CVS, Renal & Pulmonary System - All Chapters PDF

Section III Modulation of Pulmonary, Renal, and Cardiovascular Chapter 29. Drugs Affecting Renal Excretory Function / 557 Chapter 30. Renin and Angiotensin / 585 Chapter 31. Treatment of Ischemic Heart Disease / 607 Chapter 32. Treatment of Hypertension / 625 Chapter 33. The...

Section III Modulation of Pulmonary, Renal, and Cardiovascular Chapter 29. Drugs Affecting Renal Excretory Function / 557 Chapter 30. Renin and Angiotensin / 585 Chapter 31. Treatment of Ischemic Heart Disease / 607 Chapter 32. Treatment of Hypertension / 625 Chapter 33. Therapy of Heart Failure / 647 Chapter 34. Antiarrhythmic Drugs / 667 Chapter 35. Treatment of Pulmonary Arterial Hypertension / 695 Chapter 36. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs / 709 Chapter 37. Drug Therapy for Dyslipidemias / 729 https://ebooksmedicine.net/ This page intentionally left blank  29 Chapter Renal Anatomy and Physiology Principles of Diuretic Action Drugs Affecting Renal Excretory Function Edwin K. Jackson PART I: RENAL PHYSIOLOGY AND DIURETIC DRUG ACTION Adenosine Receptor Antagonists Emerging Diuretics Clinical Use of Diuretics Inhibitors of Carbonic Anhydrase PART II: WATER HOMEOSTASIS AND THE VASOPRESSIN Osmotic Diuretics Inhibitors of Na+-K+-2Cl− Symport: Loop Diuretics, High-Ceiling Diuretics SYSTEM Inhibitors of Na+-Cl− Symport: Thiazide-Type and Thiazide-Like Diuretics Vasopressin Physiology Inhibitors of Renal Epithelial Na+ Channels: K+-Sparing Diuretics Vasopressin Receptor Agonists Antagonists of Mineralocorticoid Receptors: Aldosterone Antagonists, Diseases Affecting the Vasopressin System K+-Sparing Diuretics Clinical Use of Vasopressin Agonists Inhibitors of Sodium-Glucose Symport: SGLT2 Inhibitors, Gliflozins Clinical Use of Vasopressin Antagonists Inhibitors of the Nonspecific Cation Channel: Natriuretic Peptides The kidney filters the extracellular fluid volume across the renal glomer- Glomerular Filtration uli an average of 12 times a day, and the renal nephrons precisely regulate In the glomerular capillaries, a portion of plasma water is forced through the fluid volume of the body and its electrolyte content via processes of a filter that has three basic components: the fenestrated capillary endo- secretion and reabsorption. Disease states such as hypertension, heart thelial cells, a basement membrane lying just beneath the endothelial failure, renal failure, nephrotic syndrome, and cirrhosis may disrupt cells, and the filtration slit diaphragms formed by epithelial cells that this balance. Diuretics increase the rate of urine flow and Na+ excretion cover the basement membrane on its urinary space side. Solutes of small and are used to adjust the volume or composition of body fluids in these size flow with filtered water (solvent drag) into Bowman’s space, whereas disorders. Precise regulation of body fluid osmolality is also essential. It formed elements and macromolecules are retained by the filtration is controlled by a finely tuned homeostatic mechanism that operates by barrier. adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneys—that is, water balance. Abnormalities in this Overview of Nephron Function homeostatic system can result from genetic diseases, acquired diseases, or The kidney filters large quantities of plasma, reabsorbs substances that drugs and may cause serious and potentially life-threatening deviations the body must conserve, and leaves behind or secretes substances that in plasma osmolality. must be eliminated. The changing architecture and cellular differ- Part I of this chapter first describes renal physiology, then introduces entiation along the length of a nephron are crucial to these functions diuretics with regard to mechanism and site of action, effects on urinary (Figure 29–1). Together, the two kidneys in humans produce about composition, and effects on renal hemodynamics, and then integrates 120 mL of ultrafiltrate/min, yet only 1 mL of urine/min; more than 99% diuretic pharmacology with a discussion of mechanisms of edema for- of the glomerular ultrafiltrate is reabsorbed at a high energy cost. The mation and the role of diuretics in clinical medicine. Specific therapeutic kidneys consume 7% of total-body O2 intake despite comprising only applications of diuretics are presented in Chapters 32 (hypertension) and 0.5% of body weight. 33 (heart failure). Part II of this chapter describes the vasopressin system The proximal tubule is contiguous with Bowman’s capsule and takes a that regulates water homeostasis and plasma osmolality and factors that winding path until finally forming a straight portion that dives into the perturb those mechanisms and examines pharmacological approaches renal medulla. Normally, about 65% of filtered Na+ is reabsorbed in the for treating disorders of water balance. proximal tubule. This part of the tubule is highly permeable to water, and thus, reabsorption is essentially isotonic. Between the outer and inner strips of the outer medulla, the tubule abruptly changes morphology to become the descending thin limb (DTL), which penetrates the inner Part I: Renal Physiology and Diuretic Drug Action medulla, makes a hairpin turn, and then forms the ascending thin limb (ATL). At the juncture between the inner and outer medulla, the tubule Renal Anatomy and Physiology once again changes morphology and becomes the thick ascending limb The basic urine-forming unit of the kidney is the nephron. The initial (TAL). Together, the proximal straight tubule, DTL, ATL, and TAL seg- part of the nephron, the renal (Malpighian) corpuscle, consists of a cap- ments are known as the loop of Henle. sule (Bowman’s capsule) and a tuft of capillaries (the glomerulus) residing The DTL is highly permeable to water, yet its permeabilities to NaCl within the capsule. The glomerulus receives blood from an afferent arte- and urea are low. In contrast, the ATL is permeable to NaCl and urea but is riole, and blood exits the glomerulus via an efferent arteriole. Ultrafiltrate impermeable to water. The TAL actively reabsorbs NaCl but is imperme- produced by the glomerulus collects in the space between the glomer- able to water and urea. Approximately 25% of filtered Na+ is reabsorbed ulus and capsule (Bowman’s space) and enters a long tubular portion of in the loop of Henle, mostly in the TAL, which has a large reabsorptive the nephron, where the ultrafiltrate is reabsorbed and conditioned. Each capacity. The TAL passes between the afferent and efferent arterioles and human kidney is composed of about 1 million nephrons. Figure 29–1 makes contact with the afferent arteriole by means of a cluster of special- illustrates subdivisions of the nephron. ized columnar epithelial cells known as the macula densa. The macula https://ebooksmedicine.net/  558 Abbreviations 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 ACTH: corticotropin (previously adrenocorticotropic hormone) characteristics impart the capacity to produce dilute urine, the TAL and ADH: antidiuretic hormone the DCT are collectively called the diluting segment of the nephron, and AIP: aldosterone-induced protein the tubular fluid in the DCT is hypotonic regardless of hydration status. Ang: angiotensin (e.g., AngII and AngIII) However, unlike the TAL, the DCT does not contribute to the counter- ANP: atrial natriuretic peptide current-induced hypertonicity of the medullary interstitium (described ATL: ascending thin limb in material that follows). AVP: arginine vasopressin The collecting duct system (segments 10–14 in Figure 29–1) is an area BNP: brain natriuretic peptide of fine control of ultrafiltrate composition and volume. It is here that final adjustments in electrolyte composition are made, via the adrenal steroid cGMP: cyclic guanosine monophosphate aldosterone. Vasopressin (also called ADH) modulates water permeability CHF: congestive heart failure in this part of the nephron as well. The more distal portions of the col- CKD: chronic kidney disease lecting duct pass through the renal medulla, where the interstitial fluid is CNGC: cyclic nucleotide-gated cation channel markedly hypertonic. In the absence of ADH, the collecting duct system CNP: C-type natriuretic peptide is impermeable to water, and dilute urine is excreted. In the presence of CNT: connecting tubule ADH, the collecting duct system is permeable to water, and water is reab- COX: cyclooxygenase sorbed. The movement of water out of the tubule is driven by the steep DAG: diacyglycerol concentration gradient that exists between tubular fluid and medullary CHAPTER 29 DRUGS AFFECTING RENAL EXCRETORY FUNCTION DCT: distal convoluted tubule interstitium. DDAVP: 1-deamino-8-d-AVP (desmopressin) The hypertonicity of the medullary interstitium plays a vital role in DI: diabetes insipidus the capacity of mammals and birds to concentrate urine, which is accom- DTL: descending thin limb plished by the unique topography of the loop of Henle and the specialized ECFV: extracellular fluid volume permeabilities of the loop’s subsegments. The “passive countercurrent ENaC: epithelial Na+ channel multiplier hypothesis” proposes that active transport in the TAL concen- ENCC1 or TSC: the absorptive Na+-Cl− symporter trates NaCl in the interstitium of the outer medulla. Because this segment ENCC2, NKCC2, or BSC1: the absorptive Na+-K+-2Cl− symporter of the nephron is impermeable to water, active transport in the ascending ENCC3, NKCC1, or BSC2: the secretory Na+-K+-2Cl− symporter limb dilutes the tubular fluid. As the dilute fluid passes into the collecting GFR: glomerular filtration rate duct system, water is extracted if, and only if, ADH is present. Because GPCR: G protein-coupled receptor the cortical and outer medullary collecting ducts have low permeability to IMCD: inner medullary collecting duct urea, urea is concentrated in the tubular fluid. The IMCD, however, is per- IP3: inositol trisphosphate meable to urea, so urea diffuses into the inner medulla, where it is trapped LOX: lipoxygenase by countercurrent exchange in the vasa recta (medullary capillaries that MR: mineralocorticoid receptor run parallel to the loop of Henle). Because the DTL is impermeable to salt NP: natriuretic peptide and urea, the high urea concentration in the inner medulla extracts water NPR: natriuretic peptide receptor (e.g., NPRA, B, or C) from the DTL and concentrates NaCl in the tubular fluid of the DTL. As NSAID: nonsteroidal anti-inflammatory drug the tubular fluid enters the ATL, NaCl diffuses out of the salt-permeable OAT: organic anion transporter ATL, thus contributing to the hypertonicity of the medullary interstitium. PG: prostaglandin PK: protein kinase (e.g., PKA, PKB, PKG) General Mechanism of Renal Epithelial Transport There are multiple mechanisms by which solutes may cross cell mem- PL: phospholipase (e.g., PLC, PLD) branes (see also Chapter 4). The kinds of transport achieved in a nephron PTH: parathyroid hormone segment depend mainly on which transporters are present and whether PVN: paraventricular nucleus they are embedded in the luminal or basolateral membrane. Figure 29–2 RAS: renin-angiotensin system presents a general model of renal tubular transport that can be summa- RBF: renal blood flow rized as follows: SGLT2: sodium-glucose cotransporter type 2 SIADH: syndrome of inappropriate secretion of ADH 1. Na+, K+-ATPase (sodium pump) in the basolateral membrane trans- SON: supraoptic nucleus ports Na+ into the intercellular and interstitial spaces and K+ into the TAL: thick ascending limb cell, establishing an electrochemical gradient for Na+ across the cell TGF: tubuloglomerular feedback membrane directed inward. VP: vasopressin 2. Na+ can diffuse down this Na+ gradient across the luminal membrane VRUT: vasopressin-regulated urea transporter via Na+ channels and via membrane symporters that use the energy vWD: von Willebrand disease stored in the Na+ gradient to transport solutes out of the tubular lumen and into the cell (e.g., Na+-glucose, Na+-H2PO−4, 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 densa is strategically located to sense concentrations of NaCl leaving the spaces mainly via the Na+ pump. loop of Henle. If the concentration of NaCl is too high, the macula densa 4. The action of Na+-linked symporters in the luminal membrane causes sends a chemical signal (perhaps adenosine or ATP) to the afferent arte- the concentration of substrates for these symporters to rise in the epi- riole of the same nephron, causing it to constrict, thereby reducing the thelial cell. These substrate/solute gradients then permit simple diffu- glomerular filtration rate (GFR). This homeostatic mechanism, known sion or mediated transport (e.g., symporters, antiporters, uniporters, as tubuloglomerular feedback (TGF), protects the organism from salt and and channels) of solutes into the intercellular and interstitial spaces. volume wasting. The macula densa also regulates renin release from the 5. Accumulation of Na+ and other solutes in the intercellular space cre- adjacent juxtaglomerular cells in the wall of the afferent arteriole. ates a small osmotic pressure differential across the epithelial cell.  Glomerulus 1 559 11 10 9 2 8 CORTEX 12 7 3 13 (Outer Strip) 6 OUTER (Inner Strip) MEDULLA 14 INNER 5 4 MEDULLA 1 = S1 Segment Proximal Convoluted Tubule = P1 Segment PROXIMAL TUBULE 2 = S2 Segment SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR = P2 Segment Proximal Straight Tubule 3 = S3 Segment = P3 Segment LOOP OF HENLE INTERMEDIATE 4 = Descending Thin Limb (DTL) TUBULE 5 = Ascending Thin Limb (ATL) 6 = Medullary Thick Ascending Limb (MTAL) STRAIGHT PART OF DISTAL TUBULE PARS RECTA OF DISTAL TUBULE or DISTAL STRAIGHT TUBULE or THICK ASCENDING LIMB or 7 = Cortical Thick Ascending Limb (CTAL) TUBULE DISTAL 8 = Postmacular Segment of Distal Straight Tubule TUBULE = Postmacular Segment of Thick Ascending Limb DISTAL EARLY 9 = Distal Convoluted Tubule (DCT) CONVOLUTION DISTAL TUBULE 10 = Connecting Tubule (CNT) DISTAL LATE 11 = Initial Collecting Tubule DUCT SYSTEM COLLECTING 12 = Cortical Collecting Tubule (CCT) COLLECTING 13 = Outer Medullary Collecting Duct (OMCD) DUCT 14 = Inner Medullary Collecting Duct (IMCD) Figure 29–1 Anatomy and nomenclature of the nephron. In water-permeable epithelium, water moves into the intercellu- then move down their electrochemical gradients into the intercellu- lar spaces driven by the osmotic pressure differential. Water moves lar space by both the transcellular (e.g., simple diffusion, symporters, through aqueous pores in both the luminal and the basolateral cell antiporters, uniporters, and channels) and paracellular pathways. membranes, as well as through tight junctions (paracellular pathway). Membrane-impermeable solutes remain in the tubular lumen and are Bulk water flow carries some solutes into the intercellular space by excreted in the urine with an obligatory amount of water. solvent drag. 7. As water and solutes accumulate in the intercellular space, hydrostatic 6. Movement of water into the intercellular space concentrates other sol- pressure increases, thus providing a driving force for bulk water flow. utes in the tubular fluid, resulting in an electrochemical gradient for Bulk water flow carries solute out of the intercellular space into the these substances across the epithelium. Membrane-permeable solutes interstitial space and, finally, into the peritubular capillaries. https://ebooksmedicine.net/  560 Tubular Interstitial lumen space Intercellular space Na+ Zonula occludens (tight junctions) Basolateral Membrane Simple diffusion X Media S ted tr ansp ort S,A,U X X or CH A Y Y Na+ P Solve S,A CH Dr nt Na+ ag ATP H2O OSWP CHAPTER 29 DRUGS AFFECTING RENAL EXCRETORY FUNCTION MOS IS (tran K+ ATPase scel lular WP ADP K+ OS ) CH M OS H2O IS pa CONVECTION ( ra ce llular) Simple diffusion (paracellular) Membrane Luminal Simple diffusion (transcellular) P I S,A,U S,A,U or CH Mediated transport or CH PD +/_ URINE + – – + Figure 29–2 Generic mechanism of renal epithelial cell transport (see text for details). A, antiporter; ATPase, Na+, K+-ATPase (sodium pump); CH, ion channel; I, membrane-impermeable solutes; P, membrane-permeable solutes; PD, potential difference across indicated membrane or cell; S, symporter; U, uniporter; WP, water pore; X and Y, transported solutes. Organic Acid and Organic Base Secretion oxalate (proximal tubule), symport with Na+/K+ (TAL), symport with Na+ The kidney is a major organ involved in the elimination of organic chem- (DCT), and antiport with HCO−3 (collecting duct system). Cl− crosses the icals from the body. Organic molecules may enter the renal tubules basolateral membrane via symport with K+ (proximal tubule and TAL), by glomerular filtration or may be actively secreted directly into antiport with Na+/HCO−3 (proximal tubule), and Cl− channels (TAL, DCT, tubules. The proximal tubule has a highly efficient transport system collecting duct system). for organic acids and an equally efficient but separate transport sys- Of filtered K+, 80% to 90% is reabsorbed in the proximal tubule (dif- tem for organic bases. Current models for these secretory systems are fusion and solvent drag) and TAL (diffusion), largely through the para- illustrated in Figure 29–3. Both systems are powered by the sodium cellular pathway. The DCT and collecting duct system secrete variable pump in the basolateral membrane, involve secondary and tertiary amounts of K+ by a channel-mediated pathway. Modulation of the rate active transport, and use a facilitated diffusion step. There are many of K+ secretion in the collecting duct system, particularly by aldosterone, organic acid and organic base transporters (see Chapter 4). A family of allows urinary K+ excretion to be matched with dietary intake. The tran- organic anion transporters (OATs) links countertransport of organic sepithelial potential difference VT, lumen positive in the TAL and lumen anions with dicarboxylates (Figure 29–3A). negative in the collecting duct system, drives K+ reabsorption and secre- tion, respectively. Renal Handling of Specific Anions and Cations Most of the filtered Ca2+ (~70%) is reabsorbed by the proximal tubule Reabsorption of Cl− generally follows reabsorption of Na+. In segments of by passive diffusion through a paracellular route. Another 25% of filtered the tubule with low-resistance tight junctions (i.e., “leaky” epithelium), Ca2+ is reabsorbed by the TAL in part by a paracellular route driven by such as the proximal tubule and TAL, Cl– movement can occur paracel- the lumen-positive VT and in part by active transcellular Ca2+ reabsorp- lularly. Cl− crosses the luminal membrane by antiport with formate and tion modulated by parathyroid hormone (PTH) (see Chapter 52). Most of  A Luminal space Epithelial cell Peritubular space B Luminal space Epithelial cell Peritubular space 561 K+ K+ + K+ K 1 ATPase 1 ATPase Na+ Na+ Na+ Na+ Na+ 2 Symporter Antiporter 2 – – αKG2 H+ αKG2 H+ 3 Antiporter Antiporter 3 Facilitated diffusion A– A– C+ C+ Facilitated LM BL LM BL diffusion Figure 29–3 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 ter- tiary active transport, respectively. A−, organic acid (anion); C+, organic base (cation); αKG2−, α-ketoglutarate but also other dicarboxylates. BL and LM indicate basolateral and luminal membranes, respectively. SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR the remaining Ca2+ is reabsorbed in DCT by a transcellular pathway. The In the proximal tubule, the free energy in the Na+ gradient established transcellular pathway in the TAL and DCT involves passive Ca2+ influx by the basolateral Na+ pump is used by a Na+-H+ antiporter (Na+-H+ across the luminal membrane through Ca2+ channels (TRPV5, transient exchanger type 3) in the luminal membrane to transport H+ into the receptor potential cation channel V5), followed by Ca2+ extrusion across tubular lumen in exchange for Na+. In the lumen, H+ reacts with filtered the basolateral membrane by a Ca2+-ATPase. Also, in DCT and CNT, Ca2+ HCO−3 to form H2CO3, which decomposes rapidly to CO2 and water in crosses the basolateral membrane by Na+-Ca2+ exchanger (antiport). Pi the presence of carbonic anhydrase in the brush border. Carbonic anhy- is largely reabsorbed (80% of filtered load) by the proximal tubule. The drase reversibly accelerates this reaction several thousand–fold. CO2 is Na+-Pi symporter uses the free energy of the Na+ electrochemical gradient lipophilic and rapidly diffuses across the luminal membrane into the to transport Pi into the cell. The Na+-Pi symporter is inhibited by PTH. The renal tubules reabsorb HCO−3 and secrete protons (tubular acidi- fication), thereby participating in acid-base balance. These processes are Diuretic described in the section on carbonic anhydrase inhibitors. Principles of Diuretic Action 70 Body weight (kg) Diuretics are drugs that increase the rate of urine flow; clinically useful diuretics also increase the rate of Na+ excretion (natriuresis) and of an 69 accompanying anion, usually Cl−. Most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content. 68 Although continued diuretic administration causes a sustained net Body weight decreases deficit in total-body Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line with Na+ 0 intake, a phenomenon known as diuretic braking. These compensatory mechanisms include activation of the sympathetic nervous system, Excretion > Intake activation of the renin-angiotensin-aldosterone axis, decreased arterial 200 blood pressure (which reduces pressure natriuresis), renal epithelial Counterregulatory cell hypertrophy, increased renal epithelial transporter expression, and 150 mechanisms Na+ (mEq/day) perhaps alterations in natriuretic hormones such as atrial natriuretic Na excretion Steady state still in place peptide (ANP). The net effects on extracellular volume and body weight increases 100 are shown in Figure 29–4. Excretion Diuretics may modify renal handling of other cations (e.g., K+, H+, Intake 50 Ca2+, and Mg2+), anions (e.g., Cl−, HCO−3, and H2PO−4), and uric acid. In addition, diuretics may alter renal hemodynamics indirectly. Table 29–1 compares the general effects of the major diuretic classes. 0 Days Intake > Excretion Figure 29–4 Changes in extracellular fluid volume (ECFV) and weight with Inhibitors of Carbonic Anhydrase diuretic therapy. The period of diuretic administration is shown in the shaded There are three orally administered carbonic anhydrase inhibitors— box along with its effects on body weight in the upper part of the figure and acetazolamide, dichlorphenamide, and methazolamide (Table 29–2). Na+ excretion in the lower half of the figure. Initially, when Na+ excretion exceeds intake, body weight and ECFV decrease. Subsequently, a new steady Mechanism and Site of Action state is achieved where Na+ intake and excretion are equal but at a lower ECFV Proximal tubular epithelial cells are richly endowed with the zinc metal- and body weight. This results from activation of the RAAS and SNS, “the loenzyme carbonic anhydrase, which is found in the luminal and basolat- braking phenomenon.” When the diuretic is discontinued, body weight and eral membranes (type IV carbonic anhydrase), as well as in the cytoplasm ECFV rise during a period when Na+ intake exceeds excretion. A new steady (type II carbonic anhydrase) (Figure 29–5). Carbonic anhydrase plays a state is then reached as stimulation of the RAAS and SNS wanes. RAAS, renin- role in NaHCO3 reabsorption and acid secretion. angiotensin-aldosterone system; SNS, sympathetic nervous system. https://ebooksmedicine.net/  562 TABLE 29–1 EXCRETORY AND RENAL HEMODYNAMIC EFFECTS OF DIURETICSa CATIONS ANIONS URIC ACID RENAL HEMODYNAMICS DIURETIC MECHANISM (Primary site of action) Na+ K+ H+b Ca2+ Mg2+ Cl− HCO3− H2PO4− ACUTE CHRONIC RBF GFR FF TGF Inhibitors of CA (proximal tubule) + ++ – NC V (+) ++ ++ I – – – NC + Osmotic diuretics (loop of Henle) ++ + I + ++ + + + + I + NC – I Inhibitors of Na -K -2Cl symport + + – ++ ++ + ++ ++ ++ + c + c + – V(+) NC V(–) – (thick ascending limb) Inhibitors of Na+-Cl– symport + ++ + V(–) V(+) + +c +c + – NC V(–) V(–) NC (distal convoluted tubule) Inhibitors of renal epithelial + – – – – + (+) NC I – NC NC NC NC Na+ channels (late distal tubule, collecting duct) Antagonists of mineralocorticoid + – – I – + (+) I I – NC NC NC NC receptors (late distal tubule, collecting duct) CHAPTER 29 DRUGS AFFECTING RENAL EXCRETORY FUNCTION 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, mild-to-moderate 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. CA, carbonic anhydrase; FF, filtration fraction; GFR, glomerular filtration rate; RBF, renal blood flow; TGF, tubuloglomerular feedback. TABLE 29–2 INHIBITORS OF CARBONIC ANHYDRASE DRUG RELATIVE POTENCY ORAL AVAILABILITY t1/2 (hours) ROUTE OF ELIMINATION Acetazolamide 1 ~100% 6–9 R Dichlorphenamide 30 ID ID ID Methazolamide >1; 75 & urinary [Na]:[K] ratio is 50, use 25 to 50 mg/d HCTZ (Note: May add K+-sparing diuretic to loop CrCl 20 to 50, use 50 to 100 mg/d HCTZ and/or thiazide diuretic at any point in algorithm CrCl < 20, use 100 to 200 mg/d HCTZ for K+ homeostasis.) CHAPTER 29 DRUGS AFFECTING RENAL EXCRETORY FUNCTION While maintaining other diuretics, switch loop agent to continuous infusion Figure 29–9 “Brater’s algorithm” for diuretic therapy of chronic renal failure, nephrotic syndrome, CHF, and cirrhosis. Follow algorithm until adequate response is achieved. If adequate response is not obtained, advance to the next step. For illustrative purposes, the thiazide diuretic used is hydrochlorothiazide (HCTZ). An alternative thiazide-type diuretic may be substituted with dosage adjusted to be pharmacologically equivalent to the recommended dose of HCTZ. Do not combine two K+-sparing diuretics due to the risk of hyperkalemia. CrCl indicates creatinine clearance in milliliters per minute, and ceiling dose refers to the smallest dose of diuretic that produces a near-maximal effect. *Ceiling doses of loop diuretics and dosing regimens for continuous intravenous infusions of loop diuretics are disease-state specific. Doses are for adults only. however, nothing is gained by the administration of two drugs of the that respond to vasopressin by increasing their water permeability. The same type. Thiazide diuretics with significant proximal tubular effects CNS component of the antidiuretic mechanism is called the hypothala- (e.g., metolazone) are particularly well suited for sequential blockade moneurohypophyseal system and consists of neurosecretory neurons with when coadministered with a loop diuretic. perikarya located predominantly in two specific hypothalamic nuclei, Reducing salt intake will diminish postdiuretic Na+ retention, which the supraoptic nucleus (SON) and paraventricular nucleus (PVN). Long can nullify previous increases in Na+ excretion. axons of magnocellular neurons in SON and PVN terminate in the neu- Scheduling of diuretic administration shortly before food intake will ral lobe of the posterior pituitary (neurohypophysis), where they release provide effective diuretic concentration in the tubular lumen when salt vasopressin and oxytocin (see Figure 46–1). load is highest. Synthesis of Vasopressin Vasopressin and oxytocin are synthesized mainly in the perikarya of mag- nocellular neurons in the SON and PVN. However, parvicellular neurons Part II: Water Homeostasis and the in the PVN also synthesize vasopressin, as do some non-CNS cells (see discussion that follows). Vasopressin synthesis appears to be regulated Vasopressin System solely at the transcriptional level. In humans, a 168–amino acid prepro- hormone (Figure 29–10) is synthesized and then packaged into mem- Vasopressin Physiology brane-associated granules. The prohormone contains three domains: Arginine vasopressin (ADH in humans) is the main hormone that regu- vasopressin (residues 1–9), vasopressin-neurophysin (residues 13–105), lates body fluid osmolality. The hormone is released by the posterior pitu- and vasopressin-glycopeptide (residues 107–145). The vasopressin itary whenever water deprivation causes an increased plasma osmolality domain is linked to the vasopressin-neurophysin domain through a GLY- or whenever the cardiovascular system is challenged by hypovolemia or LYS-ARG-processing signal, and the vasopressin-neurophysin is linked hypotension. Vasopressin acts primarily in the renal collecting duct to to the vasopressin-glycopeptide domain by an ARG-processing signal. increase the permeability of the cell membrane to water, thus permitting In secretory granules, an endopeptidase, exopeptidase, monooxygenase, water to move passively down an osmotic gradient across the collecting and lyase act sequentially on the prohormone to produce vasopressin, duct into the extracellular compartment. vasopressin-neurophysin (sometimes referred to as neurophysin II), and Vasopressin is a potent vasopressor/vasoconstrictor. It is also a neu- vasopressin-glycopeptide. The synthesis and transport of vasopressin rotransmitter; among its actions in the CNS are apparent roles in the depend on the preprohormone conformation. In particular, vasopres- secretion of corticotropin (ACTH) and in regulation of the cardiovascu- sin-neurophysin binds vasopressin and is critical for correct processing, lar system, temperature, and other visceral functions. Vasopressin also transport, and storage of vasopressin. Genetic mutations in either the sig- promotes release of coagulation factors by vascular endothelium and nal peptide or vasopressin-neurophysin give rise to central DI. increases platelet aggregability. Vasopressin also is synthesized by the heart and adrenal gland. In the heart, elevated wall stress increases vasopressin synthesis several-fold Anatomy of the Vasopressin System and may contribute to impaired ventricular relaxation and coronary The antidiuretic mechanism in mammals involves two anatomical com- vasoconstriction. Vasopressin synthesis in the adrenal medulla stimulates ponents: a CNS component for synthesis, transport, storage, and release of catecholamine secretion from chromaffin cells and may promote adrenal vasopressin and a renal collecting duct system composed of epithelial cells cortical growth and stimulate aldosterone synthesis.  AVP PREPROHORMONE (HUMAN) 575 –1 29 69 * * * Thr Ala Val Gly Gly Ser –23 1 9 13 105 107 145 O H2N SIGNAL AVP VP-NEUROPHYSIN VP-GLYCOPEPTIDE C − OH PEPTIDE 1 /2 O2 Gly-Lys-Arg Arg 10 11 12 106 Carbohydrate Signal Peptide ENZYMES 2Arg Endopeptidase (cleaves –1/1, 12/13, 106/107) Exopeptidase (removes residues 11, 12, 106) Lys Monooxygenase (hydroxylates Gly10 ) Lyase (forms Glycinamide at 9) O O C−C SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR H OH Carbohydrate 1 9 O 13 105 O 107 145 O H2N AVP C − NH2 H2N− VP-NEUROPHYSIN C − OH H2N VP-GLYCOPEPTIDE C − OH 1 9 1 93 1 39 Figure 29–10 Processing of human arginine vasopressin (AVP) preprohormone. More than 40 mutations in the single gene on chromosome 20 that encodes AVP preprohormone give rise to central DI. *Boxes indicate mutations leading to central DI. DI, diabetes insipidus; VP, vasopressin. Regulation of Vasopressin Secretion regulation of vasopressin secretion does not disrupt osmotic regulation; rather, hypovolemia/hypotension alters the set point and slope of the Hyperosmolality. An increase in plasma osmolality is the principal plasma osmolality–plasma vasopressin relationship. physiological stimulus for vasopressin secretion by the posterior pitu- Neuronal pathways that mediate hemodynamic regulation of vaso- itary. The osmolality threshold for secretion is about 280 mOsm/kg. pressin release are different from those involved in osmoregulation. Below the threshold, vasopressin is barely detectable in plasma, and Baroreceptors in the left atrium, left ventricle, and pulmonary veins above the threshold, vasopressin levels are a steep and relatively linear sense blood volume (filling pressures), and baroreceptors in the carotid function of plasma osmolality. Indeed, a 2% elevation in plasma osmo- sinus and aorta monitor arterial blood pressure. Nerve impulses reach lality causes a 2- to 3-fold increase in plasma vasopressin levels, which brainstem nuclei predominantly through the vagal trunk and glos- in turn causes increased solute-free water reabsorption, with an increase sopharyngeal nerve; these signals are ultimately relayed to the SON and in urine osmolality. Increases in plasma osmolality above 290 mOsm/ PVN. kg lead to an intense desire for water (thirst). Thus, the vasopressin sys- tem affords the organism longer thirst-free periods and, in the event Hormones and Neurotransmitters. Vasopressin-synthesizing magno- that water is unavailable, allows the organism to survive longer periods cellular neurons have a large array of receptors on both perikarya and of water deprivation. Above a plasma osmolality of approximately 290 nerve terminals; therefore, vasopressin release can be accentuated or mOsm/kg, plasma vasopressin levels exceed 5 pM. Since urinary con- attenuated by chemical agents acting at both ends of the magnocellular centration is maximal (~1200 mOsm/kg) when vasopressin levels exceed neuron (Iovino et al., 2014). Also, hormones and neurotransmitters can 5 pM, further defense against hypertonicity depends mainly on water modulate vasopressin secretion by stimulating or inhibiting neurons in intake rather than on decreases in urinary water loss. nuclei that project, either directly or indirectly, to the SON and PVN Hepatic Portal Osmoreceptors. An oral salt load activates hepatic por- (Iovino et al., 2014). Because of these complexities, modulation of vaso- tal osmoreceptors, leading to increased vasopressin release. This mecha- pressin secretion by most hormones or neurotransmitters is unclear. Sev- nism augments plasma vasopressin levels even before the oral salt load eral agents stimulate vasopressin secretion, including acetylcholine (by increases plasma osmolality. nicotinic receptors), histamine (by H1 receptors), dopamine (by both D1 and D2 receptors), glutamine, aspartate, cholecystokinin, neuropeptide Y, Hypovolemia and Hypotension. Vasopressin secretion is regulated substance P, vasoactive intestinal polypeptide, PGs, and AngII. Inhibi- hemodynamically by changes in effective blood volume or arterial blood tors of vasopressin secretion include ANP, γ-aminobutyric acid, and opi- pressure. Regardless of the cause (e.g., hemorrhage, Na+ depletion, oids (particularly dynorphin via κ receptors). The effects of AngII have diuretics, heart failure, hepatic cirrhosis with ascites, adrenal insuffi- received the most attention. AngII synthesized in the brain and circulat- ciency, or hypotensive drugs), reductions in effective blood volume or ing AngII may stimulate vasopressin release. Inhibition of the conversion arterial blood pressure are associated with high circulating vasopressin of AngII to AngIII blocks AngII-induced vasopressin release, suggesting concentrations. However, unlike osmoregulation, hemodynamic regula- that AngIII is the main effector peptide of the brain RAS controlling tion of vasopressin secretion is exponential; that is, small decreases (5%) vasopressin release. in blood volume or pressure have little effect on vasopressin secretion, whereas larger decreases (20%–30%) can increase vasopressin levels to Pharmacological Agents. Several drugs alter urine osmolality by stim- 20 to 30 times normal (exceeding the vasopressin concentration required ulating or inhibiting vasopressin secretion. In most cases, the mechanism to induce maximal antidiuresis). Vasopressin is one of the most potent is not known. Stimulators of vasopressin secretion include vincristine, vasoconstrictors known, and the vasopressin response to hypovolemia cyclophosphamide, tricyclic antidepressants, nicotine, epinephrine, and or hypotension serves as a mechanism to stave off cardiovascular col- high doses of morphine. Lithium, which inhibits the renal effects of vaso- lapse during periods of severe blood loss or hypotension. Hemodynamic pressin, also enhances vasopressin secretion. Inhibitors of vasopressin https://ebooksmedicine.net/  576 secretion include ethanol (see also Chapter 27), phenytoin, low doses membranes in response to V2 receptor stimulation greatly increases of morphine, glucocorticoids, fluphenazine, haloperidol, promethazine, water permeability of the apical membrane (Nejsum, 2005) (Figures oxilorphan, and butorphanol. Carbamazepine has a renal action to pro- 29–12 and 29–13). duce antidiuresis in patients with central DI but inhibits vasopressin V2 receptor activation also increases urea permeability by 400% in the secretion by a central action. terminal portions of the IMCD. V2 receptors increase urea permeability by activating a vasopressin-regulated urea transporter (termed VRUT, Vasopressin Receptors UT1, or UTA1), most likely by PKA-induced phosphorylation. Kinetics Cellular vasopressin effects are mediated mainly by interactions of the of vasopressin-induced water and urea permeability differ, and vasopres- hormone with the three types of receptors: V1a, V1b, and V2. All are sin-induced regulation of VRUT does not entail vesicular trafficking to GPCRs. The V1a receptor is the most widespread subtype of vasopressin the plasma membrane. receptor; it is found in vascular smooth muscle, adrenal gland, myo- V2 receptor activation also increases Na+ transport in TAL and col- metrium, bladder, adipocytes, hepatocytes, platelets, renal medullary lecting duct. Increased Na+ transport in TAL is mediated by three mech- interstitial cells, vasa recta in the renal microcirculation, epithelial cells anisms that affect the Na+-K+-2C1− symporter: rapid phosphorylation in the renal cortical collecting duct, spleen, testis, and many CNS struc- of the symporter, translocation of the symporter into the luminal mem- tures. V1b receptors have a more limited distribution and are found in the brane, and increased expression of symporter protein. The multiple anterior pituitary, several brain regions, pancreas, and adrenal medulla. mechanisms by which vasopressin increases water reabsorption are sum- V2 receptors are located predominantly in principal cells of the renal col- marized in Figure 29–14. lecting duct system but also are present on epithelial cells in TAL and on vascular endothelial cells. Renal Actions of Vasopressin Figure 29–11 summarizes the current model of V1 receptor-effector Several sites of vasopressin action in kidney involve both V1 and V2 recep- CHAPTER 29 DRUGS AFFECTING RENAL EXCRETORY FUNCTION coupling. Vasopressin binding to V1 receptors activates the Gq-PLC-IP3 tors. V1 receptors mediate contraction of mesangial cells in the glomer- pathway, thereby mobilizing intracellular Ca2+ and activating PKC, ulti- ulus and contraction of vascular smooth muscle cells in vasa recta and mately causing biological effects that include immediate responses (e.g., efferent arterioles. V1 receptor–mediated reduction of inner medullary vasoconstriction, glycogenolysis, platelet aggregation, and ACTH release) blood flow contributes to the maximum concentrating capacity of the and growth responses in smooth muscle cells. kidney. V1 receptors also stimulate PG synthesis by medullary interstitial Principal cells in renal collecting duct have V2 receptors on their baso- cells. Because PGE2 inhibits adenylyl cyclase in collecting ducts, stimu- lateral membranes that couple to GS to stimulate adenylyl cyclase activity lation of PG synthesis by V1 receptors may counterbalance V2 receptor– (Figure 29–12). The resulting activation of the cyclic AMP/PKA pathway mediated antidiuresis. V1 receptors on principal cells in cortical collecting triggers an increased rate of insertion of water channel–containing vesicles ducts may inhibit V2 receptor–mediated water flux by activation of PKC. (WCVs) into the apical membrane and a decreased rate of endocytosis V2 receptors mediate the most prominent response to vasopressin, which of WCVs from the apical membrane. Because WCVs contain preformed is increased water permeability of the collecting duct at concentrations functional water channels (aquaporin 2), their net shift into apical as low as 50 fM. Thus, V2 receptor–mediated effects of vasopressin occur AVP AVP AVP Interstitial space AVP Cell V1 + ? ? membrane β γ + V1 + αq PLCβ DAG PKC DAG PA PLD cytosol + + PLA2 Proteins IP3 AA COX LOX PG, TX LT Ca2+ Proteins Modulation of Ca2+ cellular signaling Calcisome Proteins Proteins Ca2+ PO4 Vasoconstriction AP-1 Glycogenolysis Platelet aggregation Cell growth ACTH Release Immediate Cell responses growth Figure 29–11 Mechanism of V1 receptor-effector coupling. Binding of AVP to V1 vasopressin receptors (V1) stimulates membrane-bound phospholipases. Stim- ulation of Gq activates the PLCβ-IP3/DAG-Ca2+-PKC pathway. Activation of V1 receptors also causes influx of extracellular Ca2+ by an unknown mechanism. PKC and Ca2+/calmodulin-activated protein kinases phosphorylate cell-type–specific proteins, leading to cellular responses. A further component of the AVP response derives from the production of eicosanoids secondary to the activation of PLA2; the resulting mobilization of arachidonic acid (AA) provides substrate for eicosanoid synthesis by the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, leading to local production of prostaglandin (PG), thromboxane (TX) and leukotriene (LT), which may activate many signaling pathways, including those linked to GS and G q. AVP, arginine vasopressin; DAG, diacyglycerol; PA, phosphatidic acid; PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D.  AVP a c 577 e P AVP Interstitial space 1 2 N A 3 4 5 N A 6 P V2 β γ Basolateral membrane b αs Adenylyl Cyclase d N C Principal cell a in collecting duct e c ATP P Degradation cAMP PKA activity 1 2 6 A N N A 3 4 P Multivesicular b Bodies (MVB) N d C (4 monomers) H2O WCVs SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Phos- phorylated Proteins Endocytosis + Figure 29–13 Structure of aquaporins. Aquaporins have six transmembrane Exocytosis domains, and the NH2 and COOH termini are intracellular. Loops b and e each contain an asparagine-proline-alanine (NPA) sequence. Aquaporins fold e Apical membran with transmembrane domains 1, 2, and 6 in close proximity and transmem- H2O brane domains 3, 4, and 5 in juxtaposition. The long b and e loops dip into the membrane, and the NPA sequences align to create a pore through which WCVs = Water Channel–Containing Vesicles water can diffuse. Most likely, aquaporins form a tetrameric oligomer. At least = Aquaporin-2 = Water Channel seven aquaporins are expressed at distinct sites in the kidney. Aquaporin 1, abundant in the proximal tubule and DTL, is essential for concentration of urine. Aquaporin 2, exclusively expressed in the principal cells of the con- Figure 29–12 Mechanism of V2 receptor-effector coupling. Binding of AVP necting tubule and collecting duct, is the major vasopressin-regulated water to the V2 receptor activates the GS-adenylyl cyclase-cAMP-PKA pathway and channel. Aquaporin 3 and aquaporin 4 are expressed in the basolateral mem- shifts the balance of aquaporin 2 trafficking toward the apical membrane of branes of collecting duct principal cells and provide exit pathways for water the principal cell of the collecting duct, thus enhancing water permeability. reabsorbed apically by aquaporin 2. Aquaporin 7 is in the apical brush border Although phosphorylation of Ser256 of aquaporin 2 is involved in V2 receptor of the straight proximal tubule. Aquaporins 6 to 8 are also expressed in kid- signaling, other proteins located in both the water channel–containing vesi- ney; their functions remain to be clarified. Vasopressin regulates water per- cles and the apical membrane of the cytoplasm also may be involved. meability of the collecting duct by influencing the trafficking of aquaporin 2 from intracellular vesicles to the apical plasma membrane (Figure 29–12). AVP-induced activation of the cAMP-PKA pathway also enhances expression at concentrations far lower than are required to engage V1 receptor– of aquaporin 2 mRNA and protein; chronic dehydration thus causes upregu- mediated actions. Other renal actions mediated by V2 receptors include lation of aquaporin 2 and water transport in the collecting duct. increased urea transport in the IMCD and increased Na+ transport in the TAL; both effects contribute to the urine-concentrating ability of the kidney. V2 receptors also increase Na+ transport in cortical collecting Nonrenal Actions of Vasopressin ducts, and this may synergize with aldosterone to enhance Na+ reabsorp- Cardiovascular System. The cardiovascular effects of vasopressin are tion during hypovolemia. complex. Vasopressin is a potent vasoconstrictor (V1 receptor medi- Pharmacological Modification of the Antidiuretic ated), and resistance vessels throughout the circulation may be affected. Response to Vasopressin Vascular smooth muscle in the skin, skeletal muscle, fat, pancreas, and The NSAIDs, particularly indomethacin, enhance the antidiuretic thyroid gland appears most sensitive, with significant vasoconstriction response to vasopressin. Because PGs attenuate antidiuretic responses also occurring in the GI tract, coronary vessels, and brain. Despite the to vasopressin and NSAIDs inhibit PG synthesis, reduced PG produc- potency of vasopressin as a direct vasoconstrictor, vasopressin-induced tion probably accounts for potentiation of vasopressin’s antidiuretic pressor responses in vivo are minimal and occur only with vasopressin response. Carbamazepine and chlorpropamide (not available in the U.S.) concentrations significantly higher than those required for maximal anti- also enhance antidiuretic effects of vasopressin by unknown mecha- diuresis. To a large extent, this is due to circulating vasopressin actions on nisms. In rare instances, chlorpropamide can induce water intoxication. V1 receptors to inhibit sympathetic efferents and potentiate baroreflexes. Several drugs inhibit the antidiuretic actions of vasopressin. Lithium is In addition, V2 receptors cause vasodilation in some blood vessels. of particular importance because of its use in the treatment of manic- Vasopressin helps to maintain arterial blood pressure during episodes depressive disorders (Kishore and Ecelbarger, 2013). Acutely, Li+ appears of severe hypovolemia/hypotension. The effects of vasopressin on the to reduce V2 receptor–mediated stimulation of adenylyl cyclase. Also, Li+ heart (reduced cardiac output and heart rate) are largely indirect and increases plasma levels of PTH, a partial antagonist to vasopressin. In result from coronary vasoconstriction, decreased coronary blood flow, most patients, the antibiotic demeclocycline attenuates the antidiuretic and alterations in vagal and sympathetic tone. Some patients with cor- effects of vasopressin, probably owing to decreased accumulation and onary insuffici