The renin angiotensin aldosterone (RAA) system plays a central role in regulating cardiovascular and renal functions, and is a key component of the blood pressure homeostasis system in humans. Renal hypoperfusion triggers the production and release of renin from the juxtaglomerular cells, converting angiotensinogen to the decapeptide angiotensin I (angiotensin [1-10]). In the next step, the dipeptidyl-carboxyl peptidase angiotensin-converting enzyme (ACE) cleaves angiotensin I into angiotensin II (angiotensin [1-8]). Angiotensin II binds to the G protein-coupled receptor, angiotensin type 1 receptor (AT1R), and increases blood pressure by facilitating vascular constriction and by increasing sodium reabsorption in the kidney. Angiotensin II also stimulates the production of the steroid hormone aldosterone, the final product of the RAA cascade. The lipophilic hormone aldosterone passes through the plasma membrane of the target cells and binds to the nuclear receptor, mineralocorticoid receptor (MCR), in the cytoplasm of renal tubular cells. The aldosterone-MCR complex translocates into the nucleus and regulates the transcription of target genes, resulting in the upregulation of electrolyte flux pathways in the kidney. There are four classes of pharmacological agents that can block the RAA system; these are ACE inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and MCR antagonists.
Angiotensin-Converting Enzyme Inhibitors
ACE, also known as kininase II, is a metalloprotease with zinc at its active center. Besides the well-known role in converting angiotensin I (Ang I) to angiotensin II (Ang II), it promotes the degradation of bradykinin. Therefore, ACE positively controls the RAA system (which increases vasoconstriction, extracellular volume, and blood pressure) and negatively controls the kinin-kallikrein-bradykinin system (which promotes vasodilation). There are membrane-bound and soluble forms ACE. Membrane-bound ACE is an ectoenzyme, anchoring to the plasma membrane with the C-terminal hydrophobic portion. The membrane-bound ACE is present in various tissues including the blood vessels, heart, kidneys, adrenal gland, and brain. The soluble form, which lacks the C-terminal anchor residues, is present in the plasma. ACE inhibitors affect both plasma and tissue ACE, blocking the generation of Ang II and suppressing the degradation of bradykinin.
Pharmacology of Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors are classified according to the chemical structure of the site of binding (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE. Captopril (the first ACE inhibitor to be developed) and alacepril (available in Japan) have a sulfhydryl moiety. ACE inhibitors with the sulfhydryl group may have properties different from those of other ACE inhibitors, such as antioxidative action, although the clinical relevance remains unknown. This sulfhydryl group may also be involved in adverse events such as skin eruptions. Captopril has a short half-life of about two hours, and needs to be administered three times a day ( Table 24.1 ). Alacepril produces captopril by releasing a phenylalanine after being deacetylated. ACE inhibitors with a carboxyl or phosphinyl moiety have a longer half-life, and are effective with a single daily dose. Fosinopril is unique in that it has a phosphinyl moiety at the ACE binding site. With the exception of captopril and lisinopril, ACE inhibitors are prodrugs that are metabolized into their active forms when absorbed from the intestinal tract. As for the route of elimination, trandolapril, fosinopril, benazepril, and temocapril are metabolized by both the liver and kidney; other ACE inhibitors are renally excreted, and serum levels can be elevated in subjects with reduced kidney function.
| Drug | Trade Name (in United States) | Usual Total Dose and/or Range—Hypertension (Frequency/Day) | Usual Total Dose and/or Range—Heart Failure (Frequency/Day) |
|---|---|---|---|
| Benazepril | Lotensin | 20-40 (1) | Not FDA approved for heart failure |
| Captopril | Capoten | 12.5-100 (2-3) | 18.75-150 (3) |
| Enalapril | Vasotec | 5-40 (1-2) | 5-40 (2) |
| Fosinopril | Monopril | 10-40 (1) | 10-40 (1) |
| Lisinopril | Prinivil, Zestril | 2.5-40 (1) | 5-20 (1) |
| Moexipril | Univasc | 7.5-30 (1) | Not FDA approved for heart failure |
| Perindopril | Aceon | 2-16 (1) | Not FDA approved for heart failure |
| Quinapril | Accupril | 5-80 (1) | 10-40 (1-2) |
| Ramipril | Altace | 2.5-20 (1) | 10 (2) |
| Trandolapril | Mavik | 1-8 (1) | 1-4 (1) |
Mechanisms of Action
The antihypertensive effects of ACE inhibitors can involve the inhibition of both Ang II production and bradykinin degradation. The diverse actions of Ang II include vascular smooth muscle cell contraction, secretion of aldosterone from the adrenal cortex, and the direct effects on renal tubules to increase Na-Cl reabsorption. Bradykinin, a polypeptide composed of nine amino acids, acts on the bradykinin B1 and B2 G protein-coupled receptors, and induces the production of prostacyclin and nitric oxide in the vascular endothelium, resulting in vasodilation. ACE inhibitors increase Ang I by blocking its conversion to Ang II. This may result in the increased formation of Ang(1-7) by ACE2, a homologue of ACE, and stimulate the Mas G protein-coupled receptors. The Ang(1-7)-Mas receptor system regulates vascular tone and acts to antagonize AT1R signaling. These effects may also play a role, although their clinical relevance has not been demonstrated.
The importance of tissue ACE activity is confirmed by an animal model that expresses ACE lacking the C-terminal region. In this model, ACE is catalytically active but is entirely secreted from the cells. The mice exhibit significant plasma ACE activity with no tissue ACE activity, resulting in profound hypotension. ACE inhibitors are capable of antagonizing plasma as well as tissue ACE; however, the extent of the ACE inhibiting activity may vary depending on the tissues. For example, a single oral dose of lisinopril suppressed plasma ACE activity at 4 hours but not at 24 hours. In contrast, the same dose of lisinopril continued to inhibit ACE through 24 hours in the kidney.
Blood Pressure-Lowering Effect and Combination With Other Antihypertensives
ACE inhibitors lower both systolic and diastolic blood pressure in hypertensive patients, and are recommended as a first-line therapy in the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8). Unlike Ca 2+ channel blockers (CCBs) and other antihypertensives, ACE inhibitors reduce vascular resistance but have little effect on heart rate. The increase in the heart rate in response to postural change is usually maintained during treatment with ACE inhibitors, and the frequency of orthostatic hypotension is low. ACE inhibitors also inhibit both central and peripheral sympathetic nerve activation by Ang II.
Although ACE inhibitors are generally effective in the treatment of hypertension, its efficacy seems weaker in the African-American hypertensive population. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), thiazide diuretics were superior to lisinopril in suppressing stroke and cardiovascular events in African Americans. The antihypertensive effects of ACE inhibitors also tend to be weaker in patients with a high salt intake presumably because of the suppressed RAA system. Conversely, as a result of the compensatory activation of RAA system, the combination with a thiazide diuretic enhances the effect of ACE inhibitors. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed that combining an ACE inhibitor perindopril with a thiazide indapamide provides a synergistic antihypertensive effect, and that the combination of the two drugs is effective in preventing stroke recurrence.
Combination with a Ca 2+ channel blocker (CCB) is also effective in controlling blood pressure. The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) showed that combining an ACE inhibitor perindopril with a CCB amlodipine was superior to the combination of atenolol and bendroflumethiazide in preventing cardiovascular events. In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, combining benazepril with amlodipine offered superior antihypertensive effects and suppression of the onset of cardiovascular events as compared with combination with hydrochlorothiazide in high-risk hypertensive patients, and also suppressed the progression of kidney damage. However, in the Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension (GUARD) study, antialbuminuric effect of combining benazepril with amlodipine was inferior to the combination with hydrochlorothiazide in diabetic patients.
Combining ACE inhibitors and angiotensin receptor blockers (ARBs) has been reported to increase adverse events such as acute kidney damage and hyperkalemia in several clinical trials, including the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study. Currently, combining these drugs is not recommended.
End-Organ Effects and Clinical Trials
Cardiac Effects
Heart Failure and Left Ventricular Dysfunction After Myocardial Infarction
ACE inhibitors reduce preload and afterload, and increase the cardiac output without increasing the heart rate. ACE inhibitors can also inhibit chronic activation of the tissue renin angiotensin system involved in the pathogenesis of left ventricular (LV) dysfunction.
The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) was the first to show that combining ACE inhibitors with other medications for heart failure reduces the risk of death. In this trial, the ACE inhibitor enalapril significantly inhibited the progression of heart failure and death in patients with New York Heart Association (NYHA) class IV heart failure. Following this trial, the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial showed that enalapril reduces all-cause mortality in NYHA class II and III cases, verifying the prognosis-improving effects of ACE inhibitors in these patient groups as well. The SOLVD prevention trial also compared enalapril with a placebo in patients with LV dysfunction (ejection fraction < 35%) who had no prior history of heart failure, and showed that enalapril significantly reduces cardiovascular mortality. These clinical trials have had a major impact on the management of chronic heart failure by showing the efficacy of long-acting ACE inhibitors.
ACE inhibitors also improve the prognosis of reduced systolic function after myocardial infarction. The Survival And Ventricular Enlargement (SAVE) trial evaluated whether or not beginning captopril administration early after the onset of LV dysfunction following acute myocardial infarction (AMI) improves the long-term prognosis. The study showed that when compared with a placebo, captopril significantly reduced total and cardiovascular mortality, and suppressed the progression to severe heart failure and the recurrence of AMI. Usefulness in reduced systolic function after MI has been consistently shown for other ACE inhibitors, such as ramipril, lisinopril, trandolapril, and zofenopril. In the CONSENSUS II trial, which evaluated the efficacy of early administration of enalapril for patients after AMI, the use of the ACE inhibitor did not reduce overall mortality. In this study, intravenous administration of enalapril within 24 hours after MI resulted in hypotensive (<90 mm Hg) episodes in 12% (placebo 3%; p < 0.001), and the timing and amount of ACE inhibitor administration possibly affected the results. Given these data, initiation of oral ACE inhibitors is recommended in patients with stable hemodynamics after MI, especially if LV function has been reduced. However, the optimal dose and timing are unknown, and hemodynamic parameters need to be monitored to prevent excessive lowering of blood pressure. Because several ACE inhibitors have been consistently found to benefit survival, their effect on cardiac dysfunction following MI is likely to be the class effect. In the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial, the clinical efficacy of the ACE inhibitor in diastolic heart failure patients with preserved systolic function (HFpEF) was not observed on the primary endpoint of combined all-cause mortality and unexpected hospitalization for heart failure, despite significant improvements in functional class and six-minute walk distance.
Atherosclerotic Vascular Disease
The Heart Outcomes Prevention Evaluation (HOPE) study investigated the protective effects of ramipril in patients with preserved LV function who had evidence of vascular disease or diabetes with one other risk factor for cardiovascular disease. In this trial, the ACE inhibitor significantly suppressed the incidence of primary endpoint, which was the composite of cardiovascular death, myocardial infarction, and stroke. A majority of patients in this study had a systolic blood pressure of 140 mm Hg or lower, and changes in blood pressure caused by therapeutic intervention were modest at 2 to 3 mm Hg, indicating that ACE inhibitors have an action independent of blood pressure. The suggested mechanisms include the improvement in vascular endothelial function via Ang II inhibition and bradykinin induction, or an improvement in fibrinolytic balance by suppressing plasminogen activator inhibitor and inducing tissue plasminogen activator (tPA). Similarly, The European Trial on Reduction of Cardiac events with Perindopril in Stable Coronary Artery Disease (EUROPA) study showed that in patients with stable coronary artery diseases, perindopril suppressed primary endpoint (cardiovascular death, myocardial infarction, or cardiac arrest). However, in the Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) study, which included patients with stable coronary artery disease with preserved ejection fraction, adding trandolapril did not reduce cardiovascular events. In this study, 70% of patients had already received lipid-lowering therapy and 72% had already received revascularization. Therefore, uncertainty remains about the protective effects of ACE inhibitors in the lower risk group.
Renal Effects
ACE inhibitors exert renoprotective actions by antagonizing the various injurious effects of Ang II, most importantly by lowering the intraglomerular pressure and improving hyperfiltration through the dilatation of renal efferent arterioles. The Ramipril Efficacy In Nephropathy (REIN) trial tested the protective effects of an ACE inhibitor ramipril in patients with decreased glomerular filtration rate (GFR) or overt proteinuria, and showed that the ACE inhibitor reduces the risk of end-stage kidney disease. In the post hoc analysis, the rate of GFR decline (delta GFR) was compared within three tertiles of basal GFR. The study showed that Ramipril decreased delta GFR by 22%, 22%, and 35% in the lowest, middle, and highest tertiles, respectively, demonstrating that the renoprotective effects of ACE inhibitors do not depend on the stage of the chronic kidney disease (CKD).
The United States Food and Drug Administration (FDA) has approved captopril for the treatment of type 1 diabetic nephropathy, based on the study showing that captopril inhibits the progression of nephropathy in type 1 diabetes. The African American Study of Kidney Disease and Hypertension (AASK) study, which evaluated the usefulness of ACE inhibitors in African Americans with hypertensive kidney damage, reported that ramipril can have a protective effect in slowing GFR decline compared with amlodipine or metoprolol, especially in patients with proteinuria (Uprot/Cr >0.22), whereas strict control of blood pressure did not slow progression of kidney disease in this population.
On the basis of the above evidence, the JNC 8 recommends ACE inhibitors (and ARBs) as first-line treatment for hypertension complicated by CKD at ages 18 years and up, for all races, irrespective of whether the patient has diabetes or not.
Diabetes
ACE inhibitors are preferably used in patients with hypertension and diabetes, based on the evidence that these agents effectively reduce blood pressure and that they prevent the progression of atherosclerotic complications. Unlike diuretics or beta-blockers, ACE inhibitors do not decrease insulin sensitivity. Rather, some studies show that these agents may have favorable effects on glycemic control. In the Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) study, which included patients with fasting hyperglycemia or impaired glucose tolerance, ramipril promoted the regression to normal glycemia (the onset of diabetes was not prevented by the ACE inhibitor). A meta-analysis published in 2011 also reported that ACE inhibitors and ARBs reduce the new onset of diabetes. Notably, the 5-year treatment of valsartan, an angiotensin receptor blocker, along with lifestyle modification, in patients with impaired glucose tolerance and cardiovascular disease or risk factors led to a decrease of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events.
Adverse Effects and Important Drug Interactions
A decrease in GFR associated with the use of ACE inhibitors is usually functional and reversible, and discontinuing ACE inhibitors returns serum creatinine to baseline levels. Nonetheless, patients with renal artery stenosis and other causes of renal hypoperfusion (e.g., hypovolemia and congestive heart failure), those taking nonsteroidal antiinflammatory drugs (NSAIDs), cyclosporine, or vasoconstrictor agents, and subjects with CKD have increased risk of having progressive deterioration of kidney function with ACE inhibitors ( Fig. 24.1 ). The combined use of ACE inhibitors with mineralocorticoid receptor antagonists or other potassium-sparing diuretics increases the risk of hyperkalemia and necessitates careful monitoring of serum K + levels and kidney function.
The use of ACE inhibitors in pregnant women is contraindicated because they cause oligohydramnios and congenital anomalies, such as fetal limb deformities, growth retardation, and renal dysfunction ( Table 24.2 ). A dry cough is observed in 20% to 30% of cases and is particularly frequent in Asian people. This is attributed to the enhanced activity of bradykinin; the symptom resolves quickly by discontinuing the ACE inhibitors. ACE inhibitors may improve airway sensitivity and have been reported to reduce the risk of pneumonia in elderly people with hypertension, likely via the inhibition of bradykinin and substance P degradation.
| Ace Inhibitors | ARBs (N [%]) | |
|---|---|---|
| Central nervous system | 9 (20.9) | 1 (8.3) |
| Cardiovascular system | 8 (18.6) | 1 (8.3) |
| Renal-urologic system | 5 (11.6) | 5 (41.7) |
| Skeletal | 4 (9.3) | 1 (8.3) |
| Pulmonary | 0 | 1 (8.3) |
| Gastrointestinal | 3 (7.0) | 0 |
| Other | 9 (20.9) | 0 |
| Not specified | 5 (11.6) | 1 (8.3) |
| Total | 43 (100) | 12 (100) |
Though rare, angioneurotic edema is a serious adverse effect, which is reported to occur in 0.1% to 0.2% of patients taking an ACE inhibitor. The actual incidence may be higher given that the Omapatrilat Cardiovascular Treatment versus Enalapril (OCTAVE) study reported angioedema in 86 of 12,634 cases (0.68%). Angioneurotic edema is commonly seen in the face and upper respiratory tract, but can also involve the intestine in some cases, causing gastrointestinal symptoms including abdominal pain and diarrhea. Combined use of dipeptidyl peptidase 4 (DPP-4) inhibitors may increase the risk of angioneurotic edema.
The use of ACE inhibitors is contraindicated in patients undergoing dialysis using acrylonitrile membranes, and those receiving immunoadsorption therapy using a dextran-sulfate or tryptophan-immobilized polyvinyl alcohol column, because the concomitant use can cause anaphylactoid reactions as a result of excessive activation of the kinin-kallikrein-bradykinin system.
Angiotensin II Receptor Blockers
The AT1R is predominantly expressed in the heart, kidneys, blood vessels, brain, and adrenal glands, and is involved in multiple functions including cardiomyocyte and vascular smooth muscle contraction, aldosterone biosynthesis, release of catecholamines from the nerve endings, and Na-Cl reabsorption in the kidney. Ang II and AT1R also act to promote cell growth and proliferation, thereby accelerating target organ dysfunction. ARBs or “sartans” inhibit these actions of Ang II by binding to AT1R. About 20% to 30% of systemic Ang II is produced via an alternative pathway rather than through ACE, such as through chymases, but ARBs also block these signals at the receptor level. The degradation of bradykinin by ACE is not inhibited, and coughing and angioedema occur much less frequently than ACE inhibitors.
Pharmacology of Angiotensin II Receptor Blockers
The use of saralasin (1-sar-8-ala-angiotensin II) in subjects with elevated plasma renin activity has provided evidence that the agents that block binding of Ang II to angiotensin receptor may be used to treat hypertension, although saralasin itself has low bioavailability. Subsequently, researchers at Takeda found that benzimidazoles (compound CV-2198 and CV-2961) have an AT1R inhibitory effect, and scientists at DuPont finally developed the first ARB losartan based on the structure of these lead compounds. Currently, eight ARBs are commercially available, and all have a high affinity for AT1R ( Table 24.3 ). The interactions between ARBs and the receptor are hydrophobic bonds between the phenyl group and AT1R, and an ionic interaction between the acidic moiety and AT1R, representing a common mechanism. Losartan has a biphenyl moiety and an acidic tetrazole group; candesartan, valsartan, irbesartan, and olmesartan all have a backbone similar to losartan. In telmisartan, the tetrazole has been substituted with a carboxyl group; in azilsartan, the tetrazole is replaced by the 5-oxo 1,2,4 oxadiazole group. In eprosartan, the biphenyl tetrazole has been substituted with benzoic acid.
| Parameter | Losartan Potassium | Valsartan | Irbesartan | Candesartan Cilexetil | Telmisartan | Eprosartan | Olmesartan Medoxomil | Azilsartan Medoxomil |
|---|---|---|---|---|---|---|---|---|
| U.S. Trade Name | Cozaar | Diovan | Avapro | Atacand | Micardis | Teveten | Benicar | Edarbi |
| Manufacturer/Marketer | Merck & Co., Inc., Generic | Novartis Pharmaceuticals Corporation | Bristol-Myers Squibb/Sanofi-Aventis Partnership | AstraZeneca, L.P. | Boehringer Ingleheim | Abbott Laboratories | Daiichi Sankyo Inc. | Takeda Pharmaceuticals US |
| Doses available | 50, 100 | 40, 80, 160, 320 | 75, 150, 300 | 4, 8, 16, 32 | 40, 80 | 400, 600 | 5, 20, 40 | 40, 80 |
| Usual initial dose (mg/day) | 50 | 80 | 150 | 8 | 40 | 600 | 20 | 40 |
| Dosing frequency (per day) | 1-2 | 1 | 1 | 1-2 | 1 | 1-2 | 1 | 1 |
| Oral bioavailability | 33% | 23% | 60%-80% | 15% | 42%-58% | 13% | 26% | 60% |
| Prodrug? | Yes | No | No | Yes | No | No | Yes | Yes |
| Active metabolite? | EXP3174 | No | No | Candesartan | No | No | Olmesartan | Azilsartan |
| Plasma elimination half-life (hour) | 1.5-2.0 (or 6-9, for EXP3174) | 6 | 11-15 | 5-9 | 24 | 5-9 | 12-15 | 11 |
| Renal/hepatic elimination (%) | 10/90 (or 50/50 for EXP3174) | 30/70 | 1/99 | 60/40 | 1/99 | 30/70 | 10/90 (age-dependent) | 55/42 |
| Trough/peak ratio (at dose, in mg) | 58-78 (50-100) | 69-76 (80-160) | >60 (≥150) | 80 (8-16) | ≥97 (20-80) | 67 (600) | 57-70 (5-80) | ∼70 (80) |
| Dose Adjustment for: | ||||||||
| eGFR <30 mL/min/1.73 m 2 | No | Caution | Caution | Caution | No | No | No | No |
| Hepatic impairment | Yes, decrease by 50% | Caution | No | No | Caution | No | No | No |
| Dialyzable | No | No | No | No | No | No | Uncertain | No |
| FDA-Approved for: | ||||||||
| Hypertension | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Severe hypertension | Yes | No | No | No | No | No | No | No |
| Prevention of ESRD in type 2 diabetic nephropathy | Yes | No | No | No | No | No | No | No |
| Prevention of progression of type 2 diabetic nephropathy | Yes | No | Yes | No | No | No | No | No |
| Heart failure in patients intolerant of ACE inhibitors | No | Yes | No | Yes | No | No | No | No |
| Heart failure | No | Yes | No | Yes | No | No | No | No |
| Prevention of stroke in hypertensive patients with left ventricular hypertrophy | Yes | No | No | No | No | No | No | No |
| Prevention of cardiovascular events in “high-risk” hypertensives | No | No | No | No | Yes (80-mg dose, in ACE-intolerant patients) | No | No | No |
| Available in combination with | HCTZ | HCTZ, amlodipine, aliskiren, HCTZ + amlodipine | HCTZ | HCTZ | HCTZ, amlodipine | HCTZ | HCTZ, amlodipine, HCTZ + amlodipine | Chlorthalidone |
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