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Altace

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Altace

Altace

CLINICAL PHARMACOLOGY

Mechanism of Action

Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see WARNINGS AND PRECAUTIONS]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma rennin activity.

The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.

Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated. While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the reninangiotensin- aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension. Although ALTACE was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.

Pharmacodynamics

Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Pharmacokinetics

Absorption

Following oral administration of ALTACE, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.

In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food.

Distribution

Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 μg/mL–10 μg/mL.

Metabolism

Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.

Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg-20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.

After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses (2.5 mg), but the difference is clinically insignificant.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal elimination phase has a prolonged half-life ( > 50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ALTACE 5 mg-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.

In patients with creatinine clearance < 40 mL/min/1.73 m², peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses. In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.

Excretion

After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance < 40 mL/min/1.73 m² had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

Clinical Studies

Hypertension

ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.

Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted [see WARNINGS AND PRECAUTIONS]. Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.

In single-dose studies, doses of 5 mg–20 mg of ALTACE lowered blood pressure within 1–2 hours, with peak reductions achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12 weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.

In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements. The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. ALTACE was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.

ALTACE was less effective in blacks than in Caucasians. The effectiveness of ALTACE was not influenced by age, sex, or weight.

In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial design study conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction ( < 0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes. The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of treatment.

Table 3: Summary of Combined Components and Endpoints—HOPE Study

Outcome Placebo
(N=4652)
n (%)
ALTACE
(N=4645)
n (%)
Relative Risk (95% CI) P-Value
Combined Endpoint
Myocardial infarction, stroke, or death from cardiovascular cause 826 (17.8%) 651 (14.0%) 0.78 (0.70-0.86) P=0.0001
Component Endpoint
Death from cardiovascular causes 377 (8.1%) 282 (6.1%) 0.74 (0.64-0.87) P=0.0002
Myocardial infarction 570 (12.3%) 459 (9.9%) 0.80 (0.70-0.90) P=0.0003
Stroke 226 (4.9%) 156 (3.4%) 0.68 (0.56-0.84) P=0.0002
Overall Mortality
Death from any cause 569 (12.2%) 482 (10.4%) 0.84 (0.75-0.95) P=0.005

Figure 1: Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the Ramipril Group and the Placebo Group

]

ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ALTACE was equally effective in ethnic subgroups.

This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to those in the overall study population.

Table 4: Summary of Combined Endpoints and Components in Diabetics—HOPE Study

Outcome Placebo
(N=1769)
n (%)
ALTACE
(N=1808)
n (%)
Relative Risk Reduction (95% CI) P-Value
Combined Endpoint
Myocardial infarction, stroke, or death from cardiovascular cause 351 (19.8%) 277 (15.3%) 0.25 (0.12-0.36) P=0.0004
Component Endpoint
Death from cardiovascular causes 172 (9.7%) 112 (6.2%) 0.37 (0.21-0.51) P=0.0001
Myocardial infarction 229 (12.9%) 185 (10.2%) 0.22 (0.06-0.36)P=0.01
Stroke 108 (6.1%) 76 (4.2%) 0.33 (0.10-0.50)P=0.007

Figure 2: The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups

The Beneficial Effect of Treatment with ALTACE - Illustration

Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.

The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, betablockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.

Heart Failure Post-Myocardial Infarction

ALTACE was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, doubleblind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2–9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.

Patients randomized to ALTACE treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ALTACE) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months.

The use of ALTACE was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

Last reviewed on RxList: 11/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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