered water (solvent drag) into Bowman’s space, whereas formed elements and macromolecules are retained by the filtration barrier. Overview of Nephron Function The kidney filters large quantities of plasma, reabsorbs substances that the body must conserve, and leaves behind or secretes substances that must be eliminated. The changing architecture and cellular differentiation along the length of a nephron are crucial to these functions (see Figure 25–1). The two kidneys in humans together produce about 120 mL of ultrafiltrate/min, yet only 1 mL of urine/min of urine; more than 99% of the glomerular ultrafiltrate is reabsorbed at a staggering energy cost. The kidneys consume 7% of totalbody O2 intake despite comprising only 0.5% of body weight. The proximal tubule is contiguous with Bowman’s capsule and takes a tortuous path until finally forming a straight portion that dives into the renal medulla. Normally, about 65% of filtered Na+ is reabsorbed in the proximal tubule, and because this part of the tubule is highly permeable to water, reabsorption is essentially isotonic. Between the outer and inner strips of the outer medulla, the tubule abruptly changes morphology to become the DTL, which penetrates the inner medulla, makes a hairpin turn, and then forms the ATL. At the juncture between the inner and outer medulla, the tubule once again changes morphology and becomes the TAL. Together, the proximal straight tubule, DTL, ATL, and TAL segments are known as the loop of Henle. The DTL is highly permeable to water, yet its permeabilities to NaCl and urea are low. In contrast, the ATL is permeable to NaCl and urea but is impermeable to water. The TAL actively reabsorbs NaCl but is impermeable to water and urea. Approximately 25% of filtered Na+ is reabsorbed in the loop of Henle, mostly in the TAL, which has a large reabsorptive capacity. The TAL passes between the afferent and efferent arterioles and makes contact with the afferent arteriole by means of a cluster of specialized columnar epithelial cells known as the macula densa. The macula densa is strategically located to sense concentrations of NaCl leaving the loop of Henle. If the concentration of NaCl is too high, the macula densa sends a chemical signal (perhaps adenosine or ATP) to the afferent arteriole of the same nephron, causing it to constrict, thereby reducing the GFR. This homeostatic mechanism, known as TGF, protects the organism from salt and volume wasting. The macula densa also regulates renin release from the adjacent juxtaglomerular cells in the wall of the afferent arteriole. Approximately 0.2 mm past the macula densa, the tubule changes morphology once again to become the DCT. Like the TAL, the DCT actively transports NaCl and is impermeable to water. Because these characteristics impart the capacity to produce dilute urine, the TAL and the DCT are collectively called the diluting segment of the nephron, and the tubular fluid in the DCT is hypotonic regardless of hydration status. However, unlike the TAL, the DCT does not contribute to the countercurrentinduced hypertonicity of the medullary interstitium (described in material that follows). The collecting duct system (segments 10–14 in Figure 25–1) is an area of fine control of ultrafiltrate composition and volume. It is here that final adjustments in electrolyte composition are made, a process modulated by the adrenal steroid aldosterone. Vasopressin (also called ADH) modulates water permeability of this part of the nephron as well. The more distal portions of the collecting duct pass through the renal medulla, where the interstitial fluid is markedly hypertonic. In the absence of ADH, the collecting duct system is impermeable to water, and dilute urine is excreted. In the presence of ADH, the collecting duct system is permeable to water, and water is reabsorbed. The movement of water out of the tubule is driven by the steep concentration gradient that exists between tubular fluid and medullary interstitium. The hypertonicity of the medullary interstitium plays a vital role in the capacity of mammals and birds to concentrate urine, which is accomplished by a combination of the unique topography of the loop of Henle and the specialized permeabilities of the loop’s subsegments. The “passive countercurrent multiplier hypothesis” proposes that active transport in the TAL concentrates NaCl in the interstitium of the outer medulla. Because this segment of the nephron is impermeable to water, active transport in the ascending limb dilutes the tubular fluid. As the dilute fluid passes into the collecting duct system, water is extracted if, and only if, ADH is present. Because the cortical and outer medullary collecting ducts have low permeability to urea, urea is concentrated in the tubular fluid. The IMCD, however, is permeable to urea, so urea diffuses into the inner medulla, where it is trapped by countercurrent exchange in the vasa recta (medullary capillaries that run parallel to the loop of Henle). Because the DTL is impermeable to salt and urea, the high urea concentration in the inner medulla extracts water from the DTL and concentrates NaCl in the tubular fluid of the DTL. As the tubular fluid enters the ATL, NaCl diffuses out of the saltpermeable ATL, thus contributing to the hypertonicity of the medullary interstitium. General Mechanism of Renal Epithelial Transport There are multiple mechanisms by which solutes may cross cell membranes (see Figure 5–4). The kinds of transport achieved in a nephron segment depend mainly on which transporters are present and whether they are embedded in the luminal or basolateral membrane. Figure 25–2 presents a Downloaded 6:8 Atransport Your IP that is 81.198.192.190 general model2024417 of renal tubular be summarized as follows: Page 5 / 46 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024+ McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility 1. Na , K+ATPase (sodium pump) in the basolateral membrane transports Na+ into the intercellular and interstitial spaces and K+ into the cell, establishing an electrochemical gradient for Na+ across the cell membrane directed inward. NaCl diffuses out of the saltpermeable ATL, thus contributing to the hypertonicity of the medullary interstitium. General Mechanism of Renal Epithelial Transport Access Provided by: There are multiple mechanisms by which solutes may cross cell membranes (see Figure 5–4). The kinds of transport achieved in a nephron segment depend mainly on which transporters are present and whether they are embedded in the luminal or basolateral membrane. Figure 25–2 presents a general model of renal tubular transport that be summarized as follows: 1. Na+, K+ATPase (sodium pump) in the basolateral membrane transports Na+ into the intercellular and interstitial spaces and K+ into the cell, establishing an electrochemical gradient for Na+ across the cell membrane directed inward. 2. Na+ can diffuse down this Na+ gradient across the luminal membrane via Na+ channels and via membrane symporters that use the energy stored in the Na+ gradient to transport solutes out of the tubular lumen and into the cell (e.g., Na+glucose, Na+H2PO4, and Na+amino acid) and antiporters (e.g., Na+H+) that move solutes into the lumen as Na+ moves down its gradient and into the cell. 3. Na+ exits the basolateral membrane into intercellular and interstitial spaces via the Na+ pump. 4. The action of Na+linked symporters in the luminal membrane causes the concentration of substrates for these symporters to rise in the epithelial cell. These substrate/solute gradients then permit simple diffusion or mediated transport (e.g., symporters, antiporters, uniporters, and channels) of solutes into the intercellular and interstitial spaces. 5. Accumulation of Na+ and other solutes in the intercellular space creates a small osmotic pressure differential across the epithelial cell. In water permeable epithelium, water moves into the intercellular spaces driven by the osmotic pressure differential. Water moves through aqueous pores in both the luminal and the basolateral cell membranes, as well as through tight junctions (paracellular pathway). Bulk water flow carries some solutes into the intercellular space by solvent drag. 6. Movement of water into the intercellular space concentrates other solutes in the tubular fluid, resulting in an electrochemical gradient for these substances across the epithelium. Membranepermeable solutes then move down their electrochemical gradients into the intercellular space by both the transcellular (e.g., simple diffusion, symporters, antiporters, uniporters, and channels) and paracellular pathways. Membraneimpermeable solutes remain in the tubular lumen and are excreted in the urine with an obligatory amount of water. 7. As water and solutes accumulate in the intercellular space, hydrostatic pressure increases, thus providing a driving force for bulk water flow. Bulk water flow carries solute out of the intercellular space into the interstitial space and, finally, into the peritubular capillaries. Figure 25–2 Generic mechanism of renal epithelial cell transport (see text for details). A, antiporter; ATPase, Na+, K+ATPase (sodium pump); CH, ion channel; I, membraneimpermeable solutes; P, membranepermeable solutes; PD, potential difference across indicated membrane or cell; S, symporter; U, uniporter; WP, water pore; X and Y, transported solutes. Downloaded 2024417 6:8 A Your IP is 81.198.192.190 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 6 / 46 Generic mechanism of renal epithelial cell transport (see text for details). A, antiporter; ATPase, Na+, K+ATPase (sodium pump); CH, ion channel; I, membraneimpermeable solutes; P, membranepermeable solutes; PD, potential difference across indicated membrane or cell; S, symporter; U, Access Provided by: uniporter; WP, water pore; X and Y, transported solutes. Organic Acid and Organic Base Secretion The kidney is a major organ involved in the elimination of organic chemicals from the body. Organic molecules may enter the renal tubules by glomerular filtration or may be actively secreted directly into tubules. The proximal tubule has a highly efficient transport system for organic acids and an equally efficient but separate transport system for organic bases. Current models for these secretory systems are illustrated in Figure 25–3. Both systems are powered by the sodium pump in the basolateral membrane, involve secondary and tertiary active transport, and use a facilitated diffusion step. There are many organic acid and organic base transporters (see Chapter 5). A family of OATs links countertransport of organic anions with dicarboxylates (Figure 25–3A). Figure 25–3 Mechanisms of organic acid (A) and organic base (B) secretion in the proximal tubule. The numbers 1, 2, and 3 refer to primary, secondary, and tertiary active transport, respectively. A−, organic acid (anion); C+, organic base (cation); αKG2−, αketoglutarate but also other dicarboxylates. BL and LM indicate basolateral and luminal membranes, respectively. Downloaded 2024417 6:8 A Your IP is 81.198.192.190 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 7 / 46 Mechanisms of organic acid (A) and organic base (B) secretion in the proximal tubule. The numbers 1, 2, and 3 refer to primary, secondary, and tertiary active transport, respectively. A−, organic acid (anion); C+, organic base (cation); αKG2−, αketoglutarate but also other dicarboxylates. BL and LM indicate Access Provided by: basolateral and luminal membranes, respectively. Renal Handling of Specific Anions and Cations Reabsorption of Cl− generally follows reabsorption of Na+. In segments of the tubule with lowresistance tight junctions (i.e., “leaky” epithelium), such as the proximal tubule and TAL, Cl− movement can occur paracellularly. Cl− crosses the luminal membrane by antiport with formate and oxalate (proximal tubule), symport with Na+/K+ (TAL), symport with Na+ (DCT), and antiport with HCO3 (collecting duct system). Cl− crosses the basolateral membrane via symport with K+ (proximal tubule and TAL), antiport with Na+/HCO3 (proximal tubule), and Cl− channels (TAL, DCT, collecting duct system). Of filtered K+, 80%–90% is reabsorbed in the proximal tubule (diffusion and solvent drag) and TAL (diffusion), largely through the paracellular pathway. The DCT and collecting duct system secrete variable amounts of K+ by a channelmediated pathway. Modulation of the rate of K+ secretion in the collecting duct system, particularly by aldosterone, allows urinary K+ excretion to be matched with dietary intake. The transepithelial potential difference VT, lumen positive in the TAL and lumen negative in the collecting duct system, drives K+ reabsorption and secretion, respectively. Most of the filtered Ca2+ (∼70%) is reabsorbed by the proximal tubule by passive diffusion through a paracellular route. Another 25% of filtered Ca2+ is reabsorbed by the TAL in part by a paracellular route driven by the lumenpositive VT and in part by active transcellular Ca2+ reabsorption modulated by PTH (see Chapter 43). Most of the remaining Ca2+ is reabsorbed in DCT by a transcellular pathway. The transcellular pathway in the TAL and DCT involves passive Ca2+ influx across the luminal membrane through Ca2+ channels (TRPV5, transient receptor potential cation channel V5), followed by Ca2+ extrusion across the basolateral membrane by a Ca2+ATPase. Also, in DCT and CNT, Ca2+ crosses the basolateral membrane by Na+Ca2+ exchanger (antiport). Pi is largely reabsorbed (80% of filtered load) by the proximal tubule. The Na+Pi symporter uses the free energy of the Na+ electrochemical gradient to transport Pi into the cell. The Na+Pi symporter is inhibited by PTH. The renal tubules reabsorb HCO3 and secrete protons (tubular acidification), thereby participating in acidbase balance. These processes are described in the section on carbonic anhydrase inhibitors. Principles of Diuretic Action Diuretics are drugs that increase the rate of urine flow; clinically useful diuretics also increase the rate of Na+ excretion (natriuresis) and of an accompanying anion, usually Cl−. Most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing totalbody NaCl content. Although continued diuretic administration causes a sustained net deficit in totalbody Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line with Na+ intake, a phenomenon known as diuretic braking. These compensatory mechanisms include activation of the sympathetic nervous system, activation of the reninangiotensinaldosterone axis, decreased arterial blood pressure (which reduces pressure natriuresis), renal epithelial cell hypertrophy, increased renal epithelial transporter expression, and perhaps alterations in natriuretic hormones such as ANP. The net effects on extracellular volume and body weight are shown in Figure 25–4. Figure 25–4 Downloaded 2024417 6:8 A Your IP is 81.198.192.190 Changes fluid volume and weightFunction, with diuretic therapy. The period of diuretic administration is shown in the shaded box alongPage with its 8 / 46 Chapter in 25:extracellular Drugs Affecting Renal Excretory Edwin K. Jackson 2+ 2+ ©2024on McGraw Hill. All Reserved. Use Policy Accessibility effects body weight inRights the upper part of theTerms figureof and Na Privacy excretion in the Notice lower half of the figure. Initially, when Na excretion exceeds intake, body weight and ECFV decrease. Subsequently, a new steady state is achieved where Na+ intake and excretion are equal but at a lower ECFV and body weight. This results from activation of the RAAS and SNS, “the braking phenomenon.” When the diuretic is discontinued, body weight and ECFV rise during a include activation of the sympathetic nervous system, activation of the reninangiotensinaldosterone axis, decreased arterial blood pressure (which reduces pressure natriuresis), renal epithelial cell hypertrophy, increased renal epithelial transporter expression, and perhaps alterations in natriuretic hormones such as ANP. The net effects on extracellular volume and body weight are shown in Figure 25–4. Access Provided by: Figure 25–4 Changes in extracellular fluid volume and weight with diuretic therapy. The period of diuretic administration is shown in the shaded box along with its effects on body weight in the upper part of the figure and Na2+ excretion in the lower half of the figure. Initially, when Na2+ excretion exceeds intake, body weight and ECFV decrease. Subsequently, a new steady state is achieved where Na+ intake and excretion are equal but at a lower ECFV and body weight. This results from activation of the RAAS and SNS, “the braking phenomenon.” When the diuretic is discontinued, body weight and ECFV rise during a period when Na2+ intake exceeds excretion. A new steady state is then reached as stimulation of the RAAS and SNS wane. Diuretics may modify renal handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl−, HCO3, and H2PO4), and uric acid. In addition, diuretics may alter renal hemodynamics indirectly. Table 25–1 compares the general effects of the major diuretic classes. Table 25–1 Excretory and Renal Hemodynamic Effects of Diureticsa DIURETIC CATIONS ANIONS URIC ACID RENAL HEMODYNAMICS MECHANISM (Primary site of N a+ K+ H+ b C a2 + M g2 + C l− HCO3 − H 2 P O4 − Acute Chronic RBF GFR FF TGF + ++ – NC V (+) ++ ++ I – – – NC + ++ + I + ++ + + + + I + NC – I (loop of Henle) Downloaded 2024417 6:8 A Your IP is 81.198.192.190 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024Inhibitors McGrawofHill. Reserved. Policy Notice Accessibility Na+All Rights ++ ++ + Terms of ++Use Privacy ++ ++ +c +c + – V(+) NC V(–) action) Inhibitors of CA (proximal tubule) Osmotic diuretics K+2Cl– symport Page 9 / 46 – Diuretics may modify renal handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl−, HCO3, and H2PO4), and uric acid. In addition, diuretics Access Provided by: may alter renal hemodynamics indirectly. Table 25–1 compares the general effects of the major diuretic classes. Table 25–1 Excretory and Renal Hemodynamic Effects of Diureticsa DIURETIC CATIONS ANIONS URIC ACID RENAL HEMODYNAMICS MECHANISM (Primary site of action) Inhibitors of CA N a+ K+ H+ b C a2 + M g2 + C l− HCO3 − H 2 P O4 − Acute Chronic RBF GFR FF TGF + ++ – NC V (+) ++ ++ I – – – NC + ++ + I + ++ + + + + I + NC – I ++ ++ + ++ ++ ++ +c +c + – V(+) NC V(–) – + ++ + V(–) V(+) + +c +c + – NC V(–) V(–) NC + – – – – + (+) NC I – NC NC NC NC + – – I – + (+) I I – NC NC NC NC (proximal tubule) Osmotic diuretics (loop of Henle) Inhibitors of Na+ K+2Cl– symport (thick ascending limb) Inhibitors of Na+ Cl– symport (distal convoluted tubule) Inhibitors of renal epithelial Na+ channels (late distal tubule, collecting duct) Antagonists of mineralocorticoid receptors (late distal tubule, collecting duct) a Except for uric acid, changes are for acute effects of diuretics in the absence of significant volume depletion, which would trigger complex physiological adjustments. b H+ includes titratable acid and NH4+. c In general, these effects are restricted to those individual agents that inhibit carbonic anhydrase. However, there are notable exceptions in which symport inhibitors increase bicarbonate and phosphate (e.g., metolazone, bumetanide). ++, +, (+),–, NC, V, V(+), V(–) and I indicate marked increase, mildtomoderate increase, slight increase, decrease, no change, variable effect, variable increase, variable decrease, and insufficient data, respectively. For cations and anions, the indicated effects refer to absolute changes in fractional excretion. Inhibitors Carbonic Downloaded of 2024417 6:8 AAnhydrase Your IP is 81.198.192.190 Chapter 25: Drugs Affecting Renal Excretory Function, Edwin K. Jackson ©2024are McGraw Hill. All Rights Reserved. of Use Privacyacetazolamide, Policy Noticedichlorphenamide, Accessibility and methazolamide (Table 25–2). There three orally administered carbonic Terms anhydrase inhibitors— Table 25–2 Page 10 / 46 In general, these effects are restricted to those individual agents that inhibit carbonic anhydrase. However, there are notable exceptions in which symport inhibitors increase bicarbonate and phosphate (e.g., metolazone, bumetanide). ++, +, (+),–, NC, V, V(+), V(–) and I indicate marked increase, mildtomoderate increase, slight increase, decrease, no change, variable effect, variable increase, variable decrease, and insufficient data, respectively. For cations and anions, the indicated effects refer to absolute changes in fractional excretion. Access Provided by: Inhibitors of Carbonic Anhydrase There are three orally administered carbonic anhydrase inhibitors—acetazolamide, dichlorphenamide, and methazolamide (Table 25–2). Table 25–2 Inhibitors of Carbonic Anhydrase DRUG RELATIVE POTENCY ORAL AVAILABILITY t 1 / 2 (hours) ROUTE OF ELIMINATION Acetazolamide 1 ~100% 6–9 R Dichlorphenamide 30 ID ID ID Methazolamide >1; 8 h) Do not use concurrently with PDE5 inhibitor Molsidomine Angina Direct NO donor Second choice for the prevention of angina Adverse effects same as above No documented advantage over GTN/ISDN/ISMN Inhaled NO Pulmonary hypertension in neonates Relatively selective effect on pulmonary vascular bed Dihydropyridines Angina Preferential arterial vasodilation → afterload reduction Amlodipine Hypertension First choice for vasospastic angina (dihydropyridines) Felodipine Rate control in atrial fibrillation (verapamil, Second choice for preventing exertional angina Lercanidipine diltiazem) Immediaterelease nifedipine and shortacting C a2 + Channel Blockers Nifedipine dihydropyridines can cause tachycardia and hypotension and Nitrendipine trigger angina Others Diltiazem and verapamil can ↓ heart rate and AV conduction; Diltiazem should not be used with β blockers Verapamil CYP3A4mediated drug interactions with verapamil and diltiazem Other unwanted effects: peripheral edema (dihydropyridines), obstipation (verapamil) Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Chapter 27: Treatment of Ischemic Heart Disease, Thomas Eschenhagen BlockersHill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility ©2024βMcGraw Atenolol Angina First choice for prevention of exertional angina Page 25 / 31 Others Diltiazem and verapamil can ↓ heart rate and AV conduction; Diltiazem should not be used with β blockers Verapamil CYP3A4mediated drug interactions with verapamil and diltiazem Access Provided by: Other unwanted effects: peripheral edema (dihydropyridines), obstipation (verapamil) β Blockers Atenolol Angina First choice for prevention of exertional angina Bisoprolol Heart failure Only antianginal drug class with proven prognostic benefits in Carvedilol Hypertension CAD Metoprolol Widely used for other indications Adverse effects: bradycardia, AV block, bronchospasm, Nadolol (prevention of arrhythmias, rate control in peripheral vasoconstriction, worsening of acute heart failure, Nebivolol atrial fibrillation, migraine, etc.) depression, worsening of psoriasis Many others Polymorphic CYP2D6 metabolism (metoprolol) Additional vasodilation (carvedilol, nebivolol) Ranolazine Angina Inhibits late Na+ and other cardiac ion currents Has weak β blocking and metabolic effects Second choice in the prevention of exertional angina CYP3A4dependent metabolism Ivabradine Angina Selectively ↓ heart rate by inhibiting HCN currents in SA node Heart failure Second choice in the prevention of exertional angina; approved in patients not tolerating β blockers or having heart rate > 75 under β blockers Unwanted effects: bradycardia, QT prolongation, atrial fibrillation, phosphenes Contraindication: combination with diltiazem or verapamil Nicorandil Angina Dual nitratelike and IKATPstimulatory action Hemodynamic profile between nitrates and dihydropyridines; ↓ afterload more than nitrates Second choice in the prevention of exertional angina Adverse effects: hypotension, headache, buccal and GI ulcers Do not combine with PDE5 inhibitor Trimetazidine Angina Metabolic shift from fatty acid to glycolytic metabolism in the heart Second choice in the prevention of exertional angina May increase the incidence of Parkinson disease Antiplatelet, Antiintegrin, and Antithrombotic Drugs Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Aspirin of thrombotic events (MI, ↓ Platelet aggregation by inhibiting COX1–mediated TxA 2 Page 26 / 31 Chapter 27: Treatment of Ischemic Heart Prevention Disease, Thomas Eschenhagen ©2024P2Y McGraw Hill.antagonists All Rights Reserved. stroke) Terms of Use Privacy Policy Notice Accessibility 12 receptor production (aspirin) or ADP receptors (P2Y12 receptor (clopidogrel, prasugrel, Acute coronary syndromes ticagrelor cangrelor [IV]) Prevention of stent thrombosis antagonists) heart Second choice in the prevention of exertional angina May increase the incidence of Parkinson disease Access Provided by: Antiplatelet, Antiintegrin, and Antithrombotic Drugs Aspirin Prevention of thrombotic events (MI, ↓ Platelet aggregation by inhibiting COX1–mediated TxA2 P2Y12 receptor antagonists stroke) production (aspirin) or ADP receptors (P2Y12 receptor (clopidogrel, prasugrel, Acute coronary syndromes ticagrelor cangrelor [IV]) Prevention of stent thrombosis antagonists) Oral use only: clopidogrel, prasugrel, ticagrelor Irreversible action: aspirin, clopidogrel, prasugrel Prodrugs: clopidogrel, prasugrel Variable, CYP2C9dependent metabolism (clopidogrel) Withdraw 5–7 days before surgery First choice in NSTEMI and STEMI Dual platelet inhibition after stenting Abciximab Percutaneous coronary interventions Antibody (abciximab) or small molecule antagonists at Eptifibatide platelet GpIIb/IIIa receptor Tirofiban Parenteral use only Highly efficient platelet inhibition Therapeutic value in the era of highly effective dual platelet inhibition unclear Heparin Acute coronary syndromes Endogenous polysaccharide, inhibits thrombin (factor IIa) and Lowmolecularweight Percutaneous coronary interventions factor Xa in an antithrombin III–dependent manner heparins (e.g., enoxaparine) Parenteral use only Heparin: short t1/2, complex pharmacokinetics, low bioavailability after subcutaneous. injection Lowmolecularweight heparin: longer halflife, renal excretion; accumulation in renal insufficiency Heparininduced thrombocytopenia Fondaparinux Acute coronary syndromes Synthetic pentasaccharide, antithrombin IIIdependent, factor Percutaneous coronary interventions Xa inhibitor Most favorable efficacysafety ratio Bivalirudin Percutaneous coronary interventions Direct thrombin (factor IIa) inhibitors Lepirudin (bivalirudin) Parenteral use only Heparininduced thrombocytopenia (HIT Advantage of bivalirudin over heparin unclear II) recombinant lepirudin BIBLIOGRAPHY Amsterdam EA, et al. 2014 AHA/ACC guideline for the management of patients with nonSTelevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol , 2014, 64 :e139–e228. [PubMed: 25260718] Angus JA, et al. Quantitative analysis of vascular to cardiac selectivity of L and Ttype voltageoperated calcium channel antagonists in human tissues. Clin Exp Pharmacol Physiol , 2000, 27 :1019–1021. [PubMed: 11117223] Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Page 27 / 31 Chapter TreatmentB.ofMitochondrial Ischemic Heart Disease, Thomas Ardehali 27: H, O’Rourke K(ATP) channels in cellEschenhagen survival and death. J Mol Cell Cardiol , 2005, 39 :7–16. [PubMed: 15978901] ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Bainbridge AD, et al. A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices. Eur J Clin Amsterdam EA, et al. 2014 AHA/ACC guideline for the management of patients with nonSTelevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol , 2014, 64 :e139–e228. [PubMed: 25260718] Access Provided by: Angus JA, et al. Quantitative analysis of vascular to cardiac selectivity of L and Ttype voltageoperated calcium channel antagonists in human tissues. Clin Exp Pharmacol Physiol , 2000, 27 :1019–1021. [PubMed: 11117223] Ardehali H, O’Rourke B. Mitochondrial K(ATP) channels in cell survival and death. J Mol Cell Cardiol , 2005, 39 :7–16. [PubMed: 15978901] Bainbridge AD, et al. A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices. Eur J Clin Pharmacol , 1993, 45 :425–430. [PubMed: 8112371] Bangalore S, et al. Clinical outcomes with betablockers for myocardial infarction: a metaanalysis of randomized trials. Am J Med , 2014, 127 :939– 953. [PubMed: 24927909] Barbato E, et al. Longterm effect of molsidomine, a direct nitric oxide donor, as an addon treatment, on endothelial dysfunction in patients with stable angina pectoris undergoing percutaneous coronary intervention: results of the MEDCOR trial. Atherosclerosis , 2015, 240 :351–354. [PubMed: 25875387] Bedenis R, et al. Cilostazol for intermittent claudication. Cochrane Database Syst Rev , 2014, (10):CD003748. Belardinelli L, et al. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart , 2006, 92 :iv6–iv14. [PubMed: 16775092] Bhatt DL, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med , 2006, 354 :1706–1717. [PubMed: 16531616] Billinger M, et al. Collateral and collateraladjacent hyperemic vascular resistance changes and the ipsilateral coronary flow reserve. Documentation of a mechanism causing coronary steal in patients with coronary artery disease. Cardiovasc Res , 2001, 49 :600–608. [PubMed: 11166273] Bloch KD, et al. Inhaled NO as a therapeutic agent. Cardiovasc Res , 2007, 75 :339–348. [PubMed: 17544387] Bodi V, et al. Prognostic value of dipyridamole stress cardiovascular magnetic resonance imaging in patients with known or suspected coronary artery disease. J Am Coll Cardiol , 2007, 50 :1174–1179. [PubMed: 17868810] Boulinguez S, et al. Giant buccal aphthosis caused by nicorandil [in French]. Presse Med , 1997, 26 :558. [PubMed: 9161430] Brown BG, et al. The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation , 1981, 64 :1089–1097. [PubMed: 6794931] Burnett AL, et al. Nitric oxide: a physiologic mediator of penile erection. Science , 1992, 257 :401–403. [PubMed: 1378650] Cannon CP, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised doubleblind study. Lancet , 2010, 375 :283–293. [PubMed: 20079528] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet , 1996, 348 :1329–1339. [PubMed: 8918275] Cheitlin MD, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol , 1999, 33 :273–282. [PubMed: 9935041] Chen Z, et al. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A , 2002, 99 :8306–8311. [PubMed: 12048254] Debbas NM, et al. The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers. Br J Clin Pharmacol , 1986, 21 :385–388. [PubMed: 3707812] Dudzinski DM, et al. The6:10 regulation and of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol , 2006, 46 :235–276. [PubMed: Downloaded 2024417 A Your IPpharmacology is 81.198.192.190 Page 28 / 31 Chapter 27: Treatment of Ischemic Heart Disease, Thomas Eschenhagen 16402905] ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Epstein BJ, Roberts ME. Managing peripheral edema in patients with arterial hypertension. Am J Ther, 2009, 16:543–553. Chen Z, et al. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A , 2002, 99 :8306–8311. [PubMed: 12048254] Debbas NM, et al. The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers. Br J Clin Pharmacol , 1986, Access Provided by: 21 :385–388. [PubMed: 3707812] Dudzinski DM, et al. The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol , 2006, 46 :235–276. [PubMed: 16402905] Epstein BJ, Roberts ME. Managing peripheral edema in patients with arterial hypertension. Am J Ther, 2009, 16:543–553. Fihn SD, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation , 2012, 126 :e354–e471. [PubMed: 23166211] Fleckenstein A, et al. Selective inhibition of myocardial contractility by competitive divalent Ca++ antagonists (iproveratril, D 600, prenylamine) [in German]. Naunyn Schmiedebergs Arch Pharmakol , 1969, 264 :227–228. [PubMed: 4242380] Fox K, et al. Ivabradine in stable coronary artery disease. N Engl J Med , 2014, 371 :2435. [PubMed: 25517716] Godfraind T, et al. Calcium antagonism and calcium entry blockade. Pharmacol Rev , 1986, 38 :321–416. [PubMed: 2432624] Godfraind T, et al. Selectivity scale of calcium antagonists in the human cardiovascular system based on in vitro studies. J Cardiovasc Pharmacol , 1992, 20 (suppl 5):S34–S41. [PubMed: 1282611] Hamm CW, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation: the Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients Presenting Without Persistent STSegment Elevation of the European Society of Cardiology (ESC). Eur Heart J , 2011, 32 :2999–3054. [PubMed: 21873419] Hasenfuss G, Maier LS. Mechanism of action of the new antiischemia drug ranolazine. Clin Res Cardiol , 2008, 97 :222–226. [PubMed: 18046526] Herrmann HC, et al. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med , 2000, 342 :1622–1626. [PubMed: 10833207] Hirsch AT, et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report. Circulation , 2006, 113 :e463–e654. [PubMed: 16549646] Ho CY, et al. Diltiazem treatment for preclinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail , 2015, 3 :180–188. [PubMed: 25543971] Kappetein AP, et al. Comparison of coronary bypass surgery with drugeluting stenting for the treatment of left main and/or threevessel disease: 3 year followup of the SYNTAX trial. Eur Heart J , 2011, 32 :2125–2134. [PubMed: 21697170] Kojda G, et al. Positive inotropic effect of exogenous and endogenous NO in hypertrophic rat hearts. Br J Pharmacol , 1997, 122 :813–820. [PubMed: 9384495] Lee CC, et al. Use of nicorandil is associated with increased risk for gastrointestinal ulceration and perforation—a nationally representative populationbased study. Sci Rep , 2015, 5 :11495. Letienne R, et al. Evidence that ranolazine behaves as a weak beta1 and beta2adrenoceptor antagonist in the rat [correction of cat] cardiovascular system. Naunyn Schmiedeberg’s Arch Pharmacol , 2001, 363 :464–471. Libby P, Pasterkamp G. Requiem for the “vulnerable plaque.” Eur Heart J , 2015, 36 :2984–2987. [PubMed: 26206212] Libby P, et al. Inflammation and atherosclerosis. Circulation , 2002, 105 :1135–1143. [PubMed: 11877368] Magnon M, et al. Intervessel (arteries and veins) and heart/vessel selectivities of therapeutically used calcium entry blockers: variable, vessel dependent indexes. J Pharmacol Exp Ther , 1995, 275 :1157–1166. [PubMed: 8531077] Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Matsubara T, et al. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. Page 29 / 31 Chapter 27: Treatment of Ischemic Heart Disease, Thomas Eschenhagen J Am Coll CardiolHill. , 2000, 35 :345–351. [PubMed: 10676679] ©2024 McGraw All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Mayer B, Beretta M. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Br J Pharmacol , 2008, 155 :170–184. Libby P, et al. Inflammation and atherosclerosis. Circulation , 2002, 105 :1135–1143. [PubMed: 11877368] Access Provided by: Magnon M, et al. Intervessel (arteries and veins) and heart/vessel selectivities of therapeutically used calcium entry blockers: variable, vessel dependent indexes. J Pharmacol Exp Ther , 1995, 275 :1157–1166. [PubMed: 8531077] Matsubara T, et al. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. J Am Coll Cardiol , 2000, 35 :345–351. [PubMed: 10676679] Mayer B, Beretta M. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Br J Pharmacol , 2008, 155 :170–184. [PubMed: 18574453] McCormack JG, et al. Ranolazine: a novel metabolic modulator for the treatment of angina. Gen Pharmacol , 1998, 30 :639–645. [PubMed: 9559312] Meany TB, et al. Exercise capacity after single and twicedaily doses of nicorandil in chronic stable angina pectoris. Am J Cardiol , 1989, 63 :66J–70J. [PubMed: 2525329] Montalescot G, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J , 2013, 34 :2949–3003. [PubMed: 23996286] Mozaffarian D, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation , 2015, 131 :e29–e322. [PubMed: 25520374] Munzel T, et al. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross tolerance. J Clin Invest , 1995, 95 :187–194. [PubMed: 7814613] Munzel T, et al. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascul Pharmacol , 2014, 63 :105–113. [PubMed: 25446162] Parker JD. Nitrate tolerance, oxidative stress, and mitochondrial function: another worrisome chapter on the effects of organic nitrates. J Clin Invest , 2004, 113 :352–354. [PubMed: 14755331] Parker JD, et al. Intermittent transdermal nitroglycerin therapy. Decreased anginal threshold during the nitratefree interval. Circulation , 1995, 91 :973–978. [PubMed: 7850984] Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med , 1998, 338 :520–531. [PubMed: 9468470] Rajaratnam R, et al. Attenuation of antiischemic efficacy during chronic therapy with nicorandil in patients with stable angina pectoris. Am J Cardiol , 1999, 83 :1120–1124, A1129. [PubMed: 10190531] Redfield MM, et al. Effect of phosphodiesterase5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA , 2013, 309 :1268–1277. [PubMed: 23478662] Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med, 2002, 112:49–57. Roffi M, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent STSegment Elevation of the European Society of Cardiology (ESC). Eur Heart J , 2016, 37 :267–315. [PubMed: 26320110] Rooke TW, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol , 2011, 58 :2020–2045. [PubMed: 21963765] Salhiyyah K, et al. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev , 2015, (9):CD005262. Sato T, et al. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATPdependent potassium channels. J Am Coll Cardiol , 2000, 35 :514–518. [PubMed: 10676702] Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Page 30 / 31 Sayed N,27: et Treatment al. Nitroglycerininduced Snitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ Res , 2008, Chapter of Ischemic Heart Disease, Thomas Eschenhagen ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility 103 :606–614. [PubMed: 18669924] Schwartz A. Molecular and cellular aspects of calcium channel antagonism. Am J Cardiol , 1992, 70 :6F–8F. [PubMed: 1332464] Salhiyyah K, et al. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev , 2015, (9):CD005262. Access Provided by: Sato T, et al. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATPdependent potassium channels. J Am Coll Cardiol , 2000, 35 :514–518. [PubMed: 10676702] Sayed N, et al. Nitroglycerininduced Snitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ Res , 2008, 103 :606–614. [PubMed: 18669924] Schwartz A. Molecular and cellular aspects of calcium channel antagonism. Am J Cardiol , 1992, 70 :6F–8F. [PubMed: 1332464] Soma J, et al. Sublingual nitroglycerin delays arterial wave reflections despite increased aortic “stiffness” in patients with hypertension: a Doppler echocardiography study. J Am Soc Echocardiogr , 2000, 13 :1100–1108. [PubMed: 11119278] Stamler JS. Nitroglycerinmediated Snitrosylation of proteins: a field comes full cycle. Circ Res , 2008, 103 :557–559. [PubMed: 18796638] Steinberg SF, Brunton LL. Compartmentation of G proteincoupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol , 2001, 41 :751–773. [PubMed: 11264475] Sydow K, et al. Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and crosstolerance. J Clin Invest , 2004, 113 :482–489. [PubMed: 14755345] Tsien RW, et al. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci , 1988, 11 :431–438. [PubMed: 2469160] Tuunanen H, et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation , 2008, 118 :1250–1258. [PubMed: 18765391] Ussher JR, et al. Treatment with the 3ketoacylCoA thiolase inhibitor trimetazidine does not exacerbate wholebody insulin resistance in obese mice. J Pharmacol Exp Ther , 2014, 349 :487–496. [PubMed: 24700885] Valgimigli M, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med , 2015, 373 :997–1009. [PubMed: 26324049] van Harten J, et al. Negligible sublingual absorption of nifedipine. Lancet , 1987, 2 :1363–1365. [PubMed: 2890954] Walsh RA, O’Rourke RA. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest , 1985, 75 :1426–1434. [PubMed: 2860122] Weisz G, et al. Ranolazine in Patients With Incomplete Revascularisation After Percutaneous Coronary Intervention (RIVERPCI): a multicentre, randomised, doubleblind, placebocontrolled trial. Lancet , 2016, 387 :136–145. [PubMed: 26474810] Wiviott SD, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med , 2007, 357 :2001–2015. [PubMed: 17982182] Yeghiazarians Y, et al. Unstable angina pectoris. N Engl J Med , 2000, 342 :101–114. [PubMed: 10631280] Yusuf S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med , 2001, 345 :494–502. [PubMed: 11519503] Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Chapter 27: Treatment of Ischemic Heart Disease, Thomas Eschenhagen ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 31 / 31 Access Provided by: Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Chapter 28: Treatment of Hypertension Thomas Eschenhagen ABBREVIATIONS Abbreviations ACE: angiotensinconverting enzyme ACEI: angiotensinconverting enzyme inhibitor Aldo: aldosterone AngII: angiotensin II ANP: atrial natriuretic peptide ARB: angiotensin receptor blocker A T1 : type 1 receptor for angiotensin II ATPase: adenosine triphosphatase AV: atrioventricular BB: β blocker β blocker: β adrenergic receptor antagonist BNP: brain natriuretic peptide BP: blood pressure CAD: coronary artery disease CCB: Ca2+ channel blocker CNS: central nervous system COX2: cyclooxygenase 2 DOPA: 3,4dihydroxyphenylalanine DRI: direct renin inhibitor ENaC: epithelial Na+ channel ESC: European Society of Cardiology GI: gastrointestinal Downloaded 2024417 6:10 A Your IP is 81.198.192.190 GFR: glomerular filtration rate Chapter 28: Treatment of Hypertension, Thomas Eschenhagen ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility HDL: highdensity lipoprotein Page 1 / 36 DRI: direct renin inhibitor ENaC: epithelial Na+ channel Access Provided by: ESC: European Society of Cardiology GI: gastrointestinal GFR: glomerular filtration rate HDL: highdensity lipoprotein HF: heart failure HTN: hypertension ISA: intrinsic sympathomimetic activity ISDN: isosorbide dinitrate JNC8: Eighth Joint National Committee MI: myocardial infarction MRA: mineralocorticoid receptor antagonist NCC: NaCl cotransporter NE: norepinephrine NO: nitric oxide NSAID: nonsteroidal antiinflammatory drug RAAS: reninangiotensinaldosterone system RAS: reninangiotensin system S A : sinoatrial SNS: sympathetic nervous system VMAT2: vesicular catecholamine transporter 2 EPIDEMIOLOGY AND TREATMENT ALGORITHMS Hypertension is the most common cardiovascular disease. Elevated arterial pressure causes hypertrophy of the left ventricle and pathological changes in the vasculature. As a consequence, hypertension is the principal cause of stroke; a major risk factor for CAD and its attendant complications, MI and sudden cardiac death; and a major contributor to heart failure, renal insufficiency, and dissecting aneurysm of the aorta. The prevalence of hypertension increases with age; for example, about 50% of people between the ages of 60 and 69 years old have hypertension, and the prevalence further increases beyond age 70. According to a recent survey in the U.S., 81.5% of those with hypertension are aware they have it, 74.9% are being treated, yet only 52.5% are considered controlled (Go et al., 2014). The success of hypertension treatment programs, such as one organized in a large integrated healthcare delivery system in the U.S. (Jaffe et al., 2013), show that these figures can be substantially improved by electronic hypertension registries tracking hypertension control rates, regular feedback to providers, development and frequent updating of an evidencebased treatment guideline, promotion of singlepill combination therapies, and followup blood pressure checks. Between 2001 and 2009, this program increased the number of patients with a diagnosis of hypertension by 78%, as well as the proportion of subjects meeting target blood pressure goals from 44% to more than 84% (Jaffe et al., 2013). Hypertension is defined as a sustained increase in blood pressure of 140/90 mmHg or higher, a criterion that characterizes a group of patients whose risk of hypertensionrelated cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mmHg and diastolic blood pressures less than 80 mmHg; these Downloaded 6:10asAsystolic Your IP is diastolic 81.198.192.190 risks increase 2024417 incrementally and blood pressures rise. Recognition of this continuously increasing risk prevents a simple definition Page 2 / 36 Chapter 28: Treatment of Hypertension, Thomas Eschenhagen of hypertension (Go et al., 2014) (Table 28–1). Although many of the clinical trials classified the severity of hypertension by diastolic pressure, ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic blood pressure. Indeed, in patients more than 50 years old, systolic blood pressures predict adverse outcomes number of patients with a diagnosis of hypertension by 78%, as well as the proportion of subjects meeting target blood pressure goals from 44% to more than 84% (Jaffe et al., 2013). Access Provided by: Hypertension is defined as a sustained increase in blood pressure of 140/90 mmHg or higher, a criterion that characterizes a group of patients whose risk of hypertensionrelated cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mmHg and diastolic blood pressures less than 80 mmHg; these risks increase incrementally as systolic and diastolic blood pressures rise. Recognition of this continuously increasing risk prevents a simple definition of hypertension (Go et al., 2014) (Table 28–1). Although many of the clinical trials classified the severity of hypertension by diastolic pressure, progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic blood pressure. Indeed, in patients more than 50 years old, systolic blood pressures predict adverse outcomes better than do diastolic pressures. Pulse pressure, defined as the difference between systolic and diastolic pressure, may add additional predictive value (PastorBarriuso et al., 2003). This may be at least in part due to higherthannormal pulse pressure indicating adverse remodeling of blood vessels, representing an accelerated decrease in blood vessel compliance normally associated with aging and atherosclerosis. Isolated systolic hypertension (sometimes defined as systolic blood pressure greater than 140–160 mmHg with diastolic blood pressure less than 90 mmHg) is largely confined to people older than 60 years. Table 28–1 American Heart Association Criteria for Hypertension in Adults BLOOD PRESSURE (mmHg) CLASSIFICATION SYSTOLIC DIASTOLIC Normal 180 or > 110 The presence of pathological changes in certain target organs heralds a worse prognosis than the same level of blood pressure in a patient lacking these findings. For instance, retinal hemorrhages, exudates, and papilledema in the eyes indicate a far worse shortterm prognosis for a given level of blood pressure. Left ventricular hypertrophy defined by electrocardiogram, or more sensitively by echocardiography or cardiac magnetic resonance imaging, is associated with a substantially worse longterm outcome that includes a higher risk of sudden cardiac death. The risk of cardiovascular disease, disability, and death in hypertensive patients also is increased markedly by concomitant cigarette smoking, diabetes, or elevated LDL; the coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. The purpose of treating hypertension is to decrease cardiovascular risk; thus, other dietary and pharmacological interventions may be required to treat these additional risk factors. Effective pharmacological treatment of patients with hypertension decreases morbidity and mortality from cardiovascular disease, reducing the risk of strokes, heart failure, and CAD (Rosendorff et al., 2015). The reduction in risk of MI may be less significant. Principles of Antihypertensive Therapy Nonpharmacological therapy, or lifestylerelated changes, is an important component of treatment of all patients with hypertension (James et al., 2014; Mancia et al., 2013). In some grade 1 hypertensives (Figure 28–1), blood pressure may be adequately controlled by a combination of weight loss (in overweight individuals), restricting sodium intake (to 5–6 g/d), increasing aerobic exercise (>30 min/d), moderating consumption of alcohol (ethanol/day ≤ 20–30 g in men [two drinks], ≤ 10–20 g in women [one drink]), smoking cessation, increased consumption of fruits, vegetables, and low fat dairy products. Figure 28–1 Treatment algorithm for adults with hypertension. Algorithm is based on recommendations of the American Heart Association and the American Downloaded 2024417 6:10 A Your IP is 81.198.192.190 College Cardiology (Go al., 2013). Thomas Eschenhagen Page 3 / 36 Chapterof28: Treatment ofet Hypertension, ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility (ethanol/day ≤ 20–30 g in men [two drinks], ≤ 10–20 g in women [one drink]), smoking cessation, increased consumption of fruits, vegetables, and low fat dairy products. Figure 28–1 Access Provided by: Treatment algorithm for adults with hypertension. Algorithm is based on recommendations of the American Heart Association and the American College of Cardiology (Go et al., 2013). The majority of patients require drug therapy for adequate blood pressure control (Figure 28–1). Optimal blood pressure goals for drug therapy are still debated, and current guidelines from cardiovascular societies differ slightly (James et al., 2014). Recently, a large comparative study in nondiabetics with increased cardiovascular risk was prematurely stopped because the group of patients treated with antihypertensives to a systolic blood pressure target of 120 mmHg, with an average of 2.8 drugs, experienced a 25% lower rate of cardiovascular end points and total mortality than the group targeted to the current standard goal target of 140 mmHg(SPRINT Research Group, 2015). The rate of adverse effects such as hypotension and worsening of renal function were higher in the intensified treatment group, yet this did not translate to a signal for real harm. The data will likely lead to a reexamination of current guidelinerecommended blood pressure targets. Arterial pressure is the product of cardiac output and peripheral vascular resistance (Figure 28–2). Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both. Drugs may decrease the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can decrease peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels (e.g., the sympathetic nervous system, the RAS). In patients with isolated systolic hypertension, complex hemodynamics in a rigid arterial system contribute to increased blood pressure; drug effects may be mediated not only by changes in peripheral resistance but also via effects on large artery stiffness (Franklin, 2000). Figure 28–2 Principles of blood pressure regulation and its modification by drugs. Cardiac output and peripheral arteriolar resistance, the major determinants of arterial blood pressure, are regulated by myriad mechanisms, including the SNS (main peripheral neurotransmitter NE), the balance between salt intake by the intestine (GI) andAsalt excretion by the kidneys, the RAAS (main agonists AngII and Aldo), and natriuretic peptides produced in the heart Downloaded 2024417 6:10 Your IP is 81.198.192.190 Page 4Note / 36 Chapter Treatment Hypertension, Thomas Eschenhagen (ANP and28: BNP). Sensorsof (green circles) provide afferent input on pressure in the heart and great vessels and on salt concentrations in the kidney. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility positive feedback between the SNS and RAAS via β1stimulated renin release and AngIIstimulated NE release. Drug classes are indicated in boldface type at their main site of action. Arrows indicate blood pressureincreasing (red) and decreasing (green) effects. Neprilysin inhibitors (e.g., sacubitril) Figure 28–2 Access Provided by: Principles of blood pressure regulation and its modification by drugs. Cardiac output and peripheral arteriolar resistance, the major determinants of arterial blood pressure, are regulated by myriad mechanisms, including the SNS (main peripheral neurotransmitter NE), the balance between salt intake by the intestine (GI) and salt excretion by the kidneys, the RAAS (main agonists AngII and Aldo), and natriuretic peptides produced in the heart (ANP and BNP). Sensors (green circles) provide afferent input on pressure in the heart and great vessels and on salt concentrations in the kidney. Note positive feedback between the SNS and RAAS via β1stimulated renin release and AngIIstimulated NE release. Drug classes are indicated in boldface type at their main site of action. Arrows indicate blood pressureincreasing (red) and decreasing (green) effects. Neprilysin inhibitors (e.g., sacubitril) are in clinical testing for hypertension and have been approved for the treatment of heart failure (in combination with an ARB). Antihypertensive drugs can be classified according to their sites or mechanisms of action (Table 28–2, Figure 28–2). The hemodynamic consequences of longterm treatment with antihypertensive agents (Table 28–3) provide a rationale for potential complementary effects of concurrent therapy with two or more drugs. Concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose related adverse effects. Table 28–2 Classes of Antihypertensive Drugs Diuretics (Chapter 25) Thiazides and related agents: chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide Loop diuretics: bumetanide, furosemide, torsemide K+sparing diuretics: amiloride, triamterene, MRA spironolactone Sympatholytic drugs (Chapter 12) β Blockers: atenolol, bisoprolol, esmolol, metoprolol, nadolol, nebivolol, propranolol, timolol α Blockers: prazosin, terazosin, doxazosin, phenoxybenzamine Mixed α/β blockers: labetalol, carvedilol Centrally acting sympatholytic agents: clonidine, guanabenz, guanfacine, methyldopa, moxonidine, reserpine C a2 + channel blockers (Chapter 27): amlodipine, clevidipine, diltiazem, felodipine, isradipine, lercanidipine, nicardipine, nifedipine,a nisoldipine, verapamil Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Reninangiotensin antagonists (Chapter 26) Page 5 / 36 Chapter 28: Treatment of Hypertension, Thomas Eschenhagen Angiotensinconverting enzyme inhibitors : benazepril, captopril, enalapril, moexipril, perindopril, quinapril, ramipril, trandolapril ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policyfosinopril, Notice lisinopril, Accessibility AngII receptor blockers: candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan Direct renin inhibitor: aliskiren Antihypertensive drugs can be classified according to their sites or mechanisms of action (Table 28–2, Figure 28–2). The hemodynamic consequences of longterm treatment with antihypertensive agents (Table 28–3) provide a rationale for potential complementary effects of concurrent therapy with two or more drugs. Concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose Access Provided by: related adverse effects. Table 28–2 Classes of Antihypertensive Drugs Diuretics (Chapter 25) Thiazides and related agents: chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide Loop diuretics: bumetanide, furosemide, torsemide K+sparing diuretics: amiloride, triamterene, MRA spironolactone Sympatholytic drugs (Chapter 12) β Blockers: atenolol, bisoprolol, esmolol, metoprolol, nadolol, nebivolol, propranolol, timolol α Blockers: prazosin, terazosin, doxazosin, phenoxybenzamine Mixed α/β blockers: labetalol, carvedilol Centrally acting sympatholytic agents: clonidine, guanabenz, guanfacine, methyldopa, moxonidine, reserpine C a2 + channel blockers (Chapter 27): amlodipine, clevidipine, diltiazem, felodipine, isradipine, lercanidipine, nicardipine, nifedipine,a nisoldipine, verapamil Reninangiotensin antagonists (Chapter 26) Angiotensinconverting enzyme inhibitors: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril AngII receptor blockers: candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan Direct renin inhibitor: aliskiren Vasodilators (Chapters 27 a n d 2 8) Arterial: diazoxide, fenoldopam, hydralazine, minoxidil Arterial and venous: nitroprusside a Only extendedrelease nifedipine is approved for hypertension. Table 28–3 Hemodynamic Effects of LongTerm Administration of Antihypertensive Agents HEART CARDIAC TOTAL PERIPHERAL PLASMA PLASMA RENIN RATE OUTPUT RESISTANCE VOLUME ACTIVITY ↔ ↔ ↓ –↓ ↑ Centrally acting –↓ –↓ ↓ –↑ –↓ α1 Blockers –↑ –↑ ↓ –↑ ↔ No ISA ↓ ↓ –↓ –↑ ↓ ISAa ↓↑ ↔ ↓ –↑ –↓ ↑ ↑ –↑ –↑ Diuretics Sympatholytic agents β Blockers Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Chapter 28: Treatment of Hypertension, Thomas Arteriolar ↑ ↑ Eschenhagen ↓ ©2024vasodilators McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility 2+ ↓ or ↑ ↓ or ↑ ↓ Page 6 / 36 Arterial and venous: nitroprusside a Access Provided by: Only extendedrelease nifedipine is approved for hypertension. Table 28–3 Hemodynamic Effects of LongTerm Administration of Antihypertensive Agents HEART CARDIAC TOTAL PERIPHERAL PLASMA PLASMA RENIN RATE OUTPUT RESISTANCE VOLUME ACTIVITY ↔ ↔ ↓ –↓ ↑ Centrally acting –↓ –↓ ↓ –↑ –↓ α1 Blockers –↑ –↑ ↓ –↑ ↔ No ISA ↓ ↓ –↓ –↑ ↓ ISAa ↓↑ ↔ ↓ –↑ –↓ ↑ ↑ ↓ ↑ ↑ ↓ or ↑ ↓ or ↑ ↓ –↑ –↑ ACEIs ↔ ↔ ↓ ↔ ↑ A T1 receptor ↔ ↔ ↓ ↔ ↑ ↔ ↔ ↓ ↔ ↓ (but renin ↑) Diuretics Sympatholytic agents β Blockers Arteriolar vasodilators C a2 + channel blockers blockers Renin inhibitor ↑, increased; ↓, decreased; –↑, increased or no change; –↓, decreased or no change; ↔, unchanged. a Heart rate can be increased at rest and decreased under exercise as a result of ISA. During rest, ISA may increase resting heart rate; during exercise, β adrenergic antagonism predominates, attenuating heart rate acceleration by NE. It generally is not possible to predict the responses of individuals with hypertension to any specific drug. For example, for some antihypertensive drugs, about twothirds of patients will have a meaningful clinical response, whereas about onethird of patients will not respond to the same drug. Racial origin and age may have modest influence on the likelihood of a favorable response to a particular class of drugs. Polymorphisms in genes involved in the metabolism of antihypertensive drugs have been identified in the CYPs (phase I metabolism) and in phase II metabolism, such as catecholOmethyltransferase (see Chapters 6 and 7). While these polymorphisms can change the pharmacokinetics of specific drugs quite markedly (e.g., five times higher plasma concentrations of metoprolol in CYP2D6 poor metabolizers), differences in efficacy are smaller (Rau et al., 2009) and of unknown clinical relevance. Polymorphisms that influence pharmacodynamic responses to antihypertensive drugs, including ACE inhibitors and diuretics, have also been identified, but evidence for clinically meaningful differences in drug response is sparse. Genomewide scanning has identified several genetic variants associated with hypertension, but the effect sizes are much smaller than that of clinically established risk factors such as overweight. Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Chapter 28: Treatment of Hypertension, Thomas Eschenhagen DIURETICS ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 7 / 36 An early strategy for the management of hypertension was to alter Na+ balance by restriction of salt in the diet. Pharmacological alteration of Na+ (e.g., five times higher plasma concentrations of metoprolol in CYP2D6 poor metabolizers), differences in efficacy are smaller (Rau et al., 2009) and of unknown clinical relevance. Polymorphisms that influence pharmacodynamic responses to antihypertensive drugs, including ACE inhibitors and diuretics, have also been identified, but evidence for clinically meaningful differences in drug response is sparse. Genomewide scanning has Access Provided by: identified several genetic variants associated with hypertension, but the effect sizes are much smaller than that of clinically established risk factors such as overweight. DIURETICS An early strategy for the management of hypertension was to alter Na+ balance by restriction of salt in the diet. Pharmacological alteration of Na+ balance became practical with the development of the orally active thiazide diuretics (see Chapter 25). These and related diuretic agents have antihypertensive effects when used alone, and they enhance the efficacy of virtually all other antihypertensive drugs. Thus, this class of drugs remains important in the treatment of hypertension. The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. The initial action of thiazide diuretics decreases extracellular volume by interacting with a thiazidesensitive NCC (SLC12A3) expressed in the distal convoluted tubule in the kidney, enhancing Na+ excretion in the urine, and leading to a decrease in cardiac output. However, the hypotensive effect is maintained during longterm therapy due to decreased vascular resistance; cardiac output returns to pretreatment values, and extracellular volume returns to almost normal due to compensatory responses such as activation of the RAS. The explanation for the longterm vasodilation induced by thiazide diuretics is unknown. Hydrochlorothiazide may open Ca2+ activated K+ channels, leading to hyperpolarization of vascular smooth muscle cells, which leads in turn to closing of Ltype Ca2+ channels and lower probability of opening, resulting in decreased Ca2+ entry and reduced vasoconstriction. Hydrochlorothiazide also inhibits vascular carbonic anhydrase, which, hypothetically, could alter smooth muscle cell systolic pH and thereby cause opening of Ca2+activated K+ channels with the consequences noted previously. The relevance of these findings—largely assessed in vitro—to the observed antihypertensive effects of thiazides is speculative. The major action of these drugs on SLC12A3—expressed predominantly in the distal convoluted tubules and not in vascular smooth muscle or the heart—suggests that these drugs decrease peripheral resistance as an indirect effect of negative Na+ balance. That thiazides lose efficacy in treating hypertension in patients with coexisting renal insufficiency is compatible with this hypothesis. Moreover, carriers of rare functional mutations in SLC12A3 that decrease renal Na+ reabsorption have lower blood pressure than appropriate controls (Ji et al., 2008); in a sense, this is an experiment of nature that may mimic the therapeutic effect of thiazides. Benzothiadiazines and Related Compounds Benzothiadiazines (“thiazides”) and related diuretics are the most frequently used class of antihypertensive agents in the U.S. Following the discovery of chlorothiazide, a number of oral diuretics were developed that have an arylsulfonamide structure and block the NCC. Some of these are not benzothiadiazines but have structural features and molecular functions that are similar to the original benzothiadiazine compounds; consequently, they are designated as members of the thiazide class of diuretics. For example, chlorthalidone (also written as chlortalidone), one of the nonbenzothiadiazines, is widely used in the treatment of hypertension, as is indapamide. Regimen for Administration of the ThiazideClass Diuretics in Hypertension Because members of the thiazide class have similar pharmacological effects, they generally have been viewed as interchangeable with appropriate adjustment of dosage (see Chapter 25). However, the pharmacokinetics and pharmacodynamics of these drugs differ, so they may not necessarily have the same clinical efficacy in treating hypertension. In a direct comparison, the antihypertensive efficacy of chlorthalidone was greater than that of hydrochlorothiazide, particularly during the night (Ernst et al., 2006), suggesting the much longer t1/2 of chlorthalidone (>24 h) compared to hydrochlorothiazide (several hours) gave more stable blood pressure reductions. In light of the considerable clinical trial data supporting the capacity of chlorthalidone to diminish adverse cardiovascular events—in comparison to that available for currently used low doses of hydrochlorothiazide— there is a growing concern that chlorthalidone may be an underutilized drug in hypertensive patients requiring a diuretic. Antihypertensive effects can be achieved in many patients with as little as 12.5 mg daily of chlorthalidone or hydrochlorothiazide. Furthermore, when used as monotherapy, the maximal daily dose of thiazideclass diuretics usually should not exceed 25 mg of hydrochlorothiazide or chlorthalidone (or equivalent). Even though more diuresis can be achieved with higher doses, some evidence suggests that doses higher than this are not generally more efficacious in lowering blood pressure in patients with normal renal function. Low doses of either thiazide reduce the risk of adverse effects such as K+ wasting and inhibition of uric acid excretion, indicating an improved risktobenefit ratio at low doses of a thiazide. However, other studies suggested that low doses of hydrochlorothiazide have inadequate effects on blood pressure when monitored in a detailed manner (Lacourciere et al., 1995). Downloaded 2024417 6:10 A Your IP in is 81.198.192.190 Clinical trials of antihypertensive therapy the elderly demonstrated the best outcomes for cardiovascular morbidity and mortality when 25 mg of Page 8 / 36 Chapter 28: Treatment of Hypertension, Thomas Eschenhagen hydrochlorothiazide or chlorthalidone was the maximum dose given; if this dose did not achieve the target blood pressure reduction, a second drug ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility was initiated (1991; Dahlof et al., 1991). A casecontrol study found a dosedependent increase in the occurrence of sudden death at doses of hydrochlorothiazide greater than 25 mg daily (Siscovick et al., 1994), supporting the hypothesis that higher diuretic doses are associated with used as monotherapy, the maximal daily dose of thiazideclass diuretics usually should not exceed 25 mg of hydrochlorothiazide or chlorthalidone (or equivalent). Even though more diuresis can be achieved with higher doses, some evidence suggests that doses higher than this are not generally more efficacious in lowering blood pressure in patients with normal renal function. Low doses of either thiazide reduce the risk of adverse effects such as K+ wasting and inhibition of uric acid excretion, indicating an improved risktobenefit ratio at low doses of a thiazide. However, otherby: studies suggested Access Provided that low doses of hydrochlorothiazide have inadequate effects on blood pressure when monitored in a detailed manner (Lacourciere et al., 1995). Clinical trials of antihypertensive therapy in the elderly demonstrated the best outcomes for cardiovascular morbidity and mortality when 25 mg of hydrochlorothiazide or chlorthalidone was the maximum dose given; if this dose did not achieve the target blood pressure reduction, a second drug was initiated (1991; Dahlof et al., 1991). A casecontrol study found a dosedependent increase in the occurrence of sudden death at doses of hydrochlorothiazide greater than 25 mg daily (Siscovick et al., 1994), supporting the hypothesis that higher diuretic doses are associated with increased cardiovascular mortality as long as hypokalemia is not corrected. Thus, if adequate blood pressure reduction is not achieved with the 25mg daily dose of hydrochlorothiazide or chlorthalidone, the addition of a second drug is indicated rather than an increase in the dose of diuretic. Urinary K+ loss can be a problem with thiazides. ACE inhibitors and ARBs will attenuate diureticinduced loss of K+ to some degree, and this is a consideration if a second drug is required to achieve further blood pressure reduction beyond that attained with the diuretic alone. Because the diuretic and hypotensive effects of these drugs are greatly enhanced when they are given in combination, care should be taken to initiate combination therapy with low doses of each of these drugs (Vlasses et al., 1983). Administration of ACE inhibitors or ARBs together with other K+sparing agents or with K+ supplements requires great caution; combining K+sparing agents with each other or with K+ supplementation can cause potentially dangerous hyperkalemia in some patients. In contrast to the limitation on the dose of thiazideclass diuretics used as monotherapy, the treatment of severe hypertension that is unresponsive to three or more drugs may require larger doses of the thiazideclass diuretics. Indeed, hypertensive patients may become refractory to drugs that block the sympathetic nervous system or to vasodilator drugs, because these drugs engender a state in which the blood pressure is very volume dependent. Therefore, it is appropriate to consider the use of thiazideclass diuretics in doses of 50 mg of daily hydrochlorothiazide equivalent when treatment with appropriate combinations and doses of three or more drugs fails to yield adequate control of the blood pressure. Alternatively, there may be a need to use highercapacity diuretics such as furosemide, especially if renal function is not normal. The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the glomerular filtration rate falls below 30 mL/min. One exception is metolazone, which retains efficacy in patients with this degree of renal insufficiency. Most patients will respond to thiazide diuretics with a reduction in blood pressure within about 4–6 weeks. Therefore, doses should not be increased more often than every 4–6 weeks. There is no way to predict the antihypertensive response from the duration or severity of the hypertension in a given patient, although diuretics are unlikely to be effective as sole therapy in patients with stage 2 hypertension (Table 28–1). Because the effect of thiazide diuretics is additive with that of other antihypertensive drugs, combination regimens that include these diuretics are common and rational. A wide range of fixeddose combination products containing a thiazide are marketed for this purpose. Diuretics also have the advantage of minimizing the retention of salt and water that is commonly caused by vasodilators and some sympatholytic drugs. Omitting or underutilizing a diuretic is a frequent cause of “resistant hypertension.” Adverse Effects and Precautions The adverse effects of diuretics are discussed in Chapter 25. Some of these determine whether a patient can tolerate and adhere to diuretic treatment. The K+ depletion produced by thiazideclass diuretics is dose dependent and variable among individuals, such that a subset of patients may become substantially K+ depleted on diuretic drugs. Given chronically, even small doses lead to some K+ depletion, which is a wellknown risk factor for ventricular arrhythmias by reducing cardiac repolarization reserve. The last has recently been used to explain that insults in a particular repolarization current do not necessarily result in QT interval prolongation, the principle clinical measure of repolarization (see Chapter 30). Hypokalemia directly reduces repolarization reserve by decreasing several K+ conductances (inward rectifier IK1, delayed rectifier IKr, and the transient outward current Ito) and increases the binding activity of IKrinhibiting drugs such as dofetilide (Yang and Roden, 1996). Hypokalemia also reduces the activity of the Na+,K+ ATPase (the Na+ pump), causing intracellular accumulation of Na+ and Ca2+, further increasing the risk of afterdepolarizations (Pezhouman et al., 2015). Consequently, hypokalemia increases the risk of druginduced polymorphic ventricular tachycardia (torsade de pointes; see Chapter 30) and the risk for ischemic ventricular fibrillation, the leading cause of sudden cardiac death and a major contributor to cardiovascular mortality in treated hypertensive patients. There is a positive correlation between diuretic dose and sudden cardiac death and an inverse correlation between the use of adjunctive K+sparing agents and sudden cardiac death (Siscovick et al., 1994). Thus, hypokalemia needs to be avoided by, for example, combining a thiazide with inhibitors of the RAS or with a K+sparing diuretic. Thiazides have residual carbonic anhydrase–inhibiting activity, thereby reducing Na+ reabsorption in the proximal tubule. The increased presentation Downloaded 2024417 6:10 A Your IP is 81.198.192.190 Page 9 / 36 of Na+ at 28: the Treatment macula densa leads to a reduced glomerular filtration rate via tubuloglomerular feedback. While this effect is clinically not meaningful in Chapter of Hypertension, Thomas Eschenhagen ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility patients with normal renal function, it reduces diuretic effectiveness and may gain importance in patients with reduced kidney function. RAS inhibitors and Ca2+ channel blockers interfere with tubuloglomerular feedback, providing one explanation for the synergistic effect on blood pressure. Erectile risk for ischemic ventricular fibrillation, the leading cause of sudden cardiac death and a major contributor to cardiovascular mortality in treated hypertensive patients. There is a positive correlation between diuretic dose and sudden cardiac death and an inverse correlation between the use of adjunctive K+sparing agents and sudden cardiac death (Siscovick et al., 1994). Thus, hypokalemia needs to be avoided by, for example, combining a Access Provided by: thiazide with inhibitors of the RAS or with a K+sparing diuretic. Thiazides have residual carbonic anhydrase–inhibiting activity, thereby reducing Na+ reabsorption in the proximal tubule. The increased presentation of Na+ at the macula densa leads to a reduced glomerular filtration rate via tubuloglomerular feedback. While this effect is clinically not meaningful in patients with normal renal function, it reduces diuretic effectiveness and may gain importance in patients with reduced kidney function. RAS inhibitors and Ca2+ channel blockers interfere with tubuloglomerular feedback, providing one explanation for the synergistic effect on blood pressure. Erectile dysfunction is a troublesome adverse effect of the thiazideclass diuretics, and physicians should inquire specifically regarding its occurrence in conjunction with treatment with these drugs. Gout may be a consequence of the hyperuricemia induced by these diuretics. The occurrence of either of these adverse effects is a reason for considering alternative approaches to therapy. However, precipitation of acute gout is relatively uncommon with low doses of diuretics. Hydrochlorothiazide may cause rapidly developing, severe hyponatremia in some patients. Thiazides inhibit renal Ca2+ excretion, occasionally leading to hypercalcemia; although generally mild, this can be more severe in patients subject to hypercalcemia, such as those with primary hyperparathyroidism. The thiazideinduced decreased Ca2+ excretion may be used therapeutically in patients with osteoporosis or hypercalciuria. Thiazide diuretics have also been associated with changes in plasma lipids and glucose tolerance that have led to some concern. The clinical significance of the changes has been disputed because the clinical studies demonstrated comparable efficacy of the thiazide diuretic chlortalidone in reducing cardiovascular risk (ALLHAT Officers, 2002). All thiazidelike drugs cross the placenta. While they have no direct adverse effects on the fetus, administration of a thiazide during pregnancy increases a risk of transient volume depletion that may result in placental hypoperfusion. Because the thiazides appear in breast milk, they should be avoided by nursing mothers. Other Diuretic Antihypertensive Agents The thiazide diuretics are more effective antihypertensive agents than are the loop diuretics, such as furosemide and bumetanide, in patients who have normal renal function. This differential effect is most likely related to the short duration of action of loop diuretics. In fact, a single daily dose of loop diuretics does not cause a significant net loss of Na+ for an entire 24h period because the strong initial diuretic effect is followed by a rebound mediated by activation of the RAS. Unfortunately, loop diuretics are frequently and inappropriately prescribed as a onceaday medication in the treatment not only of hypertension, but also of congestive heart failure and ascites. The high efficacy of loop diuretics 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 with a sloweracting, milder thiazide diuretic. Loop diuretics may be particularly useful in patients with azotemia or with severe edema associated with a vasodilator such as minoxidil. K + Sparing Diuretics Amiloride and triamterene are K+sparing diuretics that have little value as antihypertensive monotherapy but are important in combination with thiazides to antagonize urinary K+ loss and the concomitant risk of ventricular arrhythmias. They act by reversibly inhibiting the ENaC in the distal tubule membrane, the transporter responsible for the reabsorption of Na+ in exchange for K+. The importance of ENaC for hypertension is illustrated by the fact that an inherited form of hypertension, Liddle syndrome, is due to hyperactivity of ENaC. Gene expression of ENaC is mineralocorticoid sensitive, explaining the antihypertensive and K+sparing effect of another class of K+sparing diuretics, the MRAs spironolactone and eplerenone. In contrast to the immediate and shortterm inhibition of ENaC by amiloride and triamterene, the action of MRAs is delayed for about 3 days and is long lasting because MRAs regulate the density of the channel protein in the tubule membrane. The MRAs have a particular role in hypertension and heart failure (see Chapter 27) because small doses of spironolactone are often highly effective in patients with “resistant hypertension.” First described decades ago (Ramsay et al., 1980), the concept was recently validated in a prospective, placebo controlled trial comparing spironolactone (25–50 mg) with bisoprolol or doxazosin as addons in patients with uncontrolled hypertension despite triple standard antihypertensive therapy (Williams et al., 2015). Spironolactone had about a 2fold larger blood pressure–lowering effect (8.7 vs. 4.8 and 4 mmHg, respectively). The efficacy of the MRA spironolactone in resistant hypertension supports a primary role of Na+ retention in this condition. Some of the effect may be related to the socalled aldosteroneescape phenomenon, or a return to preRASinhibitor plasma aldosterone levels with extended time of treatment, observed under treatment with RAS inhibitors. Primary hyperaldosteronism occurs in a significant fraction of patients with resistant hypertension (Calhoun et al., 2002). Downloaded 2024417 A Youradverse IP is 81.198.192.190 Spironolactone has some6:10 significant effects, especially in men (e.g., erectile dysfunction, gynecomastia, benign prostatic hyperplasia). Page 10 / 36 Chapter 28: Treatment of Hypertension, Thomas Eschenhagen Eplerenone is a more specific, though lesspotent, MRA with reduced side effects. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility All K+sparing diuretics should be used cautiously, with frequent measurements of plasma K+ concentrations in patients predisposed to hyperkalemia. + triple standard antihypertensive therapy (Williams et al., 2015). Spironolactone had about a 2fold larger blood pressure–lowering effect (8.7 vs. 4.8 and 4 mmHg, respectively). The efficacy of the MRA spironolactone in resistant hypertension supports a primary role of Na+ retention in this condition. Some of the effect may be related to the socalled aldosteroneescape phenomenon, or a return to preRASinhibitor plasma aldosterone levels with Access Provided by: extended time of treatment, observed under treatment with RAS inhibitors. Primary hyperaldosteronism occurs in a significant fraction of patients with resistant hypertension (Calhoun et al., 2002). Spironolactone has some significant adverse effects, especially in men (e.g., erectile dysfunction, gynecomastia, benign prostatic hyperplasia). Eplerenone is a more specific, though lesspotent, MRA with reduced side effects. All K+sparing diuretics should be used cautiously, with frequent measurements of plasma K+ concentrations in patients predisposed to hyperkalemia. Patients should be cautioned regarding the possibility that concurrent use of K+containing salt substitutes could produce hyperkalemia. Renal insufficiency is a relative contraindication to the use of K+sparing diuretics. Concomitant use of an ACE inhibitor or an ARB magnifies the risk of hyperkalemia with these agents. DiureticAssociated Drug Interactions Because the antihypertensive effects of diuretics are additive with those of other antihypertensive agents, a diuretic commonly is used in combination with other drugs. The K+ and Mg2+depleting effects of the thiazides and loop diuretics can potentiate arrhythmias that arise from digitalis toxicity. Corticosteroids can amplify the hypokalemia produced by the diuretics. NSAIDs (see Chapter 38) that inhibit the synthesis of prostaglandins reduce the antihypertensive effects of diuretics and all other antihypertensives. The renal effects of selective COX2 inhibitors are similar to those of the traditional NSAIDs. NSAIDs and RAS inhibitors reduce plasma concentrations of aldosterone and can potentiate the hyperkalemic effects of a K+ sparing diuretic. All diuretics can decrease the clearance of Li+, resulting in increased plasma concentrations of Li+ and potential toxicity. SYMPATHOLYTIC AGENTS With the demonstration in 1940 that bilateral excision of the thoracic 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, particularly on mood. A number of sympatholytic agents are currently in use (Table 28–2). Antagonists of α and β adrenergic receptors have been mainstays of antihypertensive therapy. β Blockers β Adrenergic receptor antagonists (β blockers) were not expected to have antihypertensive effects when they were first investigated in patients with angina, their primary indication. However, pronethalol, a drug that was never marketed, was found to reduce arterial blood pressure in hypertensive patients with angina pectoris. This antihypertensive effect was subsequently demonstrated for propranolol and all other β blockers. The basic pharmacology of these drugs is discussed in Chapter 12; characteristics relevant to their use in hypertension are described here. Locus and Mechanism of Action Antagonism of β adrenergic receptors affects the regulation of the circulation through a number of mechanisms, including a reduction in myocardial contractility and heart rate (i.e., cardiac output; see Figure 27–1). Antagonism of β1 receptors of the juxtaglomerular complex reduces renin secretion and RAS activity. This action likely contributes to the antihypertensive action. Some members of this large, heterogeneous class of drugs have additional effects unrelated to their capacity to bind to β adrenergic receptors. For example, labetalol and carvedilol are also α1 blockers, and nebivolol promotes endothelial cell–dependent vasodilation via activation of NO production (Pedersen and Cockcroft, 2006) (see Figure 12–4). Pharmacodynamic Differences The β blockers vary in their selectivity for the β1 receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and vasodilating capacity. While all of the β blockers are effective as antihypertensive agents, these differences influence the clinical pharmacology and spectrum of adverse effects of the various drugs. The antihypertensive effect resides in antagonism of the β1 receptor, while major unwanted effects result from antagonism of β2 receptors (e.g., peripheral vasoconstriction, bronchoconstriction, hypoglycemia). Standard therapies are β1 blockers without intrinsic sympathomimetic activity (e.g., atenolol, bisoprolol, metoprolol). They produce an initial reduction in cardiac output (mainly β1) and a reflex induced rise in peripheral resistance, with little or no acute change in arterial pressure. In patients who respond with a reduction in blood pressure, peripheral resistance gradually returns to pretreatment values or less. Generally, persistently reduced cardiac output and possibly decreased peripheral resistance account for the reduction in arterial pressure. Nonselective β blockers (e.g., propranolol) have stronger adverse effects on D

Chapter 25_ Drugs Affecting Renal Excretory Function-merged.pdf

Document Details

Tags

Related

Full Transcript

Upgrade to continue