Drugs that interfere with the RAS play a prominent role in the treatment of cardiovascular disease. Besides β1 blockers that inhibit renin release, the following three classes of inhibitors of the RAS are utilized therapeutically (Figure 26–10):
Angiotensin receptor blockers
Direct renin inhibitors
All of these classes of agents will reduce the actions of AngII and lower blood pressure, but each has different effects on the individual components of the RAS (Table 26–2). Representative structures of agents inhibiting the RAS and reducing the effects of AngII are shown in Figure 26–11, near the end of the chapter.
Table 26–2Effects of Antihypertensive Agents on Components of The RAS |Favorite Table|Download (.pdf) Table 26–2Effects of Antihypertensive Agents on Components of The RAS
| ||DRIs ||ACEIs ||ARBs ||DIURETICS ||β1-BLOCKERS |
|PRC ||↑ ||↑ ||↑ ||↑ ||↓ |
|PRA ||↓ ||↑ ||↑ ||↑ ||↓ |
|AngI ||↓ ||↑ ||↑ ||↑ ||↓ |
|AngII ||↓ ||↓ ||↑ ||↑ ||↓ |
|ACE activity ||↔ ||Inhibition ||↔ || || |
|Aldosterone ||↓ ||↓ ||↓ ||↑ ||↓/↔ |
|Bradykinin ||↔ ||↑ ||↔ || || |
|AT1R ||↔ ||↔ ||Inhibition || || |
|AT2R ||↔ ||↔ ||Stimulation || || |
Structures of representative RAS inhibitors. Enalapril and candesartan cilexetil are pro-drugs, relatively inactive until in vivo esterases remove the region within the red box, replacing it with a hydrogen atom to form the active drug.
Angiotensin-Converting Enzyme Inhibitors
In the 1960s, Ferreira and colleagues found that venom extract from the Brazilian pit viper (Bothrops jararaca) contains factors that intensify vasodilator responses to bradykinin. These bradykinin-potentiating factors are peptides that inhibit kininase II, an enzyme that inactivates bradykinin. Erdös and coworkers established that ACE and kininase II are the same enzyme, which catalyzes both the synthesis of AngII and the destruction of bradykinin. Based on these findings, the nonapeptide teprotide (snake venom peptide that inhibits kininase II and ACE) was later synthesized and tested in human subjects. It lowered blood pressure in many patients with essential hypertension and exerted beneficial effects in patients with heart failure. The orally effective ACE inhibitor captopril was developed by analysis of the inhibitory action of teprotide, inference about the action of ACE on its substrates, and analogy with carboxypeptidase A, which was known to be inhibited by D-benzylsuccinic acid. Ondetti, Cushman, and colleagues argued that inhibition of ACE might be produced by succinyl amino acids that corresponded in length to the dipeptide cleaved by ACE. This led to the synthesis of a series of carboxy alkanoyl and mercapto alkanoyl derivatives that are potent competitive inhibitors of ACE.
The ACE inhibitors inhibit the conversion of AngI to AngII. Inhibition of AngII production lowers blood pressure and enhances natriuresis. ACE is an enzyme with many substrates; thus, there are other consequences of its inhibition, including inhibition of the degradation of bradykinin, which has beneficial antihypertensive and protective effects. ACE inhibitors increase by 5-fold the circulating levels of the natural stem cell regulator Ac-SDKP, which may also contribute to the cardioprotective effects of ACE inhibitors (Rhaleb et al., 2001). ACE inhibitors will increase renin release and the rate of formation of AngI by interfering with both short-and long-loop negative feedbacks on renin release (Figure 26–3). Accumulating AngI is directed down alternative metabolic routes, resulting in the increased production of vasodilator peptides such as Ang(1–9) and Ang(1–7) (Figures 26–1 and 26–5).
The ACE inhibitors can be classified into three broad groups based on chemical structure:
Sulfhydryl-containing ACE inhibitors structurally related to captopril
Dicarboxyl-containing ACE inhibitors structurally related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, perindopril, Figure 26–11)
Phosphorus-containing ACE inhibitors structurally related to fosinopril
Many ACE inhibitors are ester-containing prodrugs that are 100–1000 times less potent but have better oral bioavailability than the active molecules. Currently, 11 ACE inhibitors are available for clinical use in the U.S. They differ with regard to potency, whether ACE inhibition is primarily a direct effect of the drug itself or the effect of an active metabolite, and pharmacokinetics.
All ACE inhibitors block the conversion of AngI to AngII and have similar therapeutic indications, adverse-effect profiles, and contraindications. Because hypertension usually requires lifelong treatment, quality-of-life issues are an important consideration in comparing antihypertensive drugs. With the exceptions of fosinopril, trandolapril, and quinapril (which display balanced elimination by the liver and kidneys), ACE inhibitors are cleared predominantly by the kidneys. Impaired renal function significantly diminishes the plasma clearance of most ACE inhibitors, and dosages of these drugs should be reduced in patients with renal impairment. Elevated PRA renders patients hyperresponsive to ACE inhibitor–induced hypotension, and initial dosages of all ACE inhibitors should be reduced in patients with high plasma levels of renin (e.g., patients with heart failure and during salt depletion including diuretic use). ACE inhibitors differ markedly in tissue distribution, and it is possible that this difference could be exploited to inhibit some local (tissue) RAS while leaving others relatively intact.
Captopril is a potent ACE inhibitor with a Ki of 1.7 nM. Given orally, captopril is absorbed rapidly and has a bioavailability of about 75%. Bioavailability is reduced by 25%–30% with food. Peak concentrations in plasma occur within an hour, and the drug is cleared rapidly, with a t1/2 of about 2 h. Most of the drug is eliminated in urine, 40%–50% as captopril and the rest as captopril disulfide dimers and captopril–cysteine disulfide. The oral dose of captopril ranges from 6.25 to 150 mg 2–3 times daily, with 6.25 mg thrice daily or 25 mg twice daily appropriate for the initiation of therapy for heart failure or hypertension, respectively.
Enalapril maleate is a prodrug that is hydrolyzed by esterases in the liver to produce enalaprilat, the active dicarboxylic acid. Enalaprilat is a potent inhibitor of ACE with a Ki of 0.2 nM. Enalapril is absorbed rapidly when given orally and has an oral bioavailability of about 60% (not reduced by food). Although peak concentrations of enalapril in plasma occur within an hour, enalaprilat concentrations peak only after 3–4 h. Enalapril has a t1/2 of about 1.3 h, but enalaprilat, because of tight binding to ACE, has a plasma t1/2 of about 11 h. Elimination is by the kidneys as either intact enalapril or enalaprilat. The oral dosage of enalapril ranges from 2.5 to 40 mg daily, with 2.5 and 5 mg daily appropriate for the initiation of therapy for heart failure and hypertension, respectively.
Enalaprilat is not absorbed orally but is available for intravenous administration when oral therapy is not appropriate. For hypertensive patients, the dosage is 0.625–1.25 mg given intravenously over 5 min. This dosage may be repeated every 6 h.
Lisinopril is the lysine analogue of enalaprilat; unlike enalapril, lisinopril itself is active. In vitro, lisinopril is a slightly more potent ACE inhibitor than is enalaprilat. Lisinopril is absorbed slowly, variably, and incompletely (~30%) after oral administration (not reduced by food); peak concentrations in plasma are achieved in about 7 h. It is excreted unchanged by the kidney with a plasma t1/2 of about 12 h. Lisinopril does not accumulate in tissues. The oral dosage of lisinopril ranges from 5 to 40 mg daily (single or divided dose), with 5 and 10 mg daily appropriate for the initiation of therapy for heart failure and hypertension, respectively. A daily dose of 2.5 mg with close medical supervision is recommended for patients with heart failure who are hyponatremic or have renal impairment.
Cleavage of the ester moiety by hepatic esterases transforms benazepril, a prodrug, into benazeprilat. Benazepril is absorbed rapidly but incompletely (37%) after oral administration (only slightly reduced by food). Benazepril is nearly completely metabolized to benazeprilat and to the glucuronide conjugates of benazepril and benazeprilat, which are excreted into the urine and bile; peak concentrations of benazepril and benazeprilat in plasma are achieved in 0.5–1 and 1–2 h, respectively. Benazeprilat has an effective plasma t1/2 of 10–11 h. With the exception of the lungs, benazeprilat does not accumulate in tissues. The oral dosage of benazepril ranges from 5 to 80 mg daily (single or divided dose).
Cleavage of the ester moiety by hepatic esterases transforms fosinopril into fosinoprilat. Fosinopril is absorbed slowly and incompletely (36%) after oral administration (rate but not extent reduced by food). Fosinopril is largely metabolized to fosinoprilat (75%) and to the glucuronide conjugate of fosinoprilat. These are excreted in both the urine and the bile; peak concentrations of fosinoprilat in plasma are achieved in about 3 h. Fosinoprilat has an effective plasma t1/2 of about 11.5 h, a figure not significantly altered by renal impairment. The oral dosage of fosinopril ranges from 10 to 80 mg daily (single or divided dose). The initial dose is reduced to 5 mg daily in patients with Na+ or water depletion or renal failure.
An oral dose of trandolapril is absorbed without reduction by food and produces plasma levels of trandolapril (10% bioavailability) and trandolaprilat (70% bioavailability). Trandolaprilat is about 8 times more potent than trandolapril as an ACE inhibitor. Glucuronides of trandolapril and deesterification products are recovered in the urine (33%, mostly trandolaprilat) and feces (66%). Peak concentrations of trandolaprilat in plasma are achieved in 4–10 h.
Trandolaprilat displays biphasic elimination kinetics, with an initial t1/2 of about 10 h (the major component of elimination), followed by a more prolonged t1/2 (owing to slow dissociation of trandolaprilat from tissue ACE). Plasma clearance of trandolaprilat is reduced by both renal and hepatic insufficiency. The oral dosage ranges from 1 to 8 mg daily (single or divided dose). The initial dose is 0.5 mg in patients who are taking a diuretic or who have renal impairment.
Cleavage of the ester moiety by hepatic esterases transforms quinapril, a prodrug, into quinaprilat. Quinapril is absorbed rapidly (peak concentrations are achieved in 1 h), and the rate, but not extent, of oral absorption (60%) may be reduced by food (delayed peak). Quinaprilat and other minor metabolites of quinapril are excreted in the urine (61%) and feces (37%). Peak concentrations of quinaprilat in plasma are achieved in about 2 h. Conversion of quinapril to quinaprilat is reduced in patients with diminished liver function. The initial t1/2 of quinaprilat is about 2 h; a prolonged terminal t1/2 of about 25 h may be due to high-affinity binding of the drug to tissue ACE. The oral dosage of quinapril ranges from 5 to 80 mg daily.
Orally administered ramipril is absorbed rapidly (peak concentrations in 1 h; the rate but not extent of its oral absorption (50%–60%) is reduced by food. Ramipril is metabolized to ramiprilat by hepatic esterases and to inactive metabolites that are excreted predominantly by the kidneys. Peak concentrations of ramiprilat in plasma are achieved in about 3 h. Ramiprilat displays triphasic elimination kinetics (t1/2 values: 2–4, 9–18, and more than 50 h) This triphasic elimination is due to extensive distribution to all tissues (initial t1/2), clearance of free ramiprilat from plasma (intermediate t1/2), and dissociation of ramiprilat from tissue ACE (long terminal t1/2). The oral dosage of ramipril ranges from 1.25 to 20 mg daily (single or divided dose).
Moexipril’s antihypertensive activity is due to its deesterified metabolite, moexiprilat. Moexipril is absorbed incompletely, with bioavailability as moexiprilat of about 13%. Bioavailability is markedly decreased by food. The time to peak plasma concentration of moexiprilat is almost 1.5 h; the elimination t1/2 varies between 2 and 12 h. The recommended dosage range is 7.5–30 mg daily (single or divided doses). The dosage range is halved in patients who are taking diuretics or who have renal impairment.
Perindopril erbumine is a prodrug, and 30%–50% of systemically available perindopril is transformed to perindoprilat by hepatic esterases. Although the oral bioavailability of perindopril (75%) is not affected by food, the bioavailability of perindoprilat is reduced by about 35%. Perindopril is metabolized to perindoprilat and to inactive metabolites that are excreted predominantly by the kidneys. Peak concentrations of perindoprilat in plasma are achieved in 3–7 h. Perindoprilat displays biphasic elimination kinetics with half-lives of 3–10 h (the major component of elimination) and 30–120 h (owing to slow dissociation of perindoprilat from tissue ACE). The oral dosage ranges from 2 to 16 mg daily (single or divided dose).
Therapeutic Uses of ACE Inhibitors
The ACE inhibitors are effective in the treatment of cardiovascular disease, heart failure, and diabetic nephropathy.
ACE Inhibitors in Hypertension
Inhibition of ACE lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various hypertensive states except when high blood pressure is due to primary aldosteronism (see Chapter 28). The initial change in blood pressure tends to be positively correlated with PRA and AngII plasma levels prior to treatment. However, some patients may show a sizable reduction in blood pressure that correlates poorly with pretreatment values of PRA. It is possible that increased local (tissue) production of AngII or increased responsiveness of tissues to normal levels of AngII makes some hypertensive patients sensitive to ACE inhibitors despite normal PRA.
The long-term fall in systemic blood pressure observed in hypertensive individuals treated with ACE inhibitors is accompanied by a leftward shift in the renal pressure–natriuresis curve (Figure 26–9) and a reduction in TPR in which there is variable participation by different vascular beds. The kidney is a notable exception: Because the renal vessels are extremely sensitive to the vasoconstrictor actions of AngII, ACE inhibitors increase renal blood flow via vasodilation of the afferent and efferent arterioles. Increased renal blood flow occurs without an increase in GFR; thus, the filtration fraction is reduced.
The ACE inhibitors cause systemic arteriolar dilation and increase the compliance of large arteries, which contributes to a reduction of systolic pressure. Cardiac function in patients with uncomplicated hypertension generally is little changed, although stroke volume and cardiac output may increase slightly with sustained treatment. Baroreceptor function and cardiovascular reflexes are not compromised, and responses to postural changes and exercise are little impaired. Even when substantial lowering of blood pressure is achieved, heart rate and concentrations of catecholamines in plasma generally increase only slightly, if at all. This perhaps reflects an alteration of baroreceptor function with increased arterial compliance and the loss of the normal tonic influence of AngII on the sympathetic nervous system.
Aldosterone secretion is reduced, but not seriously impaired, by ACE inhibitors. Aldosterone secretion is maintained at adequate levels by other steroidogenic stimuli, such as ACTH and K+. The activity of these secretagogues on the zona glomerulosa of the adrenal cortex requires very small trophic or permissive amounts of AngII, which always are present because ACE inhibition never is complete. Excessive retention of K+ is encountered in patients taking supplemental K+, in patients with renal impairment, or in patients taking other medications that reduce K+ excretion.
The ACE inhibitors alone normalize blood pressure in about 50% of patients with mild-to-moderate hypertension. Ninety percent of patients with mild-to-moderate hypertension will be controlled by the combination of an ACE inhibitor and a Ca2+ channel blocker, a β1 adrenergic receptor blocker, or a diuretic. Diuretics augment the antihypertensive response to ACE inhibitors by rendering the patient’s blood pressure renin dependent. Several ACE inhibitors are marketed in fixed-dose combinations with a thiazide diuretic or Ca2+ channel blocker for the management of hypertension.
ACE Inhibitors in Left Ventricular Systolic Dysfunction
Unless contraindicated, ACE inhibitors should be given to all patients with impaired left ventricular systolic function whether or not they have symptoms of overt heart failure (see Chapter 29). Several large clinical studies demonstrated that inhibition of ACE in patients with systolic dysfunction prevents or delays the progression of heart failure, decreases the incidence of sudden death and myocardial infarction, decreases hospitalization, and improves quality of life. Inhibition of ACE commonly reduces afterload and systolic wall stress, and both cardiac output and cardiac index increase, as do indices of stroke work and stroke volume. In systolic dysfunction, AngII decreases arterial compliance, and this is reversed by ACE inhibition. Heart rate generally is reduced. Systemic blood pressure falls, sometimes steeply at the outset, but tends to return toward initial levels. Renovascular resistance falls sharply, and renal blood flow increases. Natriuresis occurs as a result of the improved renal hemodynamics, the reduced stimulus to the secretion of aldosterone by AngII, and the diminished direct effects of AngII on the kidney. The excess volume of body fluids contracts, which reduces venous return to the right side of the heart. A further reduction results from venodilation and an increased capacity of the venous bed.
Although AngII has little acute venoconstrictor activity, long-term infusion of AngII increases venous tone, perhaps by central or peripheral interactions with the sympathetic nervous system. The response to ACE inhibitors also involves reductions of pulmonary arterial pressure, pulmonary capillary wedge pressure, and left atrial and left ventricular filling volumes and pressures. Consequently, preload and diastolic wall stress are diminished. The better hemodynamic performance results in increased exercise tolerance and suppression of the sympathetic nervous system. Cerebral and coronary blood flows usually are well maintained, even when systemic blood pressure is reduced. In heart failure, ACE inhibitors reduce ventricular dilation and tend to restore the heart to its normal elliptical shape. ACE inhibitors may reverse ventricular remodeling via changes in preload/afterload by preventing the growth effects of AngII on myocytes and by attenuating cardiac fibrosis induced by AngII and aldosterone.
ACE Inhibitors in Acute Myocardial Infarction
The beneficial effects of ACE inhibitors in acute myocardial infarction are particularly large in hypertensive and diabetic patients. Unless contraindicated (e.g., cardiogenic shock or severe hypotension), ACE inhibitors should be started immediately during the acute phase of myocardial infarction and can be administered along with thrombolytics, aspirin, and β adrenergic receptor antagonists (ACE Inhibitor Myocardial Infarction Collaborative Group, 1998). In high-risk patients (e.g., large infarct, systolic ventricular dysfunction), ACE inhibition should be continued long term (see Chapters 27 and 28).
ACE Inhibitors in Patients Who Are at High Risk of Cardiovascular Events
Patients at high risk of cardiovascular events benefit considerably from treatment with ACE inhibitors (Heart Outcomes Prevention Study Investigators, 2000). ACE inhibition significantly decreases the rate of myocardial infarction, stroke, and death in patients who do not have left ventricular dysfunction but have evidence of vascular disease or diabetes and one other risk factor for cardiovascular disease. In patients with coronary artery disease but without heart failure, ACE inhibition reduces cardiovascular disease death and myocardial infarction (European Trial, 2003).
ACE Inhibitors in Diabetes Mellitus and Renal Failure
Diabetes mellitus is the leading cause of renal disease. In patients with type 1 diabetes mellitus and diabetic nephropathy, ACE inhibitors prevent or delay the progression of renal disease, affording renoprotection, as defined by changes in albumin excretion. The renoprotective effects of ACE inhibitors in type 1 diabetes are in part independent of blood pressure reduction. In addition, ACE inhibitors may decrease retinopathy progression in type 1 diabetics and attenuate the progression of renal insufficiency in patients with a variety of nondiabetic nephropathies (Ruggenenti et al., 2010).
Several mechanisms participate in the renal protective effects of ACE inhibitors. Increased glomerular capillary pressure induces glomerular injury, and ACE inhibitors reduce this parameter by decreasing arterial blood pressure and by dilating renal efferent arterioles. ACE inhibitors increase the permeability selectivity of the filtering membrane, thereby diminishing exposure of the mesangium to proteinaceous factors that may stimulate mesangial cell proliferation and matrix production, two processes that contribute to expansion of the mesangium in diabetic nephropathy. Because AngII is a growth factor, reductions in the intrarenal levels of AngII may further attenuate mesangial cell growth and matrix production. ACE inhibitors increase Ang(1–7) levels by preventing its metabolism by ACE. Ang(1–7) binds to Mas receptors and has protective and antifibrotic effects (Santos, 2014). In the setting of diabetes, at the level of renal epithelial podocytes, activation of AT1 receptors leads to activation of protein kinase signaling cascades, cytoskeletal rearrangements, retraction of podocyte processes, and a reduction in proteins of the slit diaphragm, all resulting in increased permeability of the renal epithelium to proteins (proteinuria). ACE inhibitors reduce these effects of AngII (Márquez et al., 2015).
ACE Inhibitors in Scleroderma Renal Crisis
The use of ACE inhibitors considerably improves survival of patients with scleroderma renal crisis.
Adverse Effects of ACE Inhibitors
In general, ACE inhibitors are well tolerated. The drugs do not alter plasma concentrations of uric acid or Ca2+ and may improve insulin sensitivity and glucose tolerance in patients with insulin resistance and decrease cholesterol and lipoprotein (a) levels in proteinuric renal disease.
A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA. Care should be exercised in patients who are salt depleted, are on multiple antihypertensive drugs, or have congestive heart failure.
In 5%–20% of patients, ACE inhibitors induce a bothersome, dry cough mediated by the accumulation in the lungs of bradykinin, substance P, or PGs. Thromboxane antagonism, aspirin, and iron supplementation reduce cough induced by ACE inhibitors. ACE dose reduction or switching to an ARB is sometimes effective. Once ACE inhibitors are stopped, the cough disappears, usually within 4 days.
Significant K+ retention is rarely encountered in patients with normal renal function. However, ACE inhibitors may cause hyperkalemia in patients with renal insufficiency or diabetes or in patients taking K+-sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.
Inhibition of ACE can induce acute renal insufficiency in patients with bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure, or volume depletion owing to diarrhea or diuretics.
In 0.1%–0.5% of patients, ACE inhibitors induce rapid swelling in the nose, throat, mouth, glottis, larynx, lips, or tongue. Once ACE inhibitors are stopped, angioedema disappears within hours; meanwhile, the patient’s airway should be protected, and if necessary, epinephrine, an antihistamine, or a glucocorticoid should be administered. African Americans have a 4.5 times greater risk of ACE inhibitor–induced angioedema than Caucasians. Although rare, angioedema of the intestine (visceral angioedema) characterized by emesis, watery diarrhea, and abdominal pain also has been reported. ACE inhibitor–associated angioedema is a class effect, and patients who develop this adverse event should not be prescribed any other drugs within the ACE inhibitor class.
If a pregnancy is diagnosed, it is imperative that ACE inhibitors be discontinued as soon as possible. ACE inhibitors and ARBs have been associated with renal developmental defects when administered in the third trimester of pregnancy, and potentially earlier. The fetopathic effects may be due in part to fetal hypotension. This possible adverse effect should be discussed with any woman of childbearing potential, as should the necessity of appropriate birth control measures.
The ACE inhibitors occasionally cause a maculopapular rash that may itch, but that may resolve spontaneously or with antihistamines.
Extremely rare but reversible side effects include dysgeusia (an alteration in or loss of taste), neutropenia (symptoms include sore throat and fever), glycosuria (spillage of glucose into the urine in the absence of hyperglycemia), anemia, and hepatotoxicity.
Antacids may reduce the bioavailability of ACE inhibitors; capsaicin may worsen ACE inhibitor–induced cough; NSAIDs, including aspirin, may reduce the antihypertensive response to ACE inhibitors; and K+-sparing diuretics and K+ supplements may exacerbate ACE inhibitor–induced hyperkalemia. ACE inhibitors may increase plasma levels of digoxin and lithium and hypersensitivity reactions to allopurinol.
Angiotensin II Receptor Blockers
Attempts to develop therapeutically useful AngII receptor antagonists date to the early 1970s. Initial endeavors concentrated on angiotensin peptide analogues. Saralasin, 1-sarcosine, 8-isoleucine AngII, and other 8-substituted angiotensins are potent AngII receptor antagonists but were of no clinical value because of lack of oral bioavailability and unacceptable partial agonist activity. A breakthrough came in the early 1980s with the synthesis and testing of a series of imidazole-5–acetic acid derivatives that attenuated pressor responses to AngII in rats. Two compounds, S-8307 and S-8308, proved to be highly specific, albeit very weak, nonpeptide AngII receptor antagonists that were devoid of partial agonist activity (Dell’Italia, 2011). Through a series of stepwise modifications, the orally active, potent, and selective nonpeptide AT1 receptor antagonist losartan was developed and approved for clinical use in the U.S. in 1995. Since then, seven additional AT1 receptor antagonists (see Drug Facts for Your Personal Formulary table) have been approved. Although these AT1 receptor antagonists are devoid of partial agonist activity, structural modifications as minor as a methyl group can transform a potent antagonist into an agonist (Perlman et al., 1997).
The AngII receptor blockers bind to the AT1 receptor with high affinity and are more than 10,000-fold selective for the AT1 receptor over the AT2 receptor. Although binding of ARBs to the AT1 receptor is competitive, the inhibition by ARBs of biological responses to AngII often is functionally insurmountable. Insurmountable antagonism has the theoretical advantage of sustained receptor blockade even with increased levels of endogenous ligand and with missed doses of drug. ARBs inhibit most of the biological effects of AngII, which include AngII-induced (1) contraction of vascular smooth muscle; (2) rapid pressor responses; (3) slow pressor responses; (4) thirst; (5) vasopressin release; (6) aldosterone secretion; (7) release of adrenal catecholamines; (8) enhancement of noradrenergic neurotransmission; (9) increases in sympathetic tone; (10) changes in renal function; and (11) cellular hypertrophy and hyperplasia. ARBs reduce arterial blood pressure in animals with renovascular and genetic hypertension, as well as in transgenic animals overexpressing the renin gene. ARBs, however, have little effect on arterial blood pressure in animals with low-renin hypertension (e.g., rats with hypertension induced by NaCl and deoxycorticosterone) (Csajka et al., 1997).
Do ARBs Have Therapeutic Efficacy Equivalent to That of ACE Inhibitors?
Although both ARBs and ACE inhibitors of drugs block the RAS, they differ in several important aspects:
ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors. ACE inhibitors reduce the biosynthesis of AngII by the action of ACE, but do not inhibit AngII generation via chymase and other ACE-independent AngII-producing pathways. ARBs block the actions of AngII via the AT1 receptor regardless of the biochemical pathway leading to AngII formation.
In contrast to ACE inhibitors, ARBs permit activation of AT2 receptors. ACE inhibitors increase renin release, but block the conversion of AngI to AngII. ARBs also stimulate renin release; however, with ARBs, this translates into a several-fold increase in circulating levels of AngII. Because ARBs block AT1 receptors, this increased level of AngII is available to activate AT2 receptors.
ACE inhibitors and ARBs increase Ang(1–7) levels by different mechanisms. ACE is involved in the clearance of Ang(1–7), so inhibition of ACE increases Ang(1–7) levels. With ARBs, AngII, the preferred substrate of ACE2, is converted to Ang(1–7).
ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin and Ac-SDKP.
Whether the pharmacological differences between ARBs and ACE inhibitors result in significant differences in therapeutic outcomes is an open question.
Oral bioavailability of ARBs generally is low (<50%) except for azilsartan (~60%) and irbesartan (~70%), and protein binding is high (>90%).
Candesartan cilexetil is an inactive ester prodrug that is completely hydrolyzed to the active form, candesartan, during absorption from the GI tract (Figure 26–11). Peak plasma levels are obtained 3–4 h after oral administration; the plasma t1/2 is about 9 h. Plasma clearance of candesartan is due to renal elimination (33%) and biliary excretion (67%). The plasma clearance of candesartan is affected by renal insufficiency but not by mild-to-moderate hepatic insufficiency. Candesartan cilexetil should be administered orally once or twice daily for a total daily dose of 4–32 mg.
Peak plasma levels are obtained 1–2 h after oral administration; the plasma t1/2 is 5–9 h. Eprosartan is metabolized in part to the glucuronide conjugate. Clearance is by renal elimination and biliary excretion. The plasma clearance of eprosartan is affected by both renal insufficiency and hepatic insufficiency. The recommended dosage of eprosartan is 400–800 mg/d in one or two doses.
Peak plasma levels are obtained about 1.5–2 h after oral administration; the plasma t1/2 is 11–15 h. Irbesartan is metabolized in part to the glucuronide conjugate, and the parent compound and its glucuronide conjugate are cleared by renal elimination (20%) and biliary excretion (80%). The plasma clearance of irbesartan is unaffected by either renal or mild-to-moderate hepatic insufficiency. The oral dosage of irbesartan is 150–300 mg once daily.
Approximately 14% of an oral dose of losartan is converted by CYP2C9 and CYP3A4 to the 5-carboxylic acid metabolite, EXP 3174, which is more potent than losartan as an AT1 receptor antagonist. Peak plasma levels of losartan and EXP 3174 occur about 1–3 h after oral administration, and the plasma half-lives are 2.5 and 6–9 h, respectively. The plasma clearances of losartan and EXP 3174 are via the kidney and liver (metabolism and biliary excretion) and are affected by hepatic but not renal insufficiency. Losartan should be administered orally once or twice daily for a total daily dose of 25–100 mg. Losartan is a competitive antagonist of the thromboxane A2 receptor and attenuates platelet aggregation. EXP 3179, another metabolite of losartan without angiotensin receptor effects, reduces COX-2 messenger RNA upregulation and COX-dependent PG generation (Krämer et al., 2002) (Figure 26–11).
Olmesartan medoxomil is an inactive ester prodrug that is completely hydrolyzed to the active form, olmesartan, during absorption from the GI tract. Peak plasma levels are obtained 1.4–2.8 h after oral administration; the plasma t1/2 is 10–15 h. Plasma clearance of olmesartan is due to both renal elimination and biliary excretion. Although renal impairment and hepatic disease decrease the plasma clearance of olmesartan, no dose adjustment is required in patients with mild-to-moderate renal or hepatic impairment. The oral dosage of olmesartan medoxomil is 20–40 mg once daily.
Peak plasma levels are obtained 0.5–1 h after oral administration; the plasma t1/2 is about 24 h. Telmisartan is cleared from the circulation mainly by biliary secretion of intact drug. The plasma clearance of telmisartan is affected by hepatic but not renal insufficiency. The recommended oral dosage of telmisartan is 40–80 mg once daily.
Peak plasma levels occur 2–4 h after oral administration; food markedly decreases absorption; the plasma t1/2 is about 9 h. Valsartan is cleared from the circulation by the liver (~70% of total clearance), and hepatic insufficiency will reduce clearance. The oral dosage of valsartan is 80–320 mg once daily.
The prodrug is hydrolyzed in the GI tract into the active form, azilsartan. The drug is available in 40- and 80-mg once-daily doses. At the recommended dose of 80 mg once a day, azilsartan medoxomil is superior to the maximal doses of valsartan and olmesartan in lowering blood pressure. Bioavailability of azilsartan is about 60% and is not affected by food. Peak plasma concentrations Cmax are achieved within 1.5–3 h. The elimination t1/2 is about 11 h. Azilsartan is metabolized mostly by CYP2C9 into inactive metabolites. Elimination of the drug is 55% in feces and 42% in urine. About 15% of the dose is eliminated as unchanged azilsartan in urine. Plasma clearance is not affected by renal or hepatic insufficiency.
Angiotensin Receptor–Neprilysin Inhibitor
A combination of sacubitril and valsartan, marketed as Entresto, is a first-in-class drug that combines the AT1 receptor antagonistic moiety of valsartan with the neprilysin inhibitor moiety of sacubitril. The complex (sacubitril, valsartan, Na+, and water [1:1:3:2.5]) dissociates into sacubitril and valsartan after oral administration. Sacubitril bioavailability is about 60%, and it is highly protein bound (94%–97%). Sacubitril is further metabolized by esterases into the active metabolite LBQ657, which has a t1/2 of 11 h. The neprilysin inhibitor blocks the breakdown of natriuretic peptides ANP, BNP, and CNP, as well as AngI and bradykinin. The drug combination lowers vascular resistance and increases blood flow. In clinical trial, this combination agent was reported to be superior to enalapril in decreasing the risk of deaths from cardiovascular causes and heart failure by 20% (McMurray et al., 2014).
Entresto is approved for treatment of heart failure with reduced ejection fraction, with a recommended dose of 100–400 mg daily, divided into two doses. Because the ACE/neprilysin inhibitor omapatrilat demonstrated an increased risk of angioedema, use of Entresto is contraindicated in conjunction with an ACE inhibitor or in patients with a history of angioedema during ACE inhibitor or ARB use. The drug should not be used in conjunction with an ARB or ACE inhibitor, and in patients with diabetes should not be used in conjunction with aliskiren. Potential adverse effects discussed for valsartan also apply to this sacubutril-valsartan combination.
A New Class of ARBs in Development
A β-arrestin-biased AT1 receptor blocker, TRV027 is a ligand that binds AT1 receptor and blocks G protein–coupled signaling while engaging β-arrestin. β-Arrestin functions as an adaptor protein that participates in receptor desensitization and internalization. In animal models, β-arrestin–biased AT1 receptor ligand increases myocyte contractility and protects against apoptosis (Kim et al., 2012). In phase II clinical studies, TRV027 decreased mean arterial pressure and was well tolerated. The safety and efficacy of TRV027 is being tested in the BLAST-HF study in patients with acute heart failure (Felker et al., 2015).
All ARBs are approved for the treatment of hypertension. ARBs are renoprotective in type 2 diabetes mellitus, and many experts now consider them the drugs of choice for renoprotection in diabetic patients.
Irbesartan and losartan are approved for diabetic nephropathy, losartan is approved for stroke prophylaxis, and valsartan and candesartan are approved for heart failure and to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction. The efficacy of ARBs in lowering blood pressure is comparable with that of ACE inhibitors and other established antihypertensive drugs, with a favorable adverse-effect profile. ARBs also are available as fixed-dose combinations with HCTZ or amlodipine (see Chapters 27–29).
The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study demonstrated the superiority of an ARB compared with a β1 adrenergic receptor antagonist with regard to reducing stroke in hypertensive patients with left ventricular hypertrophy (Dahlöf et al., 2002). Also, irbesartan appears to maintain sinus rhythm in patients with persistent, long-standing atrial fibrillation (Madrid et al., 2002). Losartan is reported to be safe and highly effective in the treatment of portal hypertension in patients with cirrhosis and portal hypertension without compromising renal function (Schneider et al., 1999).
The ELITE (Evaluation of Losartan in the Elderly) study and a follow-up study (ELITE II) concluded that in elderly patients with heart failure, losartan is as effective as captopril in improving symptoms (Pitt et al., 2000). The VALIANT (Valsartan in Acute Myocardial Infarction) trial demonstrated that valsartan is as effective as captopril in patients with myocardial infarction complicated by left ventricular systolic dysfunction with regard to all-cause mortality (Pfeffer et al., 2003). Both valsartan and candesartan reduce mortality and morbidity in patients with heart failure (reviewed by Makani et al., 2013). Current recommendations are to use ACE inhibitors as first-line agents for the treatment of heart failure and to reserve ARBs for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors.
The ARBs are renoprotective in type 2 diabetes mellitus, and many experts now consider them the drugs of choice for renoprotection in diabetic patients.
Dual Inhibition of the RAS
At present, there is contradictory evidence regarding the advisability of combining an ARB and an ACE inhibitor in patients with heart failure, with one study indicating that a combination of ARB and ACE inhibitors decreases morbidity and mortality in patients with heart failure, and another showing that combination therapy is associated with increased adverse effects and no added benefits (Dell’Italia, 2011; Makani et al., 2013; ONTARGET Investigators, 2008).
The ARBs are generally well tolerated. The incidence of angioedema and cough with ARBs is less than that with ACE inhibitors. As with ACE inhibitors, ARBs have teratogenic potential and should be discontinued in pregnancy. In patients whose arterial blood pressure or renal function is highly dependent on the RAS (e.g., renal artery stenosis), ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. ARBs enhance the blood pressure–lowering effect of other antihypertensive drugs, a desirable effect but one that may necessitate dosage adjustment. There are rare postmarketing reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.
Angiotensinogen is the only specific substrate for renin. DRIs inhibit the cleavage of AngI from angiotensinogen by renin, an enzymatic reaction that is the rate-limiting step for the subsequent generation of AngII. Aliskiren is the only DRI approved for clinical use.
Earlier renin inhibitors were orally inactive peptide analogues of the prorenin propeptide or analogues of renin-substrate cleavage site. Orally active, first-generation renin inhibitors (enalkiren, zankiren, CGP38560A, and remikiren) were effective in reducing AngII levels, but none of them made it past clinical trials due to their low potency, poor bioavailability, and short t1/2. Low-molecular-weight renin inhibitors were designed based on molecular modeling and crystallographic structural information of renin-substrate interaction (Wood et al., 2003). This led to the development of aliskiren, a second-generation renin inhibitor that is FDA approved for the treatment of hypertension. Aliskiren has blood pressure–lowering effects similar to those of ACE inhibitors and ARBs.
Aliskiren is a low-molecular-weight nonpeptide and a potent competitive inhibitor of renin. It binds the active site of renin to block conversion of angiotensinogen to AngI, thus reducing the consequent production of AngII. Aliskiren has a 10,000-fold higher affinity to renin (IC50 ~ 0.6 nM) than to any other aspartic peptidases. In healthy volunteers, aliskiren (40–640 mg/d) induces a dose-dependent decrease in blood pressure, reduces PRA and AngI and AngII levels, but increases PRC by 16- to 34-fold due to the loss of the short-loop negative feedback by AngII (Figure 26–3; Table 26–2). Aliskiren also decreases plasma and urinary aldosterone levels and enhances natriuresis (Nussberger et al., 2002).
Aliskiren is recommended as a single oral dose of 150 or 300 mg/d. Bioavailability of aliskiren is low (~2.5%), but its high affinity and potency compensate for the low bioavailability. Peak plasma concentrations are reached within 3–6 h. The t1/2 is 20–45 h. Steady state in plasma is achieved in 5–8 days. Plasma protein binding is 50% and is independent of concentration. Aliskiren is a substrate for P-glycoprotein, which contributes low bioavailability. Fatty meals significantly decrease the absorption of aliskiren. Hepatic metabolism by CYP3A4 is minimal. Elimination is mostly as unchanged drug in feces. About 25% of the absorbed dose appears in the urine as the parent drug.
Therapeutic Uses of Aliskiren
Therapeutic uses of aliskiren are discussed in Chapter 28.
Adverse Effects and Contraindications
Aliskiren is well tolerated, and adverse events are mild or comparable to placebo with no gender difference. Adverse effects include mild GI symptoms such as diarrhea at high doses (600 mg daily), abdominal pain, dyspepsia, and gastroesophageal reflux; headache; nasopharyngitis; dizziness; fatigue; upper respiratory tract infection; back pain; angiodema; and cough (much less common than with ACE inhibitors). Other adverse effects include rash, hypotension, hyperkalemia in diabetics on combination therapy, elevated uric acid, renal stones, and gout. Like other RAS inhibitors, aliskiren is not recommended in pregnancy.
Aliskiren does not interact with drugs that interact with CYPs. Aliskiren reduces absorption of furosemide by 50%. Irbesartan reduces the Cmax of aliskiren by 50%. Aliskiren plasma levels are increased by drugs, such as ketoconazole, atorvastatin, and cyclosporine, that inhibit P-glycoprotein.
Effect of Pharmacological Blood Pressure Reduction on Function of the RAS
The RAS responds to alterations in blood pressure with compensatory changes (Figure 26–3). Thus, pharmacological agents that lower blood pressure will alter the feedback loops that regulate the RAS and cause changes in the levels and activities of the system’s components. These changes, summarized in Table 26–2, should be taken into account when interpreting laboratory evaluation of patients. Furthermore, during aliskiren treatment, the assay for PRA will be inhibited by persistence of aliskiren in this ex vivo reaction, whereas the renin concentration radioimmunoassay will not be inhibited.