Angiotensin-converting enzyme (ACE) inhibitors inhibit the activity of ACE, which converts the inactive decapeptide angiotensin I (Ang I) into the potent hormone angiotensin II (Ang II) ( Fig. 48.1 , Table 48.1 ; see Chapter 49 for a review of diuretic drugs). Because Ang II plays a crucial role in maintaining and regulating BP levels by promoting vasoconstriction and kidney sodium and water retention, ACE inhibitors are powerful tools for targeting multiple pathways that contribute to hypertension. ACE inhibitors directly reduce circulating and tissue levels of Ang II, thus blocking the potent vasoconstriction induced by the hormone ( Table 48.2 ). The resulting decrease in peripheral vascular resistance is not accompanied by changes in cardiac output or glomerular filtration rate (GFR); the heart rate is unchanged or may be reduced in patients with baseline heart rates higher than 85 beats per minute. A reduction in systemic and local levels of Ang II leads to effects beyond vasodilation that contribute to the antihypertensive efficacy of ACE inhibitors (see Table 48.2 ).

Renin–angiotensin–aldosterone system (RAAS)–effect site for each type of RAAS-blocking drugs.

The two major classes of drugs that target the RAAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs) . Both these drug classes target angiotensin II, but the differences in their mechanisms of action have implications for their effects on other pathways and receptors. Both ACE inhibitors and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and kidney events. Direct inhibition of renin—the most proximal aspect of the RAAS—became clinically feasible in 2007 with the introduction of aliskiren.

AT, Angiotensin; DRI, direct renin inhibitor.

From Robles NR, Cerezo I, Hernandez-Gallego R. Renin-angiotensin system blocking drugs. J Cardiovasc Pharmacol Ther. 2014;19:14–33.

Currently, more than 15 ACE inhibitors are in clinical use. Each drug has a unique structure that determines its potency, tissue receptor-binding affinity, metabolism, and prodrug compound, but these drugs have remarkably similar clinical effects ( Tables 48.3 and 48.4 ). The drugs are classified into sulfhydryl, carboxyl, or phosphinyl categories on the basis of the ligand that binds to the ACE–zinc moiety.

ACE inhibitors help slow CKD progression through several different hemodynamic and nonhemodynamic effects ( Table 48.5 ). In patients with elevated BP, ACE inhibitors can restore the pressure-natriuresis relationship, thereby maintaining sodium balance at a lower arterial BP. The response is exaggerated in the setting of dietary sodium restriction. The mechanism responsible for this effect is the direct inhibition of proximal, and possibly distal, tubule sodium reabsorption. The increased kidney excretory capacity plays a major role in the long-term antihypertensive activity of the drugs. Clinically, the increase in sodium excretion is transitory because the reduced arterial pressure allows the sodium excretion to return to normal. However, the maintenance of normal sodium excretion at lower arterial pressures correlates with increased excretion in the setting of hypertension. After several days, inhibition of Ang II and aldosterone contributes to the natriuresis. The long-term effects on water excretion are less certain. ACE inhibitors initially induce an increase in free water clearance, but there are no long-term changes in total body weight, plasma, or extracellular fluid volume. The decrease in aldosterone caused by ACE inhibition also correlates with decreased potassium excretion, particularly in patients with impaired kidney function.

Intrarenal inhibition of ACE in the vascular wall and kidney vessels contributes to the antihypertensive activity of ACE inhibitors. Mice lacking only intrarenal ACE are protected against hypertension. ACE inhibitor–induced changes in BP correlate with the degree of inhibition of RAAS in plasma and tissues. The ACE inhibitors with the greatest tissue specificity are associated with prolonged activity at the tissue level, even after serum ACE levels have returned to normal. Consequently, they are more efficacious with once-daily dosing. Other potential kidney-protective effects that have been noted in experimental models include attenuation of oxidative stress, scavenging of free radicals, and attenuation of lipid peroxidation.

ACE inhibitors decrease circulating concentrations of Ang II and increase circulating concentrations of angiotensin (1–7) (a potential vasodilator) and plasma renin. The effects of ACE inhibitors on angiotensin peptide levels depend on the responsiveness of renin secretion. ^, When renin levels show little increase in response to ACE inhibition, the levels of Ang II and its metabolites decrease markedly, with little change in the levels of Ang I. Large increases in renin levels in response to ACE inhibition increase the levels of Ang I and its metabolites. The increased levels of Ang I can produce higher levels of Ang II through uninhibited ACE and other pathways, thereby blunting the effect of reduced Ang II. This phenomenon is termed “ACE escape” and may contribute to reduced ACE inhibitor efficacy when used over a long term.

Most of the vasoconstrictive action of Ang II is confined to the efferent arteriole. ACE inhibitors preferentially dilate the efferent arteriole by reducing the systemic and intrarenal levels of Ang II. The effect is a reduction in intraglomerular capillary pressure. Many patients with impaired kidney function exhibit a reversible fall in GFR with ACE inhibitor therapy that is not detrimental. The GFR declines initially because of hemodynamic changes, but the long-term reduction in perfusion pressure is kidney protective. Even in patients receiving hemodialysis, ACE inhibitor therapy significantly preserves residual kidney function and helps maintain urine output. An initial elevation in the serum creatinine level of up to 30% above baseline with ACE inhibitor initiation that stabilizes within the first 2 months of therapy has been considered acceptable, and it is no reason to discontinue therapy with these medications. In fact, a review of 12 randomized trials showed that in patients with CKD receiving ACE inhibitors, a stable rise in the serum creatinine of <30% was associated with long-term preservation of kidney function. ^,

Patients with severe bilateral renal artery stenosis, unilateral renal artery stenosis of a solitary kidney, severe hypertensive nephrosclerosis, volume depletion, congestive heart failure, or cirrhosis are at higher risk for deterioration in kidney function with ACE inhibitor therapy. ^, In these states of reduced kidney perfusion related to low effective arterial circulating volume or reduced perfusion because of narrowing of arterial inflow, the maintenance of kidney blood flow and GFR is highly dependent on increased efferent arteriolar vasoconstriction mediated by Ang II. Interruption of the increased tone causes a critical reduction in perfusion pressure and can lead to dramatic reductions in GFR and urinary flow, worsening of kidney ischemia and, in rare cases, anuria. The hemodynamic effect is typically reversible with cessation of therapy. Studies of atherosclerotic renovascular disease have indicated that the risks of ACE inhibitors and other RAAS blockers (e.g., azotemia, hyperkalemia, and angioedema) can be balanced by their benefits when patients are carefully monitored.

ACE inhibitors are recommended in patients with mild, moderate, and severe hypertension, regardless of age, sex, or ancestry. They are effective in patients with diabetes, obesity, and/or following kidney transplantation. All ACE inhibitors decrease urinary protein excretion in normotensive and hypertensive patients with kidney disease of various etiologies. Individual response rates vary from an increase of 31% to a decrease of 100%, and they are strongly influenced by drug dosage and dietary sodium intake. ^, Importantly, multiple randomized controlled trials (RCTs) have shown that ACE inhibitors slow the progression of kidney disease, even in advanced CKD. Moreover, one RCT showed that withdrawing ACE inhibitors and angiotensin receptor blockers (ARBs) in advanced CKD did not result in significant differences in the rate of GFR decline, nor in the requirement for initiation of kidney replacement therapy.

In most studies, ACE inhibitors elicit an adequate BP-lowering response in 40% to 60% of patients. An immediate fall in BP occurs in 70% of patients. The enhanced efficacy of ACE inhibitors in the presence of salt restriction is paralleled by the additive effects of diuretic therapy. The addition of low-dose hydrochlorothiazide (HCTZ) enhances the efficacy more than 80%, normalizing BP in another 20% to 25% of patients. Adding a thiazide agent is generally more effective than increasing the dosage of the ACE inhibitor. ^,

Neither the duration nor the degree of BP lowering is predicted by the effect on blood ACE or Ang II levels, and all ACE inhibitors appear to have comparable efficacy. The response may be due in part to interindividual variability of the ACE genotype. ^, The activity of ACE is partially dependent on the presence or absence of a 287–base pair element in intron 16, and this insertion–deletion (I/D) polymorphism of a human Al repetitive DNA element accounts for 47% of the total phenotypic variation in plasma ACE. Deletion–deletion cases have the highest ACE concentrations, I/D cases have intermediate ACE concentrations and insertion–insertion cases have the lowest. Genotype also influences tissue ACE activity, but the clinical implications remain incompletely understood.

ACE inhibitors may cause fetal or neonatal injury or death when used during the second and third trimesters of pregnancy because angiotensin appears to be required for normal fetal growth and development. Use of ACE inhibitors during the first trimester might be associated with congenital malformations, but these malformations may be related to maternal factors. A systemic review showed that among 118 cases of ACE inhibitor exposure and 68 cases of ARB exposure, neonatal complications were more frequent following exposure to ARBs. Forty-eight percent of newborns exposed to ACE inhibitors exhibited features thought to be related to RAAS inhibitor exposure, in contrast to 87% of newborns exposed to ARBs ( P < 0.0001). Among 26 newborns affected by RAAS inhibitor exposure with >6 months of follow-up, 6 (23%) developed kidney failure, 4 (15%) had hypertension, and 3 (12%) experienced neurodevelopmental delay.

A prospective, observational, controlled cohort study of ACE inhibitors and ARB exposure during the first trimester was reported in 2012. Participants were enrolled from an unselected sample of women contacting a teratogen information service. There were two comparison groups, women with hypertension treated with other antihypertensives (including α-methyldopa or calcium channel blockers [CCBs]) and healthy controls. In the ACE–ARB and disease-matched groups, the offspring exhibited significantly lower birth weights and gestational ages than those of the healthy controls ( P < 0.001 for both variables). A significantly higher rate of miscarriage was noted in the ACE–ARB group ( P < 0.001). These results suggest that ACE inhibitors and ARBs are not major human teratogens during the first trimester. There was, however, a higher rate of spontaneous abortions in the ACE–ARB group.

When a patient becomes pregnant during treatment with an ACE inhibitor or ARB, the drug should be discontinued immediately, and alternative antihypertensive therapy should be started. Pregnancy termination is at the discretion of the patient and treatment team, but physicians and patients can derive some reassurance from the small studies quoted earlier if the drug is discontinued during the first trimester. Recognizing that the benefits of ACE inhibitors are largely long term, women attempting conception should transition to an alternative antihypertensive agent with a proven safety profile in pregnancy (see Chapter 58 ).

ACE inhibitors are transferred into breast milk, but the drug levels in milk are low. Captopril and enalapril have been reviewed by the American Academy of Pediatrics and the National Institute for Health and Care Excellence (NICE) guidelines for the management of hypertension in pregnancy from the United Kingdom, and they are compatible with lactation. However, newborns may be more susceptible to the hemodynamic effects of these drugs (e.g., hypotension) and sequelae (e.g., oliguria and seizures).

Overall, ACE inhibitors are well tolerated and have relatively neutral or beneficial metabolic effects. ACE inhibitors are associated with 8% to 11% reductions in levels of low-density lipoprotein (LDL) cholesterol and triglycerides and 5% increases in levels of high-density lipoprotein (HDL) cholesterol. They do not cause perturbations of serum sodium or uric acid levels. ACE inhibitors reduce the levels of plasminogen activator inhibitor-1 and may improve fibrinolysis.

The effects of ACE inhibitors on glucose metabolism are favorable. They may improve glucose tolerance by augmenting the insulin secretory response to glucose and may also help ameliorate obesity and hyperinsulinemia. The use of ACE inhibitors has been clinically associated with a 25% to 30% reduction in the risk of developing diabetes. Several large clinical trials have evaluated the clinical relevance of this finding. Many of the ACE inhibitors require dosage adjustment in the presence of impaired kidney function ( Table 48.6 ).

The most common adverse effect (AE) of ACE inhibitors is a dry, hacking, nonproductive cough, which has been reported in up to 20% of patients. The ACE inhibitor–induced cough is thought to be secondary to hypersensitivity to bradykinins, which are increased by ACE, increased levels of prostaglandins, accumulation of substance P, a potent bronchoconstrictor, or polymorphisms in the neurokinin-2 receptor gene. The cough can begin initially or many months after the start of therapy. It is more common in women, African Americans, and Asians ^, and it may spontaneously disappear. It may be more common in patients with bronchial hyperreactivity, but ACE inhibitors are safe to use in asthmatic patients. Cessation of ACE inhibitors and switching to an ARB is an effective way to manage ACE inhibitor–induced cough. Nonsteroidal antiinflammatory drugs (NSAIDs), oral iron supplements, sodium cromoglycate, and picotamide have also been reported to reduce ACE inhibitor–induced cough.

Angioedema is a rare but potentially life-threatening complication of ACE inhibitor therapy. It occurs in 0.1% to 0.7% of patients within hours of the first dose of ACE inhibitor or after prolonged use. The absolute risk of ACE inhibitor–induced angioedema is low, but with large numbers of prescriptions written annually, many patients are at risk for this disorder. ACE inhibitor–induced angioedema accounts for one-third of all cases of angioedema seen in emergency departments.

ACE inhibitor–induced angioedema occurs five times more frequently in individuals of African ancestry. ACE inhibitor–induced angioedema involves several components, including tissue accumulation of bradykinin and inhibition of C1 esterase activity. ^, Susceptible individuals typically have defects in non-ACE, nonkininase I vasoactive pathways of bradykinin degradation; possess the XPNPEP2 gene variant; have elevated des-Arg9-BK; or are taking dipeptidyl peptidase inhibitors (e.g., sitagliptin, saxagliptin, and linagliptin) to treat diabetes. ^, Some patients also have defective degradation of substance P, thereby increasing vascular permeability.

Clinical features including asymmetric swelling confined to the face, subcutaneous or submucous membranes, and lips usually resolve with discontinuation of the therapy, but obstructive sleep apnea may be exacerbated. If the ACE inhibitor is not discontinued, the episode usually resolves, but the frequency and severity of future episodes will escalate. ^, Angioedema of the small intestine and acute appendicitis have also been reported.

Involvement of the glottis and larynx requiring airway management occurs in 10% of all cases and may result in laryngeal obstruction and death. Administration of epinephrine, histamine-2 blockers, glucocorticoids, and/or fresh-frozen plasma is indicated. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for the treatment of hereditary angioedema. However, a meta-analysis of three RCTs involving 179 patients showed no significant benefit of icatibant in time to achieve complete resolution of ACE inhibitor–induced angioedema compared with placebo or other conventional treatments (pooled mean difference 7.8 hours, 95% confidence interval [CI]–25.2 to 9.6 hours). ACE inhibitors are contraindicated in patients with known hypersensitivity.

First-dose hypotension, with a reduction in BP of up to 30%, has been reported with all ACE inhibitors in up to 2.5% of patients. In the Studies of Left Ventricular Dysfunction (SOLVD trial), hypotension was observed in 14.8% of patients versus 7.1% of individuals who received a placebo ( P < 0.0001). In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), of the 8579 patients who received ramipril, only 1.7% and 0.2% permanently stopped therapy because of hypotension and syncope, respectively.

Hypotension occurs more commonly in patients with effective arterial volume depletion, patients with high-renin hypertension, and those with heart failure with reduced ejection fraction (HFrEF). ^, Hypotension is usually well tolerated, although occasionally it is associated with syncope. In older patients, ACE inhibitor therapy more frequently causes nocturnal hypotension. The accompanying increase in the plasma norepinephrine concentration may explain the low incidence of orthostatic symptoms. In patients at high risk of orthostatic symptoms, therapy should be initiated at lower dosages, preferably after holding diuretics. Rebound hypertension has not been reported with discontinuation of ACE inhibitors.

AEs related to the chemical structure are more frequently seen with the sulfhydryl-containing captopril than with the other agents. Dysgeusia appears to be related to the binding of zinc by the ACE inhibitors. Approximately 2% to 4% of patients experience a diminution or loss of taste sensation that is associated with a metallic taste. It is usually self-limited and resolves in 2 to 3 months, even with continued therapy. However, it may be severe enough to interfere with nutrition and cause weight loss.

Cutaneous reactions manifest as a nonallergic, pruritic, maculopapular eruption that appears during the first few weeks of therapy. These reactions may be associated with a fever or arthralgias and may disappear, even with continuation of the ACE inhibitor.

Leukopenia and anemia have been reported with ACE inhibitor therapy. Among patients with normal or near-normal kidney function, ACE inhibitors may reduce hemoglobin concentrations in a dose-dependent manner. ACE inhibitors have been demonstrated to interfere with the response to erythropoietin. Patients receiving hemodialysis and kidney transplant recipients receiving erythropoietin frequently require higher dosages to maintain hemoglobin concentrations. Consequently, ACE inhibitors can be used effectively to reduce posttransplantation erythrocytosis but appear to have little effect on erythropoiesis in patients receiving hemodialysis. Neutropenia (<1000 neutrophils/mm ³ ) with myeloid hypoplasia occurs almost exclusively in patients with impaired kidney function, immunosuppression, collagen vascular disease, or autoimmune disease. Neutropenia occurs within 3 months of initiation of therapy and generally resolves 2 weeks after therapy is discontinued. ^,

Now mostly of historical interest, anaphylactoid reactions ranging from mild pruritus to bronchospasm and cardiopulmonary collapse have been reported in patients treated with ACE inhibitors who undergo dialysis with equipment that uses high-flux polyacrylonitrile, cellulose acetate, or cuprophane membranes or who undergo apheresis with equipment that uses dextran sulfate membranes. The frequency of reactions is unknown, but they occur within the first few minutes of treatment. Dialyzers manufactured with these materials are rarely used in modern dialysis practice; nevertheless, exposure of the blood to any of these compounds should be avoided when patients are receiving ACE inhibitors. The use of ACE inhibitors in patients on plasmapheresis or an exchange protocol is safe as long as effective arterial volume is managed appropriately.

Few significant drug interactions occur with ACE inhibitors. Studies have shown that aspirin dosages of 100 mg/day or less do not negate the effects of ACE inhibitors. Ang II stimulates the production of vasodilatory prostaglandins. Aspirin inhibits the production of vasodilators and antithrombotic prostaglandins. Theoretically, either agent may antagonize the effectiveness of the other. Concomitant use of ACE inhibitors and calcineurin inhibitors may exacerbate kidney hypoperfusion. Use of the mammalian target of rapamycin (mTOR) inhibitors sirolimus or everolimus in transplant recipients decreases the metabolism of bradykinins and predisposes them to angioedema with ACE inhibitors.

Hyperkalemia of more than 5.5 mmol/L was observed in 3.3% of patients taking ramipril in the ONTARGET study. Production of Ang II systemically and locally in the zona glomerulosa of the adrenal gland, which is blocked by ACE inhibitors, will reduce subsequent aldosterone synthesis and urinary potassium excretion. In a Veterans Administration Medical Center case-control study of 1818 patients using ACE inhibitors, 194 (11%) developed hyperkalemia. The results of laboratory studies indicated that a serum urea nitrogen concentration higher than 6.4 mmol/L and a serum creatinine concentration higher than 136 μmol/L, as well as congestive heart failure and long-acting ACE inhibitors, were independently associated with hyperkalemia; concurrent use of a loop diuretic or thiazide agent was associated with reduced risk. After 1 year of follow-up, 15 (10%) of 146 patients who remained on a regimen of an ACE inhibitor developed severe hyperkalemia (serum potassium >6.0 mmol/L). A serum urea nitrogen concentration higher than 8.9 mmol/L (25 mg/dL) and age older than 70 years were independently associated with subsequent severe hyperkalemia.

Hyperkalemia has been effectively and safely treated with patiromer sorbitex calcium and sodium zirconium cyclosilicate in an outpatient setting. ^, These drugs add to the outpatient pharmacopoeia for hyperkalemia management that until now has been limited to sodium and calcium polystyrene sulfonate. Correction of metabolic acidosis, if present, and the use of loop diuretics, thiazide, or thiazide-like agents or sodium-glucose transport protein 2 (SGLT2) inhibitors may also reduce the incidence and severity of hyperkalemia.

The ARBs allow more specific and complete blockade of the RAAS than the ACE inhibitors because they circumvent all pathways that lead to the formation of Ang II (see Fig. 48.1 ). For example, Ang I is metabolized by not only ACE to form Ang II but also chymase, cathepsin G, tissue plasminogen activator, and other enzymes. Ang II can be formed at sites other than those in the systemic circulation, such as the brain, kidney, and heart. Furthermore, long-term ACE inhibitor therapy is associated with a return of Ang II levels to baseline, which possibly contributes to reduced efficacy. The ARBs selectively antagonize Ang II directly at the Ang II type 1 (AT ₁ ) receptor, regardless of the source of production. Because Ang II plays a crucial multifactorial role in maintaining and regulating BP, blockade of the AT ₁ receptor with ARBs is a powerful tool for targeting multiple pathways that contribute to hypertension.

Like ACE inhibitors, ARBs directly block the vasoconstrictive action of Ang II and cause a decrease in peripheral vascular resistance. Interruption of the binding of Ang II at the tissue level also leads to other effects (beyond vasodilation) that contribute to the antihypertensive effect. Additional mechanisms include the following: 1. augmentation of kidney blood flow and reduction of aldosterone release to induce natriuresis and attenuate the compensatory increase in sodium retention that accompanies a fall in BP; 2. direct depression of tubular sodium reabsorption; ^, 3. improvement of nitric oxide–mediated endothelial function; 4. reversal of vascular hypertrophy; 5. blunting of sympathetic nervous system (SNS) activity and presynaptic norepinephrine release; 6. inhibition of postjunctional pressor responses to norepinephrine or Ang II; 7. inhibition of central Ang II–mediated sympathoexcitation and vasopressin release; 8. inhibition of centrally controlled baroreceptor reflexes; 9. inhibition of central nervous system (CNS) norepinephrine synthesis; 10. inhibition of thirst; and 11. possible inhibition of RAAS-mediated action on endothelin-1. The antihypertensive action of ARBs is dependent on activation of the RAAS and is associated with clinically insignificant increases in circulating levels of Ang II. ARBs also increase bradykinin levels by antagonizing Ang II at its type 1 receptor and diverting Ang II to its counterregulatory type 2 receptor, which potentiates vasodilation. ARBs also increase the level of other angiotensin peptides, including angiotensin-(1-7), Ang II, and angiotensin IV, which can act on their respective receptors to modulate vasoconstriction, kidney blood flow, and vascular hypertrophy.

The ARB class is composed of peptide and nonpeptide analogs that vary in structure, mechanism of receptor inhibition, metabolism, and potency. Many drugs were developed by modifying losartan, the first biologically active ARB oral agent. These drugs are categorized according to the substitution of carboxylic and other moieties into several groups—the biphenyl tetrazoles (derivatives of losartan), nonbiphenyl tetrazoles, and nonheterocyclic compounds. They are also classified according to their ability to antagonize Ang II. The competitive (surmountable) antagonists shift the dose-response curve for Ang II–mediated contraction to the right without depressing the maximal response to Ang II. The noncompetitive (insurmountable) antagonists also depress the maximal response to Ang II. The variable effects of ARBs are mediated by differences in the interaction with allosteric binding sites on the receptor, dissociation of the drug–receptor complex, removal of the agonists from tissues, or the ability to modulate the amount of internalized receptors ( Tables 48.7–48.8 ).

Intrarenal Ang II receptors are widely distributed in the afferent and efferent arterioles, glomerular mesangial cells, inner stripe of the outer medulla, and medullary interstitial cells, as well as on the luminal and basolateral membranes of the proximal and distal tubule cells, collecting ducts, podocytes, and macula densa cells. Most receptors are of the AT ₁ subclass. Circulating and predominantly locally produced Ang II interacts with the receptors; the complex is internalized and Ang II is released into the intracellular compartment, where it exerts its effects. Studies have suggested that most kidney interstitial Ang II is formed at sites not readily accessible to ACE inhibition or is formed by non-ACE pathways.

ARBs antagonize the binding of Ang II and cause a number of intrarenal changes. The overall kidney hemodynamic responses of AT ₁ receptor blockade are variable, depending on the counteracting influences of the decrease in arterial pressure. ^, Decreases in systemic arterial pressure by ARBs may be associated with compensatory activation of the intrarenal SNS. This effect is more pronounced in sodium-depleted states because activation of the renin–angiotensin system helps maintain arterial and kidney pressure. By contrast, direct intrarenal infusions of ARBs cause an increase in sodium excretion. The enhanced sodium excretion has been shown to be caused by direct inhibition of sodium reabsorption by the proximal tubules, but it may also be caused by hemodynamic changes in medullary blood flow and tubule absorption in distal nephron segments. Because Ang II blockade enhances the ability of the kidneys to excrete sodium, sodium balance can be maintained at lower arterial pressures. Ang II blockade also reduces tubuloglomerular feedback sensitivity by decreasing macula densa transport of sodium chloride to the afferent arteriole. This leads to increased delivery of sodium chloride to the distal segments for excretion, without compensatory changes in GFR.

In addition to the natriuretic and diuretic actions, short-term administration of some ARBs such as losartan has been observed to induce reversible kaliuresis in salt-depleted normotensive patients in the absence of changes in GFR. However, long-term Ang II receptor blockade does not cause appreciable changes in urinary electrolyte excretion or volume. Another property unique to losartan is induction of uricosuria. This effect is not observed with ACE inhibitors or other ARBs, including the active metabolite of losartan, and does not appear to be related to inhibition of the RAAS. Losartan has a greater affinity for the urate-anion exchanger than other antagonists, and it inhibits urate reabsorption in the proximal tubule. The uricosuria is associated with a concomitant decrease in serum urate concentrations in normal individuals, hypertensive individuals, and patients with kidney disease including kidney transplant recipients. The effect occurs within 4 hours of drug administration and is dose dependent. Long-term administration reduces serum urate concentrations by approximately 0.4 mmol/L. Concerns that increased uric acid supersaturation might perpetuate kidney uric acid deposition have not been borne out clinically, perhaps because losartan simultaneously increases urinary pH, which protects against crystal nucleation.

Hypertensive patients treated with ARBs exhibit decreases in BP, increases in kidney blood flow, and decreases in filtration fraction and kidney vascular resistance. These effects are probably a result of combined decreases in preglomerular and postglomerular resistances. It has been suggested that elevated intrarenal Ang II levels in the presence of AT ₁ receptor blockade stimulate AT ₂ receptors, which can increase the preglomerular vasodilator actions of bradykinin, cyclic guanosine monophosphate, and nitric oxide. As with ACE inhibitors, ARBs can cause an initial elevation in the serum creatinine due to these hemodynamic changes and should not be a reason to stop ARBs because, like ACE inhibitors, ARBs slow CKD progression. The lowering of efferent arteriole resistance reduces intraglomerular hydrostatic pressure, which attenuates the progression of kidney injury, and increases kidney sodium excretory capacity. In concert with the reduction in systemic arterial pressure, these actions provide more kidney protection than other classes of antihypertensive agents, despite equivalent reductions in BP. ^{, ,}

In healthy and hypertensive patients, ARBs produce dose-dependent increases in circulating Ang II levels and plasma renin activity. The increases occur at the peak plasma drug levels and persist for up to 24 hours; they remain elevated with long-term administration. Decreases in plasma concentrations of aldosterone have been reported, but they are variable. In normal individuals, decreases in aldosterone coincide with the peak interval of ARB activity; in hypertensive patients consuming a fixed-sodium diet, there are no significant changes in plasma aldosterone concentrations relative to baseline. ARBs suppress the Ang II–mediated adrenal cortical release of aldosterone, but these effects appear to be quantitatively less important than the intrarenal suppression of Ang II action. Long-term AT ₁ receptor blockade does not appear to induce aldosterone escape.

Urinary protein excretion is significantly decreased with administration of ARBs and parallels findings with ACE inhibitor therapy. Antiproteinuric effects have been described in patients with and without diabetes mellitus, as well as in kidney transplant recipients. ^, The antiproteinuric effect has a slow onset, and the dose-response curves differ from those of the antihypertensive effects, in which the maximal effect occurs at 3 to 4 weeks. Whether the antiproteinuric effects are equivalent to or better than those of ACE inhibitors remains to be determined, but it is evident that the suppression of albuminuria is equivalent at all stages of CKD. Combining ACE inhibitors and ARBs for renoprotection and proteinuria reduction is not recommended owing to the significant development of hyperkalemia, hypotension, and kidney hypoperfusion, particularly in patients with underlying CKD. ^, Like ACE inhibitors, ARBs have nonhemodynamic effects that may contribute to renoprotection, including antiproliferative actions on the vasculature and mesangium, inhibition of transforming growth factor-β (TGF-β), ^, inhibition of atherogenesis and vascular deterioration, improved superoxide production and nitric oxide bioavailability, reductions of collagen formation, reduction of mesangial matrix production, improved vascular wall remodeling, decreased vasoconstrictor effects of endothelin-1, improved endothelial function, reductions of oxidative stress and inflammation, modulation of peroxisome proliferator–activated receptor γ activity, and protection from calcineurin inhibitor injury. ARBs also reduce salt sensitivity by restoring kidney nitric oxide synthesis.

All ARBs lower BP effectively and safely in patients with mild, moderate, and severe hypertension, regardless of age, sex, or ancestry. ARBs are indicated as first-line monotherapy or add-on therapy for hypertension and are comparable in efficacy to other agents. They are safe and effective in patients with CKD, diabetes, heart failure, coronary artery disease, arrhythmias, and left ventricular hypertrophy (LVH) and kidney transplant recipients. Some but not all studies have shown a weak lowering of the risk for new and recurrent atrial fibrillation because of the beneficial structural and electrical effects on the atria. ^, ARBs have been shown to diminish the rate of persistent atrial fibrillation in patients with preexisting recurrent atrial fibrillation. The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study showed no measurable benefit of ARBs for the prevention of recurrent stroke but may have been underpowered to show an effect in its well-treated patient population.

In most patients, ARBs offer BP lowering comparable with that of all other antihypertensive drug classes, with an improved tolerability profile. They provide effective control over a 24-hour period and are generally suitable for once-daily dosing (see Table 48.7 ). ^, ARBs do not affect the normal circadian BP variation. The long onset of action (4–6 weeks) avoids the first-dose hypotension and rebound hypertension that are commonly observed with some other drugs. There is a dose-dependent response with newer agents, but losartan and valsartan have a relatively flat dose-response curve. Azilsartan, candesartan, irbesartan, and olmesartan may have the greatest efficacy, with a longer duration of action because of their noncompetitive binding, and telmisartan may have an added advantage by the inhibition of SNS activation through an antioxidant effect in experimental models. ^,

ARBs may reversibly decrease kidney function and elevate serum potassium concentrations; serum chemistries should be checked after initiation or increase in dosage of these drugs. The overall incidence of hyperkalemia from ARBs is 3.3%, similar to that of ACE inhibitors. Participants in the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM; n = 7599) program were randomized to standard heart failure therapy plus candesartan or placebo, with recommended monitoring of serum potassium and creatinine levels. The authors assessed the incidence and predictors of hyperkalemia over the median 3.2 years of follow-up. Candesartan increased the risk of incident hyperkalemia compared with placebo 5.2% versus 1.8% (difference, 3.4%; P < 0.0001). Risk factors for hyperkalemia in treated patients with symptomatic heart failure include advanced age, male sex, baseline hyperkalemia, impaired kidney function, diabetes, or combined RAAS blockade. As with ACE inhibitors, hyperkalemia associated with ARB use can be medically managed. ^,

ARBs should be stopped immediately at the onset of pregnancy with the first missed menstrual period in the first trimester, as discussed previously in the context of ACE inhibitor use, because ARBs may cause fetal or neonatal death and congenital abnormalities when used during the second and third trimesters of pregnancy. Breastfeeding is not contraindicated, according to Kidney Disease Improving Global Outcomes (KDIGO) and NICE guidelines; however, low drug levels are detected in breast milk. ^,

Overall, ARBs have neutral metabolic effects and are superior to most other hypertensive classes with respect to tolerability. ARBs do not cause hypernatremia or hyponatremia, and hyperkalemia is relatively uncommon. In the ONTARGET study, a serum potassium concentration higher than 5.5 mmol/L was observed in 3.3% of patients who resigned from the study and is comparable with that observed with ACE inhibitor therapy. ARBs have no effect on serum lipids in hypertensive patients but may improve the abnormal lipoprotein profile of patients with proteinuric kidney disease and reduce obesity-related morbidity. ^, ARBs have favorable effects on serum glucose concentrations and insulin sensitivity. Clinical trials comparing ARB-based therapy with treatment with other antihypertensive agents in patients with hypertension with and without LVH demonstrated a 25% reduced risk of the development of diabetes in the ARB-treated group. ^, The mechanism for this effect has not been defined. ^, Increased levels of liver transaminases are occasionally reported, but the effects are usually transient, even with continued therapy.

Clinically relevant AEs are not observed more frequently than in placebo-treated patients. Because ARBs do not interfere with kinin metabolism, cough is rare, which is a major clinical advantage. The incidence of cough in patients with a history of ACE inhibitor–induced cough is no greater than in those receiving placebo. Similarly, the incidence of angioedema and facial swelling is no greater than that with placebo, but such swelling can occur. ARBs are typically associated with a more potent antiinflammatory response than ACE inhibitors. The most frequent AEs are headache (14%), dizziness (2.4%), and fatigue (2%), which occur at rates lower than those with placebo. ARB therapy does not worsen sexual activity and may even improve it. Like ACE inhibitors, ARBs may cause minor decreases in the hemoglobin concentration; they may also lower the hemoglobin effectively in posttransplantation erythrocytosis. Rarely, there have been associated cutaneous eruptions.

A spruelike enteropathy associated with olmesartan therapy has been reported. ^, In a systematic review of 54 patients, the clinical presentation was characterized by diarrhea (95%) and weight loss (89%). Less common symptoms were fatigue, nausea, vomiting, and abdominal pain. The patients had been taking olmesartan for 6 months to 7 years. A laboratory examination showed normochromic, normocytic anemia (45%) and hypoalbuminemia (39%). HLA-DQ2 or HLA-DQ8 was observed in more than 70%. Antibody testing for celiac disease was negative. Duodenal villous atrophy in varying degrees was described in all the reported patients, and they all showed resolution of diarrhea. The U.S. Food and Drug Administration (FDA) issued a drug safety communication on July 13, 2013 ( http://www.fda.gov/Drugs/DrugSafety/ucm359477.htm ).

ARBs have not been shown to increase the risk of cancer. Although one meta-analysis suggested a slightly increased risk of cancer with ARBs relative to other antihypertensive agents, there were questions about the study’s methodology and exclusion of certain key RCTs that would have changed the results had they been included. Subsequent meta-analyses and cohort studies demonstrated no association of ARBs with cancers of any type in large populations, and one study suggested that ARBs may actually lower the incidence. A subsequent systematic review of observational and interventional studies suggested that the use of ACE inhibitors and ARBs may improve cancer outcomes.

β-Adrenergic receptor antagonists (β-blockers) exert their antihypertensive effects by attenuating sympathetic stimulation through the competitive antagonism of catecholamines at the β-adrenergic receptor. However, the precise mechanism of the antihypertensive effect of β-blockers remains incompletely understood. β ₁ -Adrenergic receptor blockade has generally been considered responsible for the BP-lowering effect; however, β ₂ -receptor blockade has an independent antihypertensive effect. Inhibition of β ₁ -adrenergic receptors in the juxtaglomerular cells in the kidney may inhibit renin release. A direct action on the CNS, with a reduction in CNS sympathetic outflow, may also be involved. Attenuation of cardiac pressor stimuli related to β-blockade may result in baroreceptor resetting. In addition, adrenergic neuron output may be blocked because of the inhibition of β ₂ -adrenergic receptors at the vascular wall.

β ₁ -Selective blockers may have a slightly more potent antihypertensive effect than nonselective agents. This differential effect may be in the range of 2 to 3 mm Hg. It may be that β ₂ -blockade in some fashion blunts the antihypertensive effects of β ₁ -blockade. The β ₂ partial agonist activity may mediate peripheral vasodilator effects that could contribute to the antihypertensive action. A β ₁ -selective antagonist with partial agonist activity at the β ₁ receptor may result in less hypotensive effect. The magnitude and clinical significance of these differences are unclear.

In addition to β-adrenergic antagonist properties, certain drugs have antihypertensive effects that are mediated through different mechanisms ( Table 48.9 ), including α ₁ -adrenergic antagonist activity and effects on nitric oxide–dependent vasodilator action. Partial agonist activity is a property of certain β-blockers that results from a small degree of direct stimulation of the β-adrenergic receptor by the drug, while simultaneously blocking the same receptor to access by stimulating catecholamines. Whether the presence of partial agonist activity is advantageous or disadvantageous remains unclear. Drugs with partial agonist activity slow the resting heart rate less than drugs that lack this pharmacologic effect. The exercise-induced increase in heart rate is similarly blocked by both groups of drugs. However, β-blockers with nonselective partial agonist activity may reduce peripheral vascular resistance and cause less atrioventricular conduction depression than drugs without partial agonist activity. The specificity of partial agonist activity for β ₁ or β ₂ receptors may also have a role in the antihypertensive response to a given drug.

β-Blockers may be nonspecific and block β ₁ – and β ₂ -adrenergic receptors, or they may be relatively specific for β ₁ -adrenergic receptors. β ₁ -adrenergic receptors are found predominantly in heart, adipose, and brain tissue, whereas β ₂ receptors predominate in the lung, liver, smooth muscle, and skeletal muscle. Many tissues, however, have both β ₁ and β ₂ receptors, including the heart, and it is important to realize that the concept of a cardioselective drug is only relative.

β-Blockers differ significantly in gastrointestinal absorption, first-pass hepatic metabolism, protein binding, lipid solubility, penetration into the CNS, and hepatic or kidney clearance. β-Blockers that are eliminated primarily by hepatic metabolism have a relatively short plasma half-life; however, the duration of the clinical pharmacologic effect does not correlate well with the plasma half-life in many of these drugs. Water-soluble drugs that are eliminated by the kidney may have longer half-lives. Bioavailability varies greatly across the class, as does the degree to which individual agents are dialyzed.

α- and β-Adrenergic receptors in the kidney mediate vasoconstriction and vasodilation, as well as renin secretion. β-Blockers may influence kidney blood flow and GFR through their effects on cardiac output and BP in addition to direct effects on intrarenal adrenergic receptors. β-Adrenergic receptors have been localized to the juxtaglomerular apparatus in autoradiographic studies. β ₂ Receptors predominate in the kidney. The degree of specificity of β-adrenergic blockers for β ₁ and β ₂ receptors might be expected to influence the effect on kidney function, as might the degree of intrinsic partial agonist activity. In general, the short-term administration of a β-adrenergic blocker usually results in a reduction of GFR and effective kidney plasma flow. This effect is independent of whether the drug has β ₁ selectivity or intrinsic partial agonist activity. Nebivolol, carvedilol, and celiprolol, however, have vasodilatory properties and have been shown to increase GFR and kidney plasma flow. Nebivolol dilates glomerular afferent and efferent arterioles by a nitric oxide–dependent mechanism, in contrast to metoprolol, which had no similar effect. This effect may be mediated by the increased synthesis of vasodilatory nitric oxide. Nadolol, when administered intravenously, has been shown in some studies to increase kidney plasma flow and glomerular filtration, whereas oral administration may result in decreased blood flow and GFR. β ₁ -Selective drugs, when administered orally, tend to produce smaller reductions in GFR and kidney plasma flow. The long-term use of propranolol has been characterized by a 10% to 20% decrease in kidney plasma flow and GFR. The degree of reduction in GFR and kidney plasma flow is modest and probably not of clinical significance in most cases. Labetalol, with its combined α and β blockade, has shown little effect on kidney hemodynamics. The fractional excretion of sodium has been observed to decrease by up to 20% to 40% in some studies of the acute kidney effects of β blockade.

β-Blockers provide effective therapy for the management of mild-to-moderate hypertension, but their use as first-line therapy was not recommended in the 2017 American College of Cardiology (ACC)/AHA guidelines based on results from a contemporaneous systematic review and network meta-analysis. In that review, β-blockers were found to be less effective than calcium channel blockers (CCBs) or thiazide or thiazide-like agents for reducing stroke and cardiovascular risk. No significant differences in outcomes were observed in these class-to-class comparisons by age, sex, race, and diabetes mellitus status. For patients with CKD who may need multiple antihypertensive agents to effectively manage BP, the combination of β-blockers with nondihydropyridine CCBs can cause excessive heart rate lowering (bradycardia) and should be avoided.

β-Blockers are recommended for patients with specific comorbid conditions. ^, For example, the use of β-blockers after an acute myocardial infarction (MI) has been shown to reduce morbidity and mortality, although one randomized trial called into question the benefit of these agents post-MI after early coronary angiography among lower-risk patients with preserved left ventricular ejection fraction. Other studies have shown a 20% reduction in total mortality and a 32% to 50% reduction in sudden death with β-blocker therapy in patients who have experienced an MI. For treatment of hypertension in patients with a history of MI (at least in the past year), β-blockers may still be the drugs of choice. ^{, ,}

Patients with coexisting heart failure and hypertension are another group that benefit from treatment with β-blockers. The Cardiac Insufficiency Bisoprolol Study II demonstrated a 20% reduction in mortality in patients with moderate heart failure randomly assigned to therapy with a β-blocker. Hospitalizations for heart failure and sudden cardiac death were also significantly lower in the β-blocker group. Similar benefits were observed in randomized trials of metoprolol succinate and carvedilol. Over the long term, treatment with β-adrenergic blockers improves exercise tolerance, left ventricular geometry, and left ventricular structure and reduces myocardial oxygen demand. The magnitude of heart rate reduction with β-blockers, but not the dose, is significantly associated with the survival benefit in heart failure. β-Blockers may differ in effects on cardiovascular outcomes. A meta-analysis has suggested that the vasodilatory β-blocker carvedilol has a greater benefit on all-cause mortality in HFrEF compared with β ₁ -selective β-blockers, although this distinction has not been observed in all studies. Genetic polymorphisms affecting the β ₁ -adrenergic receptor, the α _2C -adrenergic receptor and the G protein–coupled receptor kinase have been suggested to modify heart failure risk and the response to β-blocker therapy.

Agents with β ₁ -selectivity or intrinsic sympathetic activity have a therapeutic advantage over nonselective β-adrenergic antagonists in the treatment of patients with bronchospastic airway disease, chronic obstructive pulmonary disease, peripheral vascular disease, and diabetes mellitus. ^{, ,} Bronchoconstriction is mediated in part by β ₂ -adrenergic receptors in the airways. β-Blockade with nonselective agents can lead to increased airway resistance. This increase is less likely to occur with β ₁ -selective agents. β ₁ -Selectivity is relative, however, and may be less apparent at higher dosages. In general, patients with severe bronchospastic airway disease should not receive β-blockers. In patients with mild-to-moderate disease, β ₁ -selective agents may be used cautiously; it has been proposed that they have beneficial effects on airway hyperresponsiveness.

Symptoms of peripheral artery disease may be exacerbated by β-blocker therapy. Cold extremities and absent pulses have been described in patients with severe disease. Raynaud phenomenon has been reported with nonselective β-blockade. Blockade of β ₂ -receptor–mediated skeletal muscle vasodilation, as well as decreased cardiac output, may contribute to vascular insufficiency. However, a meta-analysis showed that treatment with β-blockers does not worsen intermittent claudication or walking capacity in patients with mild-to-moderate peripheral artery disease. Current treatment guidelines do not recommend against the use of β-blockers in patients with peripheral artery disease, evidence is limited, and controversy remains.

The CNS symptoms of sedation, sleep disturbance, depression, and visual hallucinations have been reported with β-blockers. In a review of 15 randomized trials involving more than 35,000 patients, β-blockers were not associated with a significant increase in the risk of reported depressive symptoms (6/1000 patient-years; 95% CI, −7 to 19). β-Blockers were associated with a small but significant annual increase in reported fatigue (18/1000 patient-years; 95% CI, 5–30). These symptoms may be more common with lipid-soluble β-blockers and less common with nebivolol.

β-Blockers are associated with weight gain and an increased risk of new-onset diabetes mellitus, ^, perhaps by mediating increases in glycogenolysis and gluconeogenesis from amino acids and glycerol and inhibiting glucose uptake in the periphery. β-Blockers differ in terms of their effects on glucose metabolism. Nonvasodilating β-blockers such as metoprolol decrease insulin sensitivity and are associated with a worsening of glycemic control, whereas nebivolol does not. ^, In patients with established diabetes mellitus, β-blockers can blunt the effects of epinephrine secretion resulting from hypoglycemia and lead to hypoglycemia unawareness. ^,

Nonselective β-blockers and, to a lesser degree, β ₁ -selective agents have been associated with a rise in the serum potassium level. Suppression of aldosterone and inhibition of β ₂ -linked, sodium–potassium membrane transport in skeletal muscle have been proposed as possible mechanisms. ^, This effect may be of most relevance to patients with CKD and in patients treated with ACE inhibitors or ARBs, particularly when used in conjunction with MRAs for resistant hypertension.

β-Blockers can affect plasma lipids. Long-term use of β-blockers has been associated with an increase in triglyceride levels and a decrease in the level of HDL cholesterol. β-Blockers with increased β ₁ selectivity or with partial agonist activity appear to have less effect on the lipid profile. Nonselective β-blockers without partial agonist activity may decrease the HDL cholesterol level by up to 20%; an increase in triglyceride levels of up to 50% has been reported. The effects of β-blockade on lipid metabolism are due primarily to the modulation of lipoprotein lipase activity. Very-low-density lipoprotein (VLDL) cholesterol and triglyceride metabolism is reduced in the setting of unopposed β-adrenergic stimulation of lipoprotein lipase activity. Decreased VLDL metabolism results in decreases in HDL cholesterol levels.

β-Blockers were associated with a small but significant annual increase in reported sexual dysfunction (5/1000 patients; 95% CI, 2–8). None of the AEs differed by lipid solubility.

Abrupt withdrawal of β-blockers may be associated with rebound hypertension and worsening angina in patients with coronary artery disease. MI has been reported. These withdrawal symptoms may be caused by increased sympathetic activity, which could reflect adrenergic receptor upregulation during long-term sympathetic blockade. Gradual tapering of β-blockers decreases the risk of withdrawal. Withdrawal symptoms have been reported more commonly with abrupt discontinuation of relatively short-acting drugs.

Initially introduced in the 1960s as antianginal agents, dihydropyridine CCBs are now advocated as first-line therapy for hypertension. ^, The pharmacologic effects of these drugs are related to their ability to attenuate cellular calcium uptake. CCBs inhibit the entry of calcium or its mobilization from intracellular stores. Calcium channels have binding sites for activators and antagonists. The voltage-dependent, L-type calcium channel is a multimeric complex composed of α ₁ -, α ₂ -, ω-, β-, and γ-subunits. These channels have different binding sites for the various CCBs and are regulated by voltage-dependent and receptor-dependent events involving protein phosphorylation and G-protein coupling resulting from, for example, β-adrenergic stimulation. Each class of CCB is quantitatively and qualitatively unique; the CCB compounds possess different sensitivities and selectivities for binding pharmacologic receptors and the slow calcium channel in various vascular tissues. Even within the dihydropyridine class, there is considerable pharmacologic variability. This differential selectivity of action has important clinical implications for the use of these drugs and explains why the CCBs vary considerably in their effects on regional circulatory beds, sinus and AV nodal function, and myocardial contractility. The selectivity further explains the diversity of indications for clinical use, ancillary effects, and side effects.

CCBs uniformly lower peripheral vascular resistance in patients regardless of age, sex, ancestry, salt sensitivity, or comorbid conditions. There are at least three mechanisms through which CCBs lower BP. First, CCBs reduce peripheral vascular resistance by attenuating the calcium-dependent contractions of vascular smooth muscle. Contraction of vascular smooth muscle depends on the total cytosolic calcium concentration, which in turn is regulated by two distinct mechanisms. Depolarization of vascular smooth muscle tissue depends on the inward flux of calcium through voltage-sensitive L-type and T-type calcium channels. Hypertensive patients have an abnormal influx of calcium, which promotes increased peripheral vascular resistance. Calcium is released from the sarcoplasmic reticulum in response to extracellular calcium influx via a nonvoltage-dependent pathway. Cytosolic calcium binds to calmodulin, initiating a sequence of cellular events that promote the interaction between actin and myosin and results in smooth muscle contraction. Therefore the importance of calcium channels lies in their pivotal role in linking cell membrane electrical activity to biologic responses. Calcium influxes through L-type channels from extracellular sources and intracellular sources are both attenuated by CCBs. ^,

Second, CCBs decrease vascular responsiveness to Ang II and the synthesis and secretion of aldosterone. CCBs also interfere with α ₂ -adrenergic receptor–mediated vasoconstriction and possibly α ₁ -adrenergic receptor–mediated vasoconstriction. ^, The maximal vasodilatory response, as measured by forearm blood flow, appears to be inversely related to the patient’s plasma renin activity and Ang II concentration. Thus it is possible that there is a greater influence of the calcium influx–dependent vasoconstriction in patients with low-renin hypertension.

Finally, CCBs may induce mild diuresis. Dihydropyridines, in particular, reduce preglomerular resistance and maintain or increase the GFR because of their preferential vasodilatory action on the kidney afferent arteriole. The vasorelaxant properties of nifedipine and verapamil appear to be nitric oxide independent, whereas those of amlodipine are partly nitric oxide dependent. ^, This effect of amlodipine is thought to be mediated by the inhibition of local ACEs and increases in vasodilatory bradykinins. Subsequently, decreased tubular sodium reabsorption and improved kidney blood flow and natriuresis are observed. The sodium excretion rate tends to correlate with the reduction in BP.

Despite their shared mechanism of action, the CCBs are a heterogeneous group of compounds. They differ with respect to pharmacologic profile, chemical structure, pharmacokinetic profile, tissue specificity, receptor binding, clinical indications, and side-effect profile ( Tables 48.14 and 48.15 ). Two primary subtypes are distinguished on the basis of their behavior: dihydropyridines and nondihydropyridines. The nondihydropyridines are further divided into two classes—benzothiazepines (diltiazem) and diphenylalkylamines (verapamil). Their distinctly different pharmacologic effects are summarized in Tables 48.14 and 48.15 .

Although all CCBs vasodilate coronary and peripheral arteries, the dihydropyridines are the most potent. Because medications in this subclass of CCBs are membrane-active drugs, they exert a greater effect on the peripheral vessels than on myocardial cells, which depend less heavily on the external calcium influx. Their potent vasodilatory action prompts a rapid compensatory increase in sympathetic nervous activity, as mediated by baroreceptor reflexes creating a neutral or positive inotropic stimulus. Longer-acting dihydropyridines, however, do not appear to activate the SNS. By contrast, the nondihydropyridines are moderately potent arterial vasodilators but directly decrease AV nodal conduction and have negative inotropic and chronotropic effects, which are not abrogated by the reflex increase in sympathetic tone. Because of their negative inotropic action, their use is contraindicated in patients with HFrEF. As expected, these drugs are more effective at reducing stress-induced cardiovascular responses than dihydropyridines.

A clinically useful classification system for CCBs categorizes them by their duration of action into short-acting and long-acting agents (see Tables 48.14 and 48.15 ). This schema is helpful because the short-acting agents are no longer recommended for the management of hypertension because of their rapid duration of action and risk of orthostatic hypotension and associated complications, as well as stimulation of the SNS, which may predispose patients to angina, MI, and stroke. The long-acting drugs are commonly divided into three generations. First-generation agents, such as nifedipine, have shorter half-lives and require multiple daily doses. Second-generation agents have been modified into extended-release (ER) formulations, requiring once-daily dosing. The third-generation agents have intrinsically longer plasma or receptor half-lives, possibly related to their greater lipophilicity.

All CCBs exert natriuretic and diuretic effects. ^, Experimental studies and studies in humans with hypertension have indicated that the increase in sodium excretion is, in part, independent of vasodilatory action or changes in GFR, kidney blood flow, or filtration fraction. This effect is probably the result of changes in kidney sodium handling that can potentiate the antihypertensive vascular effect. In normal persons, CCBs acutely increase sodium excretion, frequently in the absence of changes in BP. In hypertensive persons, the short-term administration of CCBs uniformly increases sodium excretion 1.1- to 3.4-fold; the magnitude of the increase is not related to the decrease in BP.

The natriuretic effect appears to persist in the long term. Long-term administration of CCBs to hypertensive patients results in a cumulative sodium deficit that is abruptly reversed with the discontinuation of the drug. Natriuresis occurs 3 to 6 hours after the morning dose. The net negative sodium balance levels off after the first 2 to 3 days of administration but persists for the duration of therapy. There are no significant changes in long-term body weight, serum concentrations of potassium, urea nitrogen, catecholamines, or GFR. Moreover, stimulation of renin release and aldosterone does not occur to an appreciable degree. It has been postulated that the natriuresis induced by CCBs increases distal sodium delivery to the macula densa, suppressing renin release. Because Ang II mediates aldosterone synthesis by way of cytosolic calcium messengers, CCBs blunt this response as well.

The mechanism whereby CCBs induce natriuresis appears to be direct inhibition of kidney tubular sodium and water absorption. Dihydropyridines increase urinary flow rate and sodium excretion without changing the filtered water and sodium load. Studies have suggested that CCBs may diminish sodium uptake at the amiloride-sensitive sodium channels. Inhibition of water reabsorption occurs distally to the late distal tubule. Proximal tubular sodium reabsorption may be inhibited by higher dosages. One possible mediator of this effect is atrial natriuretic peptide. In human studies, CCBs augment atrial natriuretic peptide release and potentiate its action at the level of the kidney. Other potential mediators are under investigation. How much the natriuretic effects contribute to the antihypertensive response is unknown, but unlike effects of other vasodilators, the changes attenuate the expected adaptive changes in sodium handling.

The kidney hemodynamic effects of CCBs are variable and depend primarily on which vasoconstrictors modulate the kidney vascular tone. Experimentally, CCBs improve GFR in the presence of the vasoconstrictors norepinephrine and Ang II, as well as others, by preferentially attenuating afferent arteriolar resistance. The efferent arteriole appears to be refractory to these vasodilatory effects. Patients with primary hypertension appear to be more sensitive to the kidney hemodynamic effects of CCBs than normotensive patients, and this effect is more pronounced with more advanced CKD. Short-term administration of CCBs results in little change in, or augmentation of, GFR and kidney plasma flow, no change in the filtration fraction, and reduction of kidney vascular resistance. Long-term administration is not associated with significant changes in kidney hemodynamics. The response is maximal in the presence of Ang II, which selectively causes postglomerular vasoconstriction. Clinically significant changes are counteracted by the reduction in kidney perfusion pressure coincident with a reduction of BP.

The long-term effects of CCBs on kidney function are variable. ^, In hypertensive patients, the effects on kidney hemodynamics vary. Some patients exhibit no change in GFR, whereas others have an exaggerated increase in GFR and kidney plasma flow. Even normotensive patients with a family history of hypertension have an exaggerated hemodynamic response.

The effects of CCBs on proteinuria also vary with respect to the specific drug and the degree of BP reduction achieved. Some dihydropyridines increase protein excretion by up to 40%. It is not clear whether this increase is a result of hemodynamic vasodilation at the afferent arteriole, resulting in increased glomerular capillary pressure (because CCBs directly impair kidney autoregulation), changes in glomerular basement membrane permeability, or increased intrarenal Ang II. By contrast, felodipine, diltiazem, and verapamil do not appear to have this effect and may lower protein excretion, possibly by also decreasing the efferent arteriolar tone and glomerular pressure. Clinical implications of these differential effects remain to be determined.

Large clinical trials underscore this controversy. In African Americans with hypertension and mild-to-moderate CKD, treatment with an ACE inhibitor demonstrated superior renoprotective effects compared with amlodipine. This effect was independent of BP reduction and was more evident in proteinuric patients; it was also suggestive in patients with <300 mg of protein/day at baseline. Hypertensive patients with diabetic nephropathy also fared worse with amlodipine than with ARB therapy. Patients experienced higher rates of progression of CKD and all-cause mortality in the amlodipine- and placebo-treated groups. The latter effect was independent of the achieved BP. However, it should be emphasized that coadministration of a dihydropyridine and a RAAS inhibitor does not abrogate the protective effect of RAAS inhibitors on kidney function. ^, It has been postulated that the selective dilation of the afferent arteriole favors an increase in glomerular capillary pressure that perpetuates progression.

All long-acting CCBs are considered among first-line antihypertensive agents and appear to be equally efficacious and safe vis-à-vis blood pressure lowering. ^, In contrast to other vasodilators, CCBs attenuate the reflex increase of neurohormonal activity that accompanies a reduction in BP, and in the long term, they inhibit or do not change the sympathetic activity. ^, The longer-acting agents such as amlodipine produce sustained SBP reductions of 10 to 14 mmHg in placebo-controlled RCTs when used as monotherapy, with no appreciable development of tolerance. The CCBs are effective in young, middle-aged, and older patients with white coat hypertension and mild, moderate, or severe hypertension. Their efficacy may be determined by genetic polymorphisms. CCBs are equally efficacious in men and women, in patients with a high or low plasma renin activity regardless of dietary salt intake. Effects of CCBs are diminished in smokers. CCBs are effective and safe in patients with hypertension and coronary artery disease, as well as in patients with ESKD. CCBs also reduce adverse cardiovascular events and slow the progression of atherosclerosis in normotensive patients with coronary artery disease.

The use of CCBs is contraindicated in patients with HFrEF (except, perhaps, amlodipine or felodipine). These drugs should not be used as first-line antihypertensive agents in patients with heart failure, a history of MI, or unstable angina.

Among the different categories, dihydropyridines appear to be the most powerful for reducing BP but may also be associated with more pronounced activation of baroreceptor reflexes. Dihydropyridines induce a more prominent shift in the sympathovagal balance that favors sympathetic predominance compared with nondihydropyridines. In general, however, compared with other vasodilators, CCBs attenuate the reflex increase in sympathetic activity—increased heart rate, cardiac index, plasma norepinephrine levels, and renin activity.

The nondihydropyridines verapamil and, to a lesser extent, diltiazem exert greater effects on the heart and have less vasoselectivity. These drugs typically reduce the heart rate, slow AV conduction, and depress contractility ( Table 48.16 ). Generally, they should not be used together with β-blockers because of increased risk for heart block.

CCBs are not associated with significant impairments in glycemic control or sexual dysfunction. The rapid antihypertensive action of CCBs may encourage patient adherence. Orthostatic changes tend not to occur because venoconstriction remains intact. AEs are usually transient and are the direct result of vasodilation. Hypotension is most common with intravenous administration. The most common AE of the dihydropyridines is peripheral edema; it is dose related and thought to be the result of uncompensated precapillary vasodilation, which causes increased intracapillary hydrostatic pressure. The edema is not responsive to diuretics but improves or resolves with the addition of an ACE inhibitor or ARB, which preferentially vasodilates postcapillary beds and reduces intracapillary hydrostatic pressure. Other AEs related to vasodilation include headache, nausea, dizziness, and flushing, and occur more commonly in women. The nondihydropyridines verapamil and isradipine more commonly cause constipation and nausea. The gastrointestinal effects are directly related to the inhibition of calcium-dependent smooth muscle contraction–reduced peristalsis and relaxation of the lower esophageal sphincter. Another common AE of dihydropyridines is gingival hyperplasia, which is exacerbated in patients who are also taking cyclosporine. Dihydropyridines lead to the accumulation of gingival inflammatory B-cell infiltrates as stimulated by bacterial plaque, immunoglobulins, and folic acid, which causes the growth of the gingiva. This growth can be controlled with regular periodontal treatment and reversed with discontinuation of the drug.

CCBs are notable among antihypertensive agents because of their metabolic neutrality. Because the calcium influx across β-cell membranes helps regulate insulin release, CCBs might predispose to low insulin levels. At typical therapeutic levels, CCBs have no effect on serum glucose concentrations, insulin secretion, or insulin sensitivity in persons with and without diabetes mellitus. The use of CCBs was not significantly associated with incident diabetes compared with other antihypertensive agents in a meta-analysis of RCTs. The association with diabetes was lowest for ACE inhibitors and ARBs, followed by CCBs, β-blockers, and diuretics. Furthermore, it was recently demonstrated that CCBs can even prevent diabetes and increase β-cell survival in vitro. The mechanism behind the β-cell mass destruction is the human islet cell protein TXNIP (thioredoxin-interacting protein), which is upregulated by hyperglycemia. Orally administered verapamil resulted in a reduction of TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from streptozotocin-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in ob/ob mice. CCBs do not increase triglyceride or LDL cholesterol and do not reduce HDL cholesterol. CCBs do not precipitate hyponatremia, hyperkalemia, hypokalemia, or hyperuricemia. Therefore they are suitable agents for patients with dysmetabolic syndromes or diabetes.

Properties beyond their antihypertensive actions make the CCBs particularly useful in certain clinical situations. CCBs lower arterial pressure and also have variable effects on cardiac function. All CCBs are vasodilators and increase coronary blood flow. With the exception of the short-acting dihydropyridines, most CCBs reduce heart rate, improve myocardial oxygen demand, improve ventricular filling, diminish ventricular arrhythmias, reduce myocardial ischemia, and conserve contractility, ^, making them suitable for patients with angina or diastolic dysfunction. In short-term use, CCBs improve diastolic relaxation; when administered over a long term, they reduce left ventricular wall thickness, may prevent the development of hypertrophy and may improve arterial compliance. These effects may be crucial in hypertensive patients because LVH is one of the strongest risk predictors for cardiovascular morbidity and mortality. Verapamil may also be used for secondary cardioprotection to reduce reinfarction rates in patients who are intolerant of β-blockers (unless they have concomitant heart failure) and in patients with chronic headaches. The BP-independent inhibition of atherogenesis by CCBs may be another indication to use a CCB, particularly in high-risk patients, such as those with diabetes and ESKD. ^,

The use of CCBs may prevent or slow the decline of dementia. In the Systolic Hypertension in Europe (SYST-EUR) trial, nitrendipine use was associated with a lower risk of incident dementia, a finding also seen in some other observational studies. ^, However, a meta-analysis of data from 31,090 individual participants from 6 observational studies found no significant benefit of CCB over other antihypertensive classes on dementia risk.

Drug interactions are not uncommon ( Table 48.17 ). Concurrent use of a CCB and amiodarone exacerbates sick sinus syndrome and AV block. Diltiazem, verapamil, and dihydropyridines have been shown to increase the levels of cyclosporine (including the microemulsion formulation), tacrolimus, and sirolimus. This interaction may be clinically useful for reducing the dosage and cost associated with immunosuppressive therapy. Frequent monitoring of serum concentrations of calcineurin inhibitor is recommended. Diltiazem is a potent inhibitor of CYP3A4, which is responsible for the metabolism of methylprednisolone. Coadministration of diltiazem and methylprednisolone resulted in a more than 2.5-fold increase in the steroid blood level and enhanced adrenal suppressive responses. Coadministration of diltiazem also increased nifedipine levels by 100% to 200%. This combination has additive antihypertensive efficacy and appears to be safe. Concomitant administration of CCBs with the digitalis glycosides resulted in up to a 50% increase in serum digoxin concentrations because of reduced kidney clearance of digoxin, an effect that appears to be dose dependent. Insofar as dihydropyridine CCBs partially suppress aldosterone synthesis, they provide an attractive alternative for patients who cannot tolerate blockade of the RAAS.

Several issues regarding the inherent safety of CCBs have come under scrutiny. CCBs may be associated with an increased risk of gastrointestinal hemorrhage, particularly in older persons. Diltiazem inhibits platelet aggregation in vitro, but the clinical relevance of this finding has not been substantiated. A systematic review and meta-analysis of 17 studies showed a marginally higher pooled risk of GI bleeding among CCB users (RR 1.17, CI 1.01–1.36), but this increased risk was observed primarily in observational studies that did not adjust for prior history of GI bleeding. Nonetheless, it is prudent to use caution when coadministering CCBs with NSAIDs because NSAIDs may exacerbate the risk of bleeding and may antagonize the antihypertensive effects of CCBs. ^, There have been concerns regarding a possible relation between the long-term use of CCBs and breast cancer. A population case–control study of breast cancer showed that the use of CCBs for more than 10 years was associated with ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2–4/9; P =.04) and lobular breast cancer (OR, 2.6; 95% CI, 1.3–5.3; P =.01), respectively. However, two recent large population-based observational studies demonstrated no association between CCB use and breast cancer. ^,

Short-acting CCBs have been associated with a small increased risk of MI in meta-analyses ^, when compared with other agents. It has been speculated that the disadvantageous activation of the RAAS and SNS induced by the short-acting agents may predispose to myocardial ischemia. Currently, there is no evidence to prove the existence of additional beneficial or detrimental effects of CCBs on coronary disease events, including fatal or nonfatal MIs and other deaths from coronary heart disease. Because of the potential risk, however, as well as for simplicity and improved patient adherence, longer-acting agents should be considered over short-acting CCBs for the management of hypertension. ^,

The use of CCBs has also been associated with the development of chyloperitoneum among patients receiving peritoneal dialysis. ^, A rare complication, chyloperitoneum seems to be most frequently described with the use of the dihydropyridines manidipine and lercanidipine. Cessation of the CCB generally leads to complete resolution. The mechanism of chyloperitoneum via CCBs in PD is not clear but possibly related to inhibition of lymphatic pump contraction.

Central adrenergic agonists act by crossing the blood-brain barrier and have a direct agonist effect on α ₂ -adrenergic receptors located in the midbrain and brainstem. Binding to the I ₁ imidazoline receptors in the brain may also play a role in the inhibition of central sympathetic output. ^, Drugs in this class bind to the α-adrenergic or I ₁ imidazoline receptors with some degree of specificity ( Table 48.18 ). Moxonidine and rilmenidine have a 30-fold greater specificity for the I ₁ imidazoline receptor than the α ₂ receptor. Clonidine, by contrast, exhibits a fourfold greater specificity for the I ₁ imidazoline receptor than for the α ₂ receptor.

AEs are thought to be largely related to α ₂ -receptor binding. Moxonidine and rilmenidine have reduced central side effects because of the lower activity at the α ₂ receptor relative to other agents. ^, In addition to decreasing the total sympathetic outflow, binding to these receptors results in increased vagal activity. A reduction in catecholamine release and turnover, as evidenced by decreased biochemical markers of noradrenergic activity, such as plasma concentrations of norepinephrine, correlated with the magnitude of BP lowering.

Stimulation of both receptor types is probably mediated through the same neuronal pathways. The classic α ₂ -receptor agonists, such as clonidine and α-methyldopa (acting through its active metabolite, α-methylnorepinephrine), result in vasodilation in the resistance vessels and thus a reduction in peripheral vascular resistance. Despite vasodilator action, reflex tachycardia generally does not occur, probably as a result of peripheral sympathetic inhibition.

The selective I ₁ receptor agonists moxonidine and rilmenidine are predominantly arterial vasodilators that lead to a reduction in peripheral vascular resistance. Moxonidine is associated with a reduction in plasma renin activity. The central α ₂ -adrenergic agonists may also stimulate peripheral α ₂ -adrenergic receptors. This effect predominates at high drug concentrations. These receptors mediate vasoconstriction, which may result in a paradoxical increase in BP. Overall, these drugs generally result in a decrease in peripheral vascular resistance, slowing of the heart rate, and either no change or a mild decrease in cardiac output. ^, The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 48.19 and 48.20 .

Clonidine is a central-acting α-adrenergic agonist. ^{, ,} The usual oral dosage is 0.1 mg two to three times daily, adjusted as needed in 0.1- to 0.2-mg increments. The usual maintenance dosage is 0.3 to 0.9 mg daily in two to three divided doses. Total doses more than 1.2 mg daily are usually not associated with a greater effect. The onset of activity is 30 to 60 minutes after an oral dose. The peak antihypertensive activity occurs within 2 to 4 hours. The duration of the antihypertensive effect is 6 to 10 hours. The half-life of the absorbed drug is 6 to 23 hours. Hepatic metabolism to inactive metabolites is followed by kidney excretion. Transdermal patches are available and may be applied on a once-weekly basis. The drug half-life with the transdermal patch is approximately 20 hours after removal of the patch. With a transdermal patch, steady-state drug levels are reached within approximately 3 days. Dose adjustment is not needed for patients with any degree of CKD including ESKD. Approximately 5% of clonidine body stores are removed after a 5-hour hemodialysis session.

Guanfacine is a centrally acting antihypertensive drug with actions similar to those of clonidine. Effective dosages are 1 to 3 mg daily. Peak levels are noted between 1 and 4 hours. The drug half-life is approximately 17 hours. The drug is 70% protein bound. It is metabolized in the liver, with kidney excretion of 40% to 75% as an unchanged drug. Limited data are available on dosing in CKD, but dosage adjustments do not appear warranted.

α-methyldopa (or methyldopa) is a methyl-substituted amino acid that is active after conversion to an active metabolite. This active metabolite, α-methylnorepinephrine, accumulates in the CNS and is selective for α ₂ -adrenergic receptors. The initial dosage of α-methyldopa in hypertension is 250 mg two to three times daily. This dose may be increased at intervals of not less than 2 days until a therapeutic response is achieved. The usual maintenance dosage is 500 mg to 2 g daily in two to four doses. The maximum recommended daily dose is 3 g. An initial response occurs within 3 to 6 hours after dosing. The peak response occurs at 6 to 9 hours. The drug is approximately 50% metabolized by the liver. The drug half-life is increased in patients with CKD. Excretion in the urine is largely in the form of an inactive metabolite. The dosing interval should be increased to every 12 to 24 hours in patients with advanced CKD. Approximately 60% of α-methyldopa is removed with hemodialysis. A supplemental dose is recommended after dialysis treatment.

Moxonidine is a central I ₁ imidazole and α ₂ -receptor agonist. ^{, ,} Serum concentration peaks are reached within 30 to 180 minutes; 90% of the dose is excreted through the urine within 24 hours, and 50% of this is as unchanged drug. The average half-life is 2 hours. For the management of hypertension, the starting dosage is 0.2 to 0.4 mg/day. The dose may be increased after several weeks to 0.2 to 0.3 mg twice daily. The maximum daily dose is 0.6 mg. Selectivity for the I ₁ imidazoline receptor results in fewer central AEs, such as dry mouth and sedation, compared with those of clonidine. Drug clearance is delayed in patients with impaired kidney function. Single doses of 0.2 mg and a maximum daily dosage of 0.4 mg should not be exceeded in patients with CKD.

Rilmenidine is a centrally acting imidazole receptor and α ₂ -adrenergic receptor agonist. ^{, ,} Rilmenidine binds preferentially to central I ₁ imidazoline receptors in the brainstem. At higher doses, rilmenidine can bind and activate central α ₂ -adrenergic receptors. Antihypertensive effects occur within 1 hour after a single 1-mg dose. The duration of action is 10 to 12 hours. The concentration after oral dosing peaks at approximately 2 hours. Steady-state plasma levels are reached by day 3. Rilmenidine is eliminated primarily unchanged in the urine. The usual oral dosage is 1 mg once or twice daily. Dose reductions are required for patients with impaired kidney function. In patients with advanced CKD, the dose should be decreased to 1 mg every other day.

Central α ₂ – and I ₁ imidazoline receptor agonists have little, if any, clinically important effect on kidney plasma flow, GFR, or the RAAS. The fractional excretion of sodium is unchanged. Body fluid composition and weight are not altered. These agents may result in decreased kidney vascular resistance, as mediated by a decrease in preglomerular capillary resistance related to decreased levels of circulating catecholamines.

The antihypertensive efficacy of this class of drugs has been confirmed in large numbers of patients and although not considered first-line, they provide effective monotherapy for hypertension. Moxonidine and rilmenidine have been associated with decreased plasma glucose concentrations and may improve insulin sensitivity. These drugs may also decrease total cholesterol, LDL, and triglyceride levels ^{, ,} and may play a role in the management of metabolic syndrome. They may also be of benefit in patients with congestive heart failure. Treatment with rilmenidine and moxonidine reverses LVH and improves arterial compliance. This effect was associated with a reduction in plasma concentrations of atrial natriuretic peptide.

Stimulation of α ₂ -adrenergic receptors in the CNS induces several AEs of these drugs, including sedation and drowsiness. The most common AE related to α ₂ -adrenergic activation is dry mouth caused by a decrease in salivary flow. This decrease is attributed to centrally mediated inhibition of cholinergic transmission. Clonidine in high doses may precipitate a paradoxic hypertensive response related to the stimulation of postsynaptic vascular α ₂ -adrenergic receptors. α-Methyldopa use has been associated with a positive result on the direct Coombs test in patients with and without hemolytic anemia. Because of a long history of safe use during pregnancy, α-methyldopa remains a common therapeutic agent for hypertensive disorders of pregnancy and for essential hypertension during pregnancy. ^, Despite its position as one of the first-line agents for management of hypertension in pregnancy, α-methyldopa is no longer commercially available in the United States. ^, The α ₂ -adrenergic agonists are associated with sexual dysfunction and may produce gynecomastia in men and galactorrhea in men and women.

Abrupt cessation of α ₂ -adrenergic blockers may result in rebound hypertension, which occurs 18 to 36 hours after the cessation of short-acting agents. Patients may experience tachycardia, tremor, anxiety, headache, nausea, and vomiting. This syndrome may be related to downregulation of the α ₂ -adrenergic receptors in the CNS in the setting of long-term use of these agents. These agents have a higher specificity for the I ₁ receptor and appear to produce significantly fewer CNS effects, such as dry mouth and drowsiness. Rebound hypertension secondary to abrupt withdrawal has not been associated with moxonidine or rilmenidine.

Reserpine, a Rauwolfia alkaloid, reduces BP by decreasing the activity of central and peripheral noradrenergic neurons. Reserpine blocks norepinephrine and dopamine uptake into the storage granules of noradrenergic neurons. The result is norepinephrine depletion. A similar effect is seen in central dopaminergic and serotoninergic neurons. At the dosages currently used to treat hypertension, the major effect of the use of reserpine is in the CNS. Reserpine results in a rapid reduction in cardiac output, heart rate, and peripheral vascular resistance. Enhanced vagal activity may also be involved. Tolerance to the antihypertensive effects of reserpine does not occur.

Reserpine is used at initial dosages of 0.1 to 0.25 mg daily. Approximately 40% of an oral dose is absorbed. The half-life is 50 to 100 hours. Extensive hepatic metabolism occurs; 1% is recovered as unchanged compound in the urine. The maximal clinical effect is observed 2 to 3 weeks after initiation of therapy. No dosage adjustment is necessary for patients with kidney insufficiency. Dosage supplementation is not required after hemodialysis.

The GFR and kidney plasma flow are not affected by reserpine therapy. Kidney vascular resistance may be reduced, perhaps mediated by decreased sympathetic stimulation of vascular α-adrenergic receptors. Significant effects on the RAAS have not been observed. Kidney handling of sodium and potassium is unchanged.

Reserpine provides effective therapy as a single agent or in combination with HCTZ or HCTZ and hydralazine. ^, This has been observed in numerous large and small trials, including the Veterans Administration Cooperative Study on Antihypertensive Agents, Hypertension Detection and Follow-up Program, and the Multiple Risk Factor Intervention Trial. Reserpine used in combination with a diuretic has shown comparable efficacy to combinations of β-blockers and diuretics. In these studies, the dose of reserpine was between 0.1 and 0.3 mg daily, which is many times lower than the doses used in the 1960s that led to reserpine’s reputation as having a poor side-effect profile. The most common AE of reserpine is nasal congestion, which is reported in 6% to 20% of patients. Unlike other AEs, nasal congestion does not appear to decrease at lower drug dosages and is thought to be related to the cholinergic effects of the drug. Increased gastric motility and gastric acid secretion can occur; however, the incidence of dyspepsia or peptic ulcer disease with reserpine therapy is not greater than that with other antihypertensive drug treatments. Inability to concentrate, sedation, sleep disturbance, and depression have been reported. Other AEs include weight gain, increased appetite, and sexual dysfunction.

Direct-acting vasodilators reduce BP by decreasing peripheral vascular resistance. These drugs act directly on vascular smooth muscle with the selective vasodilation of the arteriolar resistance vessels and have little or no effect on the venous capacitance vessels. There is no effect on the functioning of carotid or aortic baroreceptors. The vasodilating effects are thought to involve inhibition of calcium uptake into the cells. Decreases in arterial pressure are associated with a decrease in peripheral resistance and a reflex increase in cardiac output. Sodium and water retention are promoted secondary to the stimulation of renin release and possibly by direct effects on kidney tubules. The arteriolar dilation produced by these drugs causes a decrease in cardiac afterload, and the absence of venodilation leads to an increase in venous return to the heart, which produces an elevated preload. These combined effects result in increased cardiac output. The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 48.21 and 48.22 .

The initial oral dose of hydralazine for hypertension should be 10 mg four times daily, increasing to 50 mg four times daily over several weeks. Patients may require doses of up to 300 mg/day. Dosing can be changed to twice daily for maintenance. The drug may also be used as an intravenous bolus injection or a continuous infusion. The elimination half-life is 1.5 to 8 hours and varies with the acetylation rate in the liver. Slow and fast acetylators have been described. The onset of action is approximately 1 hour. In patients with mild-to-moderate CKD, the dosing interval should be increased to every 8 hours. In patients with advanced CKD, the dosing interval should be increased to every 8 to 24 hours. No dose supplement is required after hemodialysis or peritoneal dialysis (see Table 48.6 ).

Minoxidil is more potent than hydralazine. For severe hypertension, the initial recommended starting dose is 2.5 mg as a single daily dose, increasing to 10 to 20 or 40 mg in single or divided doses. Minoxidil is usually used in conjunction with salt restriction and diuretics to prevent fluid retention. Concomitant therapy with a β-adrenergic blocking agent is often required to control tachycardia related to minoxidil use. The onset of the antihypertensive effect is within 30 to 60 minutes. The peak response occurs at 4 to 8 hours. The drug is 90% metabolized by the liver. The glucuronide metabolite has reduced pharmacologic effects but accumulates in patients with ESKD. Kidney excretion is 90%. Dose adjustments may be required for patients with advanced CKD, although the mean daily doses required to control BP are similar in patients with normal and impaired kidney function (see Table 48.6 ).

Hydralazine and minoxidil both increase the juxtaglomerular cell secretion of renin, which is associated with increased Ang II and aldosterone levels. Long-term use is associated with the return of plasma aldosterone levels to baseline. Retention of salt and water may be attributed to direct drug effects on the proximal convoluted tubule. Kidney vascular resistance is decreased in association with a relaxation of resistance vessels. GFR and kidney plasma flow are preserved.

Hydralazine is commonly used in practice to reduce afterload in heart failure among patients with reduced left ventricular function. Hydralazine has been frequently used to treat pregnancy-associated hypertension in view of its relatively low teratogenicity. Its use can cause adrenergic activation and fluid retention.

Treatment with hydralazine has been associated with the development of drug-induced autoimmunity, including systemic lupus erythematosus and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Hydralazine-induced lupus generally occurs early in therapy and can occur in 6% to 10% of patients receiving high doses of hydralazine; kidney involvement is rare. It is seen most frequently in women and rarely in African Americans. Hydralazine-induced lupus is reversible when hydralazine is discontinued, but months may be required for complete clearing of symptoms. Hydralazine-induced ANCA-associated vasculitis generally occurs with longer duration of treatment and involves high titers of myeloperoxidase-specific (MPO) ANCA antibodies. It manifests as rapidly progressive glomerulonephritis (RPGN). Treatment often involves not only cessation of hydralazine but also immunosuppression and, in some cases, plasmapheresis. In one case series of 51 patients with hydralazine-induced ANCA GN and follow-up data available, 37% of patients reached the combined endpoint of ESKD or death, while the remaining 63% had favorable outcomes with mean serum creatinine at end of follow-up of 1.49 mg/dL.

Minoxidil is commonly reserved for severe or intractable hypertension. ^, Minoxidil is frequently a last-resort therapy in patients with CKD unresponsive to other therapies. It must nearly always be used in combination with a β-blocker and a loop diuretic to prevent tachycardia and fluid retention. Hypertrichosis is a common AE. Pericarditis and pericardial effusions have been described. An increase in left ventricular mass has been reported, which may be related to adrenergic hyperactivity. Oral minoxidil has gained renewed popularity as an off-label treatment for androgenetic hair loss in women and men.

The nonselective agents phentolamine and phenoxybenzamine have an occasional role in hypertension management. Phentolamine is administered parenterally, and the longer-acting agent phenoxybenzamine has been used orally for the management of hypertension associated with pheochromocytoma. Phenoxybenzamine is a moderately selective, peripheral α ₁ -adrenergic antagonist. Its specificity for the α ₁ -adrenergic receptor is 100 times greater than that for the α ₂ -adrenergic receptor.

Phenoxybenzamine is a long-acting α-adrenergic blocking agent. This agent irreversibly and covalently binds to α receptors only. β Receptors and the parasympathetic system are not affected by phenoxybenzamine. The total peripheral resistance is decreased, and cardiac output increases with phenoxybenzamine. Phenoxybenzamine is also believed to inhibit the uptake of catecholamines into adrenergic nerve terminals and extraneural tissues. The usual oral dose of phenoxybenzamine for the treatment of pheochromocytoma is initially 10 mg twice daily, with the dose gradually increased every other day to dosages ranging between 20 and 40 mg two or three times daily. The final dosage should be determined by the BP response. Phenoxybenzamine may be administered with a β-blocking agent if tachycardia becomes excessive during therapy. The pressor effects of a pheochromocytoma must be controlled by α-blockade before β-blockers are initiated. With oral use, the pheochromocytoma symptoms decrease after several days. The oral bioavailability is 20% to 30%. The drug is extensively metabolized by the liver. Phenoxybenzamine should be administered cautiously to patients with kidney impairment. Specific dosage recommendations are not available.

Phentolamine is an α-adrenergic blocking agent that produces peripheral vasodilation and cardiac stimulation, with a resulting decrease in BP in most patients. The drug is used parenterally. The usual dose is 5 mg, repeated as needed. The onset of activity with intravenous dosing is immediate. The drug is not absorbed well orally; its half-life is 19 minutes. Phentolamine is metabolized by the liver, with 10% excreted in the urine as unchanged drug.

Phenoxybenzamine has no clear effect on RAAS. Blood volume and body weight are not altered. Salt and water retention do not occur. GFR and effective kidney plasma flow would be expected to increase. Kidney vascular resistance probably decreases in proportion to the degree of blockade of α-adrenergic receptors.

Phenoxybenzamine is used primarily as an agent to counteract the excessive α-adrenergic tone associated with pheochromocytoma. Tachycardia may result from an α-adrenergic blockade, which unmasks β-adrenergic effects with epinephrine-secreting tumors. This may be controlled with concurrent use of a β-adrenergic antagonist. α-Adrenergic blockade must be initiated before β-adrenergic blockade to avoid paradoxic hypertension. AEs of phenoxybenzamine are sedation, weakness, nasal congestion, hypertension, and tachycardia.

Drugs of the peripheral α ₁ -adrenergic antagonist class, including doxazosin, prazosin, and terazosin, are selective antagonists of the postsynaptic α ₁ -adrenergic receptor. These drugs, which blunt the increases in arteriolar and venous tone mediated by norepinephrine released from sympathetic nerve terminals, act at the α ₁ -adrenergic receptor located postjunctionally in the blood vessel wall. The affinity of these drugs for the α ₂ receptor is low. Because of the selective α ₁ action, there is no interference with the negative feedback control mechanisms that are mediated by the prejunctional α ₂ receptors. As a result, the reflex tachycardia associated with the blockade of the presynaptic α ₂ receptor decreases substantially. The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 48.23 and 48.24 .

Table 48.24

Pharmacodynamic Properties of Peripheral α ₁ -Adrenergic Antagonists

Drug	Initial Dose (mg)	Usual Dose (mg)	Maximum Dose (mg)	Interval	Peak Response (h)	Duration of Response (h)
Doxazosin	1	8	16	qd, qid	4–8	24
Prazosin	1	3–20	20	bid, qid	0.5–1.5	10
Terazosin	1	5	20	qd, bid	3	24

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