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From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M. Gabriel Khan © Humana Press Inc., Totowa, NJ
3 Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) play a pivotal role in the management of heart failure (HF) and hypertension.
These agents are cardioprotective and increase survival in patients with
• HF.
• Left ventricular (LV) dysfunction.
• Acute myocardial infarction (MI). The Survival of Myocardial Infarction Long-Term Evalu- ation (SMILE) study (1) showed that zofenopril administered to patients with acute anterior infarction improved survival.
• Hypertension with LV hypertrophy (LVH).
• Hypertension with diabetes and proteinuria.
• A high risk for cardiovascular events, as documented by the Heart Outcomes Prevention Evaluation HOPE study (2).
Tissue angiotensin II production appears to be an important modulator of tissue func- tion and structure. Angiotensin II produced in cardiac myocytes has been shown to play a role in stretch-induced hypertrophy and in the process of myocardial remodeling post infarction (3).
Three classes of ACE inhibitors have been developed. Most ACE inhibitors except cap- topril and lisinopril possess a carboxylic radical, are transformed in the liver to the active agent, and are thus prodrugs.
Class I: Captopril is not a prodrug; it is the active drug, but with metabolism, the metabo- lites are also active. Only captopril and zofenopril contain a sulfhydryl (SH) group.
Class II: All other available agents except lisinopril are prodrugs and become active only after hepatic metabolism to the diacid (Table 3-1).
Class III: Lisinopril is not a prodrug and is the only water-soluble agent; it is excreted unchanged by the kidneys. Lipid solubility does not confer clinical benefits beyond those observed with lisinopril.
The pharmacologic features and dosages of ACE inhibitors are given in Tables 3-1 and 3-2 and in Chapter 8.
MECHANISM OF ACTION
Vascular stretch of the renal afferent arteriole and the sodium concentration in the
distal tubule, sensed by the macula densa and an interplay of beta-adrenergic receptors,
Table 3-1 Pharmacologic Profile and Dosages of ACE Inhibitors BenazeprilCaptoprilCilazaprilEnalaprilFosinoprilLisinoprilPerindoprilQuinaprilRamiprilTrandolapril USA + CanadaLotensinCapotenInhibaceVasotecMonoprilPrinivil,AceonAccuprilAltaceMavik Zestril UK—CapotenVascaceInnovaceStarilCarace,AceonAccuprinTritaceGopten/ ZestrilOdrik EuropeCibaceLopril,InibaceXanef,Carace,AcertilAccuproTritaceGopten LopirinRenitecZestril ProdrugYesNoYesYesYesNoYesYesPartialYes Action Apparent (h)10.52–42–43–6 Peak effect (h)21–244–83–6 Duration (h)12–248–12>2412–2424–3024–48 Half-life (h)10–112–3>4011>2413>24>2414–3024 Metabolism—PartlyHepaticNonePartial hepatic EliminationRenalRenalRenalRenalRenal +RenalRenalRenalRenalRenal heptatic SH groupNoYesNoNoNoNoNoNoNoNo Tissue specificityNoNoYesNoYesNoYesYesYes Equivalent dose10 mg100 mg2.520 mg1020 mg31510 mg2 Initial dose5–10 mg6.25 mg1.52.5mg52.5 mg22.5–52.5–50.5 Total daily dose Hypertension10–20 mg25–150 mg1.5–5 mg5–40 mg5–40 mg5–40 mg2–8 mg5–40 mg2.5–15 mg1–4 mg Heart failure—75–150 mg—10–35 mg—10–35 mg— Dose frequencya1 daily2–3 daily1 daily1–2 daily1 daily1 daily1 daily1 daily1 daily1 daily Supplied, tabs5, 10, 20,12.5, 25,1, 2.5,2.5, 5, 10,10, 20 mg2.5, 5, 10,2, 4 mg5, 10, 20,1.25, 2.5,0.5, 1, 40 mg50, 100 mg5 mg20 mg20, 40 mg40 mg5, 10 mg2 mg aIncrease dosing interval with renal failure or in the elderly.
44
control the release of renin from the juxtaglomerular cells located in the media of the afferent renal arteriole (4–7).
Stimuli to the release of renin include
• A decrease in renal blood flow (ischemia), hypotension, and reduction of intravascular volume.
• Sodium depletion or sodium diuresis.
• Beta-adrenoceptor activation.
The enzyme renin is a protease that cleaves the leucine 10–valine 11 bond from angio- tensinogen to form the decapeptide angiotensin I (7). ACE now cleaves histidine–leucine from angiotensin I, resulting in the formation of angiotensin II, which causes
• Vasoconstriction about 40 times more intense than that caused by norepinephrine. Vaso- constriction occurs predominantly in arterioles and, to a lesser degree, in veins; this action is more pronounced in the skin and kidney, with some sparing of vessels in the brain and muscle (8).
• Renal effects: marked sodium reabsorption occurs in the proximal tubule.
• Adrenal effects: aldosterone release enhances sodium and water reabsorption and potassium excretion in the renal tubule distal to the macula densa. Angiotensin II also promotes release of catecholamines from the adrenal medulla.
• Increased sympathetic outflow and facilitated ganglionic stimulation of the sympathetic ner- vous system (7,9).
• Modest vagal inhibition, which may explain the lack of tachycardia in response to the marked vasodilator effect of ACE inhibitors.
• Enhanced antidiuretic hormone secretion, resulting in free water gain.
ACE inhibitors are competitive inhibitors of angiotensin-converting enzyme, and therefore they prevent the conversion of angiotensin I to angiotensin II. The consequences of this action are as follows:
• Arteriolar dilation causes a fall in total systemic vascular resistance, blood pressure, and afterload; these three terms are interrelated but are not synonymous (10).
• Sympathetic activity decreases because of attenuation of angiotensin-related potentiation of sympathetic activity and release of norepinephrine. The diminished sympathetic activity causes further vasodilation with additional reduction in afterload and some decrease in preload. It is because of this further indirect antisympathetic and vagal effect that heart rate is not increased by ACE inhibitors, as opposed to several other groups of vasodilators.
• Reduction in aldosterone secretion promotes sodium excretion and potassium retention.
• Vascular oxidative stress is favorably influenced (9) because vascular superoxide is re- duced. Thus, ACE inhibitors are believed to have important antioxidant properties superior
Table 3-2
Profile of Angiotensin II Receptor Blockers
Active Bioavailability Half-life Dose once
Drug metabolite (%) (h) Food effect daily (mg)
Candesartan No 15 9 None 4–16
Irbesartan No 60–80 11–15 None 150–300
Losartan Yes 33 6–9 Minimal 50–100
Valsartan No 25 6 50% 80–160
to those of vitamin E and other antioxidants. A review by Burnier gives details and relevant references (10). Vascular wall endothelium, smooth muscle, and fibroblasts contain enzyme systems that use nicotinamide adenine dinucleotide and its reduced form (NADH and NADPH) for the production of superoxide anion that is increased in response to angioten- sin II. ACE activity has been noted to increase in atheromatous plaques, and inhibition appears to influence inflammatory reaction favorably within the arterial wall. Angiotensin II is a mitogen for vascular smooth muscle cells that can be inhibited. Superoxide is a major source of hydrogen peroxide; thus, smooth muscle cell proliferation may be limited. Also, nitric oxide (NO) activity appears to improve because superoxide reacts with NO (10).
• Increased free water loss by blocking of angiotensin-mediated vasopressin release causes free water loss, resulting in some protection from dilutional hyponatremia. This action is important in patients with severe HF.
• Increased bradykinin-converting enzyme is the same as kinase II, which causes degrada- tion of bradykinin. The accumulation of bradykinin stimulates release of vasodilatory NO and prostacyclin that may protect the endothelium and contribute to arterial dilation and to a decrease in peripheral vascular resistance. Thus, indomethacin and other prostaglan- din inhibitors reduce the effectiveness of ACE inhibitors. Captopril has been shown to be uricosuric (11), and it reduces hyperuricemia.
• Arteriolar hyperplasia is decreased. ACE inhibitors have been shown to decrease arterio- lar hyperplasia caused by hypertension. Therapy with cilazapril for 1 yr appears to correct the structural and functional abnormalities in the resistance arteries of patients with mild essential hypertension.
ACE gene polymorphism contributes to the modulation and adequacy of the neuro- hormonal response to ACE inhibitor long-term administration in HF (12). Patients with HF with aldosterone escape have been shown to have a higher prevalence of DD genotype compared with patients with normal aldosterone levels (12). The antihypertensive response to ACE inhibition has also been shown in a small series to be more pronounced in subjects with ACE DD genotype than in those with the ACE-11 genotype (12). Genetic screening of large populations of patients, however, remains controversial.
ACE INHIBITORS VERSUS OTHER VASODILATORS
The reversal of iatrogenic hypokalemia caused by ACE inhibition is an important asset in the management of patients with hypertension and HF, who often require diuretic therapy.
The suppression of ADH activity by ACE inhibitors decreases free water gain, which is useful in the management of the hyponatremic patient with HF. This salutary effect is not observed with other vasodilators.
• Both ACE inhibitors and calcium antagonists are effective in preventing LVH and also
cause it to regress when present, but other vasodilators do not consistently prevent hypertro-
phy or cause regression. LVH is an independent risk factor for sudden death, and its preven-
tion is therefore an important aspect of pharmacologic therapy. ACE inhibitors are generally
well tolerated, with few adverse effects, whereas fewer than 33% of patients tolerate hydra-
lazine or alpha
1-blockers after 6 mo of therapy at doses sufficient to achieve goal blood pres-
sure. ACE inhibitors cause marked arteriolar vasodilation and a significant decrease in
venous tone, resulting in a decrease in afterload and preload. In contrast with other vasodila-
tors, with the exception of calcium antagonists, they cause afterload reduction, but their
administration sets in motion compensatory mechanisms that have several effects tending
to counteract their beneficial action.
• Prazosin and other alpha
1-blockers cause a decrease in afterload and a mild decrease in preload, but they increase heart rate and cardiac ejection velocity, resulting in a deleterious rate of rise of aortic pressure. These agents cause sodium and water retention that neces- sitates an increase in prazosin dosage and often requires added diuretic therapy. Tachyphy- laxis occurs, and clinical trials have proved prazosin to be ineffective for prolonging life in the setting of HF.
• Hydralazine has had extensive clinical testing. The Veteran’s Administration Heart Fail- ure Trial (VHeFT II) (12) showed the drug to be effective in HF when combined with the venodilator effect of nitrates. Hydralazine causes a marked enhancement in heart rate and cardiac ejection velocity. This action is undesirable in patients with ischemic heart disease and limits the usefulness of this agent. Other vasodilators of this class, including alpha
1- adrenergic receptor blockers (trimazosin, indoramin, terazosin), cause undesirable effects similar to those of prazosin and hydralazine. Other vasodilators, except for those that have a primary renal and adrenal action, of necessity cause a stimulation of the renin-angiotensin system as well as an adrenal release of catecholamine and sympathetic stimulation to com- pensate for the arteriolar dilation. These untoward effects, however, allow for the occa- sional combination of one of the aforementioned vasodilators with an ACE inhibitor.
• Nitroglycerin is predominantly a venous dilator and decreases preload. A minimal decrease in afterload occurs with the use of intravenous (IV) nitroglycerin, but not oral nitrates. These agents are useful in the management of chronic HF only when they are added to arteriolar vasodilators.
CLINICAL INDICATIONS Hypertension
ACE inhibitors and ARBs are indicated for hypertension of all grades. Because these agents do not cause sodium and water retention, they can often be used as monotherapy without a diuretic. This is a major advantage in terms of compliance and avoids the bio- chemical and lipid derangements produced by diuretics. Also, one-a-day preparations are available. Their low side effect profile, especially with the quality-of-life advantages over some other antihypertensive agents, has resulted in their widespread use.
As outlined earlier, their built-in protection from reflex sympathetic stimulation, result- ing in an increase in heart rate and the rate of rise of aortic pressure, is a major advantage over alpha
1-adrenergic receptor antagonists (alpha-blockers) and similar vasodilators.
ACE inhibitors and ARBs retain potassium and avoid the need for gastric-irritating potas- sium supplements. These agents have proved to be effective in the prevention of LVH and therefore have the potential to decrease cardiac mortality, because LVH is an indepen- dent risk factor for sudden death.
Rebound hypertension observed after withdrawal of clonidine, guanabenz, guanfacine, methyldopa, and, rarely, calcium antagonists and beta-blockers is not a feature of ACE inhibition.
ACE inhibitors are most effective in young patients, aged less than 55 yr, with essential
hypertension who usually have increased renin activity. In this subset of patients, ACE
inhibitors prescribed as monotherapy are effective in about 50% of cases. In patients with
more severe hypertension, ACE inhibitors in combination with diuretics are effective in
up to 65%. ACE inhibitors are slightly less effective in reducing blood pressure in non-
white patients and in the elderly, although studies indicate a sufficiently good response
to justify a trial of ACE inhibitors or ARBs as monotherapy in the elderly when other agents
are contraindicated or poorly tolerated. The antihypertensive action of ACE inhibitors is multifactorial and partially depends on the renin and sodium status. Thus, it is not surpris- ing that ACE inhibitors have been shown to be effective in elderly patients with low renin status.
ACE inhibitors and ARBs are particularly effective in lowering blood pressure in patients with high renin-angiotensin states, such as
• In combination with moderate to high doses of diuretics for the management of resistant hypertension.
• In malignant hypertension.
• In hypertension resulting from oral contraceptive use.
• In coarctation of the aorta.
• Immediately after dialysis in patients with chronic renal failure, when sodium and volume depletion is associated with enhancement of the renin-angiotensin system and responds to ACE inhibition (13).
• For the management of hypertensive patients with concomitant HF, for which ACE inhibi- tors are ideal. In this subset of patients, the systolic blood pressure should be maintained at less than 140 mmHg. The use of ACE inhibitors complements therapy with diuretics because diuretic use in this context stimulates the renin-angiotensin system.
ACE inhibitors are highly recommended in the following clinical situations:
• In the hypertensive diabetic patient, ACE inhibitors are first-choice agents because they do not adversely affect glucose metabolism, they have a proven effect in reducing diabetic proteinuria, and there is some evidence suggesting prolongation of nephron life. ACE inhi- bition enhances insulin-mediated uptake of glucose, and this effect may be important in the management of hypertensives with diabetes.
• These drugs are useful in hypertensive patients with hyperlipidemia because these agents produce no change in lipid parameters. When needed, a combination with a beta-blocking drug may provide cardioprotection.
• Tissue ACE inhibition allows for the use of ACE inhibitors to decrease blood pressure in patients who have undergone nephrectomy.
Although these agents are very effective in patients with renovascular hypertension, they must be used, if at all, with extreme caution because severe renal insufficiency may occur in patients with bilateral renal artery stenosis or stenosis in a solitary kidney. Because ACE inhibitors cause dilation of the efferent arteriole, they may precipitate renal failure or the loss of a kidney.
Heart Failure
ACE inhibitors have provided a major improvement in the management of HF, result- ing in both amelioration of symptoms and an increase in survival when they are used in combination with diuretics and digoxin (14). The fall in cardiac output with HF triggers a compensatory response that involves enhancement of the sympathetic nervous system and the renin-angiotensin-aldosterone system. As a result of these adjustments, systemic vascular resistance and afterload are increased inappropriately, with further deteriora- tion in cardiac performance, and a vicious circle ensues (see Chapter 12). ACE inhibitors play a vital role in halting the counterproductive pathophysiologic events that tend to per- petuate, rather than correct, cardiac decompensation.
The beneficial effects of diuretics in the management of HF are limited by excessive
stimulation of the renin-angiotensin system; the addition of ACE inhibitors results in
further amelioration. This improvement is partly the result of reduced arterial and venous tone, but changes in fluid and electrolyte balance are also important.
Stimulation of the sympathetic and the renin-angiotensin-aldosterone system causes intense sodium and water retention in the proximal and distal nephron. Also, an increase in venous tone occurs. Both adjustments result in an increase in filling pressure, which enhances preload. ACE inhibitors partially inhibit sodium and water retention and decrease venous tone, which produces a decrease in preload, an improvement or decrease in symp- toms and signs of pulmonary congestion, and an increase in exercise tolerance. The im- provement in functional capacity is superior to that observed with hydralazine and is similar to the combination of hydralazine and isosorbide dinitrate.
The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) (15) indicated an increased survival in New York Heart Association (NYHA) class IV patients treated for over 6 mo with enalapril added to diuretics and digoxin. The 6-mo mortality rate was 26% in patients treated with enalapril, versus 44% in those given diuretic and digoxin alone (p < 0.001). Forty-two percent of the group treated with enalapril showed functional class improvement compared with 22% in the control group (p = 0.001). In a study of patients with HF with an ejection fraction of less than 35%, enalapril improved survival and decreased the number of hospitalizations for HF (16). The VHeFT II trial, at an average 2.5-yr follow-up, showed a modest improvement in survival, the mortality rate being 33% for enalapril added to diuretics and digoxin, versus 38% in patients given a diuretic and digoxin along with hydralazine and isosorbide dinitrate (12).
It is clear that ACE inhibitors improve survival in certain categories of patients, and benefit is beyond question for patients with NYHA class IV HF (15). There is as yet no convincing evidence that these drugs decrease mortality in patients with NYHA class II HF and, although VHeFT II results suggest some benefit in class II patients, this is not statistically significant (see Chapter 12).
In the management of patients with HF, it is of paramount importance to commence with the smallest dose of ACE inhibitor, enalapril 2.5 mg or captopril 6.25 mg once or twice daily, and to titrate the dose slowly over several days, to avoid relative hypovolemia and hypotension, which can worsen cerebral and coronary perfusion. In a randomized study, patients with HF and concomitant angina showed an increase in angina and a reduced exercise tolerance when treated with captopril (17). The deleterious effects were related to the hypotensive effect of captopril. Poor diastolic coronary perfusion to contractile myocardial segments supplied by arteries with significant stenosis may precipitate angina in patients with HF. Caution is therefore especially necessary when ACE inhibitors are combined with calcium antagonists, nitrates, or other agents that may result in the low- ering of blood pressure.
Acute Myocardial Infarction
After acute MI, there is stimulation of the renin-angiotensin system resulting in in-
creased myocardial wall stress, as well as cardiac dilation that may ultimately increase mor-
bidity and mortality. The process by which the left ventricle dilates and progressively
enlarges after infarction is called ventricular remodeling. After MI, some patients develop
an increase in LV size and an increase in end-systolic and end-diastolic volumes. ACE
inhibitors cause favorable myocardial remodeling. These agents have been shown to
decrease the incidence of HF and the rate of hospitalization in postinfarction patients with
ejection fraction < 40 in the Survival and Ventricular Enlargement (SAVE) and Acute
Infarction Ramipril Efficacy (AIRE) studies (see Chapter 12).
In the SMILE trial (1), patients with anterior MI were treated early with zofenopril regardless of HF. Treatment lasted only 6 wk and resulted in a significant reduction in deaths and HF. After 1 yr, mortality was lower in the treated group than in the placebo group. In the AIRE trial, ramipril administered to patients within 3–10 d of acute MI with transient signs and symptoms of HF caused a significant 27% reduction in the risk of death at 15 mo, a benefit that was maintained for 5 yr.
Renoprotection
Based mainly on retrospective studies, ACE inhibitors were noted to slow the progres- sion of renal disease in nondiabetic patients. In the African American Study of Kidney Disease and Hypertension, an ACE inhibitor was shown to be more effective than a cal- cium antagonist in retarding the progression of renal disease. ACE inhibitors have been shown in trials to slow progression in patients with type 1 diabetes with microalbuminuria, but they have not been conclusively shown in RCTs to cause renoprotection in patients with type 2 diabetes. A small study of 92 patients comparing enalapril and losartan in hypertensive type 2 diabetes indicated equal protection.
Results of two large randomized controlled trials (RCTs) with ARBs are now available:
both losartan (18) and irbesartan (19) retarded the progression of nephropathy caused by type 2 diabetes independent of reduction in blood pressure. The average blood pressure during the course of the irbesartan trials was 144/83 mmHg with placebo and 143/83 mmHg in the treated group (see Chapter 22). ARBs are the first line of treatment for patients with type 2 diabetes with or without hypertension. Most important, lowering of blood pres- sure to <130 mmHg, a difficult goal with monotherapy, appears to be nonessential (see also the blood pressure range and the discussion of the benefit of beta-blockers in the United Kingdom Prospective Diabetes Study Group in Chapter 1).
Coarctation of the Aorta
In this condition, the renin-angiotensin system is especially active, and these agents have a role.
Pulmonary Hypertension
ACE inhibitors may lower pulmonary artery pressure and may increase cardiac output and functional capacity. As with other agents, the improvement is generally not spectacular.
Scleroderma Renal Crisis
This condition is associated with activation of the renin-angiotensin system with rapid progression of renal failure. ACE inhibitor therapy may prevent disease progression and improve survival (20). An interesting case report (21) indicates the failure of losartan to control blood pressure caused by scleroderma renal crisis but with excellent control achieved with an ACE inhibitor. Thus, there may be subtle differences between ACE inhibitors and ARBs that may be important in clinical management.
Bartter’s Syndrome Correction of hyperkalemia is achieved.
CONTRAINDICATIONS
• Renal artery stenosis in a solitary kidney or significant bilateral renal artery stenosis (22).
In patients with tight renal artery stenosis, renal circulation is critically dependent on high
levels of angiotensin II. A sharp decrease in angiotensin II concentration causes dilation of the glomerular efferent arteriole, resulting in a marked fall in renal blood flow that may cause the loss of a kidney. This catastrophic event is heralded by a sharp rise in serum crea- tinine concentration.
• Significant aortic stenosis is a contraindication.
• Hypertrophic and restrictive cardiomyopathy, constrictive pericarditis, and hyperten- sive hypertrophic “cardiomyopathy” of the elderly with impaired ventricular relaxation (23) are contraindications.
• Severe carotid artery stenosis is a contraindication.
• Renal failure, serum creatinine level greater than 2.3 mg/dL, 203 µmol/L (glomerular filtra- tion rate [GFR] 40 mL/min). Caution is necessary when ACE inhibitors are used in patients with renal failure because worsening of renal failure or hyperkalemia may occur.
• Angina complicating HF or hypertension is a contraindication because, in these situations, ACE inhibitors may cause an increase in angina (17).
• Severe anemia is a relative contraindication to the use of all vasodilators.
• Preexisting neutropenia is a contraindication because of the effect on white blood cell function.
• Pregnancy and lactation are contraindications.
• Immune-related renal disease or coadministration of agents that alter immune function, immunosuppressives, procainamide, tocainide, probenecid, hydralazine, allopurinol, and perhaps acebutolol and pindolol, which have been reported to cause a lupus-like syndrome, are contraindications.
• Porphyria is a contraindication.
• Uric acid renal calculi are contraindications because these agents are uricosuric (11).
ADVICE, ADVERSE EFFECTS, AND INTERACTIONS Hypotension
Symptomatic hypotension is not uncommon in patients with HF who are already being treated with diuretics or in patients with unilateral tight renal artery stenosis with high circulating renin levels.
Renal Failure
Development or worsening of renal failure may result from relative hypotension or in patients with tight renal artery stenosis.
Hyperkalemia
This may be precipitated by an increase in renal failure, by the use of potassium-spar- ing diuretics or potassium supplements or the use of salt substitutes, and in patients with hyporeninemic hypoaldosteronism.
Cough
A dry, ticklish, irritating, nonproductive cough occurs in up to 20% of patients, but it
was observed in 32% in one series and is clearly dose related, occurring with equal fre-
quency with captopril, enalapril, and lisinopril. ACE is the same as kinase II, which de-
grades bradykinin completely. The accumulation of bradykinin appears to be responsible
for the cough. The cough responds to treatment with sulindac or other nonsteroidal anti-
inflammatory drugs (NSAIDs). ARBs, however, do not cause cough, and angioedema
rarely occurs. This newer class of cardioactive agents is discussed at the end of this chapter.
Loss of Taste Sensation
This side effect is uncommon and can occur with all ACE inhibitors because the effect appears to be related to the binding of zinc by the ACE inhibitor. A metallic or sour taste in the mouth occurs in some patients with most agents. Mouth ulcers are not uncommon.
Angioedema
This rare complication is important because it can be life-threatening, and deaths have occurred (24,25). The occurrence appears to be slightly more common with longer acting ACE inhibitors than with captopril. Bradykinin and kallidin mediate hereditary angio- edema. Thus, ACE inhibition results in an accumulation of bradykinin, which can cause angioedema.
Angioedema is usually observed after the very first few doses or within the first month (24), but it can occur after the first dose or after several months of therapy. Cases have been reported within the first year of therapy. Warning signs include localized facial swell- ing or unilateral facial edema and periorbital edema, which is usually mild and subsides with cessation of drug therapy. Swelling may progress over a few hours to the lips, tongue, and larynx, with obstruction to the airway, which may be resistant to antihistamines and IV epinephrine. The severity of laryngeal edema may render endotracheal intubation impos- sible (25,26), and it may necessitate emergency tracheostomy. Thus, all patients taking an ACE inhibitor who develop mild facial edema and initially respond to antihistamine should be hospitalized, given epinephrine and antihistamine, and observed in an intensive care setting, because, rarely, a rebound, worsening, life-threatening situation can ensue (25,26) and should be prevented. Antihistamines alone may not suffice and, whereas an injection of antihistamine may appear to cause relief over a few hours, severe angioedema may still develop (25,26).
Rash
A pruritic rash may occur in up to 10% of patients, typically maculopapular on the arms and trunk, occasionally involving the face. Pruritus may be severe. An urticarial or erythe- matous eruption, sometimes associated with eosinophilia, may ensue, and, very rarely, pemphigus and onycholysis have been reported. Captopril and enalapril appear to exhibit the same incidence of rash.
Proteinuria
This occurs in fewer than 1% of captopril-treated patients and mainly in those with underlying renal collagen vascular disease or other immunologic abnormality with a dose of captopril in excess of 150 mg/d. Proteinuria results from stimulation of immune mech- anisms and relative hypotension, and it also occurs with other ACE inhibitors.
Neutropenia, Agranulocytosis
This complication is very rare and occurs mainly in patients with collagen vascular disease and other immunologic disturbances. This complication usually manifests within the first 4 mo of therapy and reverses about 3 wk after cessation of ACE inhibitor therapy.
Mild Dyspnea and/or Wheeze
This may develop, particularly in some asthmatic patients, within the first few weeks
of ACE inhibitor therapy (27).
Anaphylactoid Reactions
In patients given ACE inhibitors, anaphylactoid reactions may occur during desensiti- zation treatment with bee or wasp venom. Discontinuation of the ACE inhibitor for at least 24 h before treatment is advisable.
Captopril
This drug appears to inhibit the diuretic action of furosemide in ambulatory patients (see Chapter 12).
Uncommon Adverse Effects
These include headache, dizziness, fatigue, nausea, diarrhea, impotence, loss of libido, myalgia, muscle cramps, hair loss, hepatitis, cholestatic jaundice, acute pancreatitis, and the occurrence of antinuclear antibodies.
Interactions
Interactions may occur with allopurinol, acebutolol, hydralazine, procainamide, pin- dolol, tocainide, and immunosuppressives because these drugs alter the immune response.
With diuretics, hypotensive effects have been emphasized, and potassium-sparing diure- tics or potassium supplements may cause life-threatening hyperkalemia. Lithium levels may increase, and toxicity has been reported.
INDIVIDUAL ACE INHIBITORS
Pharmacologic Profile and Individual Differences
The pharmacologic profiles of the commonly used ACE inhibitors are given in Table 3-1.
Subtle Differences
Short-acting ACE inhibitors such as captopril have obvious advantages in the treat- ment of hypertensive emergencies because the several hours’ delay of peak action of other ACE inhibitors does not allow their use when blood pressure lowering is required urgently.
Angioedema appears to be slightly more common with enalapril than is observed with captopril, and the longer-acting ACE inhibitors are not exempt from this life-threatening adverse effect. Quinapril, ramipril, and some other ACE inhibitors inhibit tissue renin production. The renin-angiotensin system not only is confined to blood vessels and the kidney but also exists in the heart, liver, adrenals, brain, pituitary glands, salivary glands, gut, uterus, ovaries, and other tissues. The possible theoretical benefit of inhibiting tissue renin-angiotensin systems, however, has not yet been translated into clearly defined clin- ical differences among the various ACE inhibitors. Quinapril and ramipril penetrate to myo-cardial ACE binding sites. Myocardial angiotensin has a minimal positive inotropic effect and thus could conceivably be implicated in the development of myocardial hyper- trophy. Long-acting preparations with half-lives ranging from 24 to 48 h include cilazapril, perindopril, quinapril, ramipril, spirapril, and zofenopril. Zofenopril is five times more potent than captopril, but it is the only other compound of those mentioned that has an SH group.
Hypotension
Short-acting compounds have an advantage in the initial management of patients with
HF. The observation period after the first dose is 1–2 h for captopril, 2–4 h for enalapril,
and 2–10 h for longer acting compounds. When hypotension occurs, cessation of the drug leads to quicker recovery with the shorter acting compounds. Also, renal failure may be more protracted with longer-acting agents. The agents that are not prodrugs (Table 3-1) have a rapid onset of action. Lisinopril is not a prodrug, and its action is not affected by concurrent administration of food or liver transformation.
Drug name: Captopril Trade name: Capoten Supplied: 12.5, 25, 50 mg
Dosage: Hypertension: 12.5–50 mg twice daily, max. 150 mg daily;
see text for further advice
Heart failure: 6.25 mg test dose, 6.25–12.5 mg twice daily; titrate over days to weeks to 25–50 mg twice daily; see text for further advice
Dosage (Further Advice)
Heart failure: When feasible, discontinue diuretics for 24 h before the initial dose of captopril 6.25 mg. Lower doses (e.g., 3 mg) have been used in special situations, includ- ing HF after MI. Observe the blood pressure every 15 min after dosing for 2 h. If hypotension does not occur, give 6.25 mg twice daily for 1–2 d and then, depending on the urgency of the situation, 12.5 mg twice daily, increasing, if needed, to 25 mg twice daily. Most patients require a dose of 37.5–50 mg daily. Maximum suggested dose is 100 mg daily in two or three divided doses if renal function is normal. If interrupted, diuretics should be recommenced approx 24–36 h after the initial dose of captopril. At times, it is not possible to discontinue diuretics completely, and the dose is halved. Also, nitrates should be withheld, to allow the introduction of captopril without producing hypotension or presyncope.
Hypertension: The initial dose is 12.5 mg on d 1 and then twice daily, increasing over the next days or weeks as needed, to a maintenance dose of 25–50 mg twice daily. The maximum dose is 150 mg daily in two divided doses in patients with normal renal func- tion. In patients with renal dysfunction, the total dose should be decreased and the dosing interval increased. In elderly hypertensive patients and in patients with renal impairment or with concomitant diuretic use, the initial dose should be 6.25 mg.
The action, indications, contraindications, and adverse effects of captopril are given under the general discussion of ACE inhibitors.
Pharmacokinetics
Food has been shown to cause about a 33% reduction in absorption of captopril, so the
drug should be given 1 h before meals on an empty stomach. The effect on blood pressure,
however, does not appear to be affected by giving the drug with food. About 50% of the
absorbed captopril is metabolized by the liver and is eliminated with the active drug by the
kidney, with a plasma half-life of approximately 2–3 h. Captopril is 25–30% albumin
bound; some binding occurs to endogenous thiol compounds, and the drug does not cross
the blood-brain barrier. An apparent action on blood pressure is observed within half an
hour of oral ingestion, with a peak effect in 1–2 h and duration of 8–12 h, so in the man-
agement of hypertension or HF, twice-daily dosage produces a 24-h therapeutic effect.
Drug name: Enalapril
Trade names: Vasotec, Innovace (UK) Supplied: 2.5, 5, 10, 20 mg
Dosage: Hypertension: 5–20 mg daily, max. 40 mg; see text for further advice Heart failure: 2.5 mg test dose, then 10–15 mg once or twice daily, max.
30 mg daily; see text for further advice
Dosage (Further Advice)
Heart failure: The dose of diuretics should be halved or held for 24 h to allow for the introduction of enalapril. This is sometimes not possible, and the initial dose of enalapril must be given under close hospital supervision. The initial dose is 2.5 mg orally; observe under close supervision with blood pressure monitoring for 2–6 h. In the absence of hypotension, give 2.5 mg twice daily for a few days, and reintroduce diuretics as soon as possible to prevent the recurrence or worsening of HF. The dose of enalapril is increased to 5 mg twice daily for several days and, if needed, to 7.5–10 mg twice daily, which is approximately equivalent to 75–100 mg captopril daily; the suggested maximum dose is 30 mg, preferably in two divided doses. Patients with HF often have concomitant renal dysfunction, and the once-daily dosing of enalapril is usually sufficient to produce a salutary response. A twice-daily enalapril dose, however, allows for finer titration and may avoid relative hypotension. The effective median dose in CONSENSUS was 18 mg, and in VHeFT it was 15 mg.
Hypertension: Discontinue diuretics for 2–3 d, and then give 2.5 mg daily, increasing slowly over several weeks to 5–10 mg daily. With more severe hypertension, the starting dose could be 2.5 mg on the first day and then 5 mg daily. If blood pressure control is not achieved with a dose of 10 mg, increase the dose to 10 mg in the morning and 5 mg at night. Failure to control the condition with this dose should prompt the reintroduction of the diuretic. The maximum dose of enalapril should be kept to 30 mg daily, equivalent to 150 mg captopril. A dose of 40 mg is rarely necessary, except with severe or resistant hypertension requiring therapy.
Pharmacokinetics
After oral dosing, about 60% of the drug is absorbed and is not influenced by ingestion of food. Enalapril is inactive and undergoes hepatic hydrolysis to the active enalaprilat.
Peak effect of enalaprilat is at about 5 h; after multiple dosing, the plasma half-life is approx 11 h. The peak hypotensive effect is observed from 4 to 6 h after oral dosing, and excretion is virtually all renal. The dose of enalapril may need to be increased in patients with severe liver dysfunction.
The adverse effects and contraindications of enalapril have been given earlier under ACE inhibitors.
Drug name: Lisinopril
Trade names: Prinivil, Zestril, Carace Supplied: 2.5, 5, 10, 20 mg
Dosage: Hypertension: 5–20 mg once daily, max. 40 mg; see text for further advice Heart failure: 2.5–5 mg once daily, increasing over weeks to 10–20 mg
daily, max. 40 mg daily
Dosage (Further Advice)
As with other ACE inhibitors, it is recommended, if feasible, to discontinue diuretics for at least 2 d before commencing lisinopril and to recommence diuretics a few days to weeks later, if needed. Initially, give 2.5 mg daily, increasing slowly over weeks with evaluation of blood pressure and renal function, to a maintenance dose of 5–20 mg once daily. The maximum suggested dose of lisinopril is 30 mg daily; doses in excess of 20 mg usually do not cause further lowering of blood pressure (27–29). In the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial (29), a daily dose of 30–35 mg versus 2.5–5 mg reportedly caused a significant decrease in hospitalizations, but the decrease was only 14%, with no reduction in total mortality.
Pharmacokinetics
The drug is well absorbed when given orally, and absorption is not influenced by food.
Lisinopril is not a prodrug and does not undergo hepatic metabolism. The drug is hydro- philic and is completely eliminated by the kidney with a plasma half-life of 13 h, but the elimination half-life is long, up to 30 h. An apparent action is observed in 2–4 h with peak effect at 4–8 h and duration of action of 24–30 h. Lisinopril is the only water-soluble ACE inhibitor.
Drug name: Benazepril Trade name: Lotensin Supplied: 5, 10, 20, 40 mg
Dosage: 5 mg daily, increasing over weeks to 10–20 mg daily, max. 40 mg The plasma half-life is about 11 h; the terminal half-life is 21–22 h.
Drug name: Cilazapril
Trade names: Inhibace, Vascace (UK) Supplied: 1, 2.5, 5 mg
Dosage: 1–2, 5 mg daily, max. 5 mg
Cilazapril is a prodrug and undergoes hepatic metabolism to the active form cilazaprilat with a terminal half-life that exceeds 40 h.
Drug name: Fosinopril
Trade names: Monopril, Staril (UK) Supplied: 10, 20 mg
Dosage: 5–10 mg once daily, increasing gradually to 20 mg daily, max. 40 mg;
see text for further advice
Dosage (Further Advice)
Avoid taking within 2 h of antacids. Fosinopril undergoes hepatic and renal elimination.
More of the drug is removed through the liver with increasing renal failure (30). Fosinopril
appears to cause less cough than is observed with other ACE inhibitors. The terminal half-
life is approximately 13 h, but inhibition of serum ACE lasts 24 h after a 40-mg dose of
the drug.
Drug name: Perindopril Trade name: Aceon Supplied: 2, 4, 8 mg
Dosage: 2 mg daily; maintenance 4 mg, max. 8 mg
The drug is long acting, given once daily, and has tissue specificity, although the exact benefit of this activity is not yet clinically apparent. The terminal half-life is 27–33 h.
Drug name: Quinapril
Trade names: Accupril, Accupro (UK) Supplied: 5, 10, 20, 40 mg
Dosage: 2.5–5 mg initially, increasing to 10–40 mg daily, max. 60 mg
Drug name: Ramipril
Trade names: Altace, Tritace (UK) Supplied: 1.25, 2.5, 5, 10 mg
Dosage: 1.25–2.5 mg daily, increasing over weeks to 5–10 mg; max. 15 mg once daily or two divided doses
The drug is partially metabolized to the active form, ramiprilat, and is partially a prodrug.
Ramiprilat is about 70% and ramipril approximately 50% protein bound. The effective half-life is 14–18 h, but accumulation of the drug occurs resulting in a terminal half-life of up to 110 h. The maximal effect is observed in about 6 h, with duration of action exceeding 24 h. The drug has tissue-specific ACE inhibitor activity.
The HOPE study showed that in a high-risk group of patients (81% ischemic heart disease, 11% stroke, 38% diabetes), 10 mg of ramipril given for a mean of 4.5 yr caused a reduction of 22% in the primary outcome of MI, stroke, or death from cardiovascular diseases (2). In diabetic patients after adjustment for the changes in systolic (2.4 mmHg) blood pressure, ramipril lowered the risk of the combined primary outcome by 25%.
Drug name: Spirapril
Trade names: Renpress, Sandopril Supplied: 12.5 mg
Dosage: 6.5–12.5 mg daily, max. 30 mg
The drug is well absorbed when given orally. The onset of action occurs in 1 h after ingestion, with a prolonged duration of action reflecting a half-life of about 72 h. The drug is eliminated by the liver and kidney.
Drug name: Trandolapril Trade names: Mavik, Gopten (UK) Supplied: 0.5, 1, 2 mg
Dosage: 0.5–1 mg daily, max. 4 mg
This agent without SH moiety has a long plasma half-life of 24 h. It is rapidly hydro- lyzed to trandolaprilat, the active compound, which has high lipophilicity that enhances tissue penetration (31).
Drug name: Zofenopril
Dosage: Initially 7.5 mg every 12 h; titrate slowly to 15–30 mg daily
The dose outlined under dosage was administered for 6 wk in the SMILE study (1).
Patients with acute anterior infarcts were randomized at a mean of 15 h from the onset of symptoms. Therapy resulted in a significant reduction in the incidence of severe HF and improved survival at 1-yr follow-up. Efficacy was observed mainly in patients with previous infarction. Further clinical trials with ACE inhibitors administered within 6 h of onset of symptoms are required to document the safety and efficacy of very early ACE inhibitor therapy.
ANGIOTENSIN II RECEPTOR BLOCKERS
There are two main types of angiotensin II receptor: AT
1and AT
2. Most actions of angiotensin II are mediated through the AT
1receptor. ARBs specifically block the an- giotensin II receptor AT
1, and this causes blockade of the renin-angiotensin aldosterone system, although we know that the blockade is not complete. Because angiotensin can be synthesized outside the renin-angiotensin system, angiotensin receptor antagonists could produce more effective control of angiotensin II than ACE inhibitors. The major pathway for angiotensin II production in the heart is not ACE but a serine protease, chymase. Angiotensin I can be converted to angiotensin II by enzymes such as cathepsin, trypsin, and heart chymase, but the exact contribution of these alternative pathways to the generation of angiotensin II is unclear.
Angiotensin II blockade causes an increased flux of superoxide that improves NO bioactivity. Most important, AT
2receptors are not blocked by ARBs. It appears that AT
2receptors mediate a physiologic cardioprotective role: production of bradykinin, NO, prostaglandins in the kidney, inhibition of cell growth, promotion of cell differentiation, and apoptosis. A review by Burnier (10) gives details and relevant references. Their proven beneficial effect in type 2 diabetes (18,19,31), in which no proven effect of ACE inhibi- tors has emerged, will render ARBs a popular choice in diabetics, particularly because of the absence of cough and the virtual absence of angioedema (32). ACE inhibitors need to be tested against ARBs in patients with type 2 diabetes. Of all drug classes, patients are more likely to remain on long-term treatment with ARBs (33). ARBs work selectively at the AT
1receptor and have no effect at the AT
2receptor. The most notable advantage of ARBs is that they do not cause cough, a bothersome complication of ACE inhibitors;
the rare but serious occurrence of angioedema with ACE inhibitors does not appear to be provoked by ARBs, although a few cases have been reported.
Overall differences between ARBs and ACE inhibitors have not been noted in clinical
trials. The Evaluation of Losartan in the Elderly (ELITE) study (32) reported nearly equiv-
alent effects for losartan and captopril on the progression of HF, but there was an unex-
pected reduction in the incidence of sudden death in the losartan group. This study was
underpowered and was not confirmed by the better powered ELITE II study (34), which
did not show a difference in mortality or in sudden death. One should be careful, however,
before concluding that ARBs are less effective than ACE inhibitors for HF based solely
on the results of ELITE II. The results of CHARM clearly indicated that the ARB can- desartion is equal to ACE inhibitor therapy for the management of heart failure (see the results of CHARM in Chapter 22).
Drug name: Candesartan
Trade names: Atacand, Amias (UK)
Supplied: 8, 16, 32 mg; 8, 16 mg; UK 4, 8, 16 mg
Dosage: Initially 8 mg once daily (4 mg in the elderly or in hepatic/renal impairment), then 8–16 mg; max. 32 mg daily
Half-life: 9 h, 9–12 h in elderly Excretion: 60% renal; 40% bile
Drug name: Irbesartan
Trade names: Avapro, Aprovel (UK) Supplied: 75, 150, 300 mg
Dosage: 150–300 mg once daily (initial dose 75 mg in the elderly) Half-life: 11–15 h
Excretion: 80% renal; 20% bile
Drug name: Losartan Trade name: Cozaar Supplied: 25, 50 mg
Dosage: 25–50 mg once or twice daily (initially in the elderly and in those with hepatic or renal impairment 25 mg daily); max. 100 mg daily
See Table 3-2 for a comparison of ARBs. Olmesartan (Benicar) causes significant reductions in blood pressure at 20–40 mg once daily.
Drug name: Valsartan Trade name: Diovan Supplied: 40, 80 mg
Dosage: 80–160 mg once daily (initial dose in the elderly 40 mg); max. 320 mg Caution: Neutropenia has been reported in 1.9% of valsartan-treated patients. In- creased hepatic enzymes and the rare occurrence of severe hepatic dysfunction with two fatalities have been reported in association with marketed ARBs.
Drug name: Telmisartan Trade name: Micardis Supplied: 40, 80 mg
Dosage: 20–80 mg once daily Half-life: 24 h
Excretion: 98% in the feces
Drug name: Eprosartan Trade name: Teveten Supplied: 400, 600 mg
Dosage: 300–400 mg twice daily; or 300–800 mg once daily Half-life: 7 h
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SUGGESTED READING
Jhund P, McMurray JV. Does aspirin reduce the benefit of an angiotensin-converting enzyme inhibitor?:
Choosing between the Scylla of observational studies and the Charybdis of subgroup analysis. Circulation 2006;113:2566–2568.
Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy–induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–2481.
