Actions of Mapryl in details
A multicenter, placebo-controlled, double-blind study of left ventricular dysfunction (SOLVD) assessed the effects of Mapryl in 6,797 patients. 2,569 patients with all degrees of symptomatic heart failure (primarily mild to moderate New York Heart Association Class II and III) were randomized into the Treatment Arm, and 4,228 patients with asymptomatic left ventricular dysfunction were randomized into the Prevention Arm. The combined results demonstrated an overall reduced risk for the development of major ischemic events. Mapryl decreased the incidence of myocardial infarction and reduced the number of hospitalizations for unstable angina pectoris in patients with left ventricular dysfunction.
In addition, in the Prevention Arm, Mapryl significantly prevented the development of symptomatic heart failure and reduced the number of hospitalizations for heart failure. In the Treatment Arm, Mapryl, as an adjunct to conventional therapy, significantly reduced overall mortality and hospitalization for heart failure and improved NYHA functional class.
In a similar study involving 253 patients with severe heart failure (New York Heart Association Class IV), Mapryl was shown to improve symptoms and reduce mortality significantly.
The cardioprotective properties of Mapryl were demonstrated in these studies by the beneficial effects on survival and retardation of the progression of heart failure in patients with symptomatic heart failure; retardation of the development of symptomatic heart failure in asymptomatic patients with left ventricular dysfunction; and prevention of coronary ischemic events in patients with left ventricular dysfunction, specifically reduction in the incidence of myocardial infarction and reduction in hospitalization for unstable angina pectoris.
Pharmacology: Pharmacodynamics: Administration of Mapryl to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.
Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of Mapryl has not been associated with rapid increase in blood pressure.
Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of Mapryl. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related. However, at recommended doses, antihypertensive and hemodynamic effects have been shown to be maintained for at least 24 hours.
The onset of action after intravenous administration of enalaprilat usually occurs within a few minutes of administration with the maximum effect occurring within 4 hours.
The duration of hemodynamic effects appears to be dose-related. However, for doses within the recommended dosage range, the duration of effect of Injection Mapryl in most patients is approximately six hours.
Antihypertensive treatment with Mapryl leads to a significant regression of left ventricular hypertrophy with preservation of left ventricular systolic performance.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of Mapryl there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.
Chronic administration of Mapryl to patients with essential hypertension and renal insufficiency may be associated with improvements in renal function, evidenced by increased glomerular filtration rate.
In short term clinical studies in diabetic and nondiabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of Mapryl.
Hemodynamic changes seen during intravenous therapy with enalaprilat are similar to those seen with oral Mapryl.
When given together with thiazide-type diuretics, the blood pressure-lowering effects of Mapryl are at least additive. Mapryl may reduce or prevent the development of thiazide-induced hypokalemia.
Treatment with Mapryl is not usually associated with adverse effects on plasma uric acid.
Treatment with Mapryl has been associated with favorable effects on plasma lipoprotein fractions and favorable or no effect on total cholesterol levels.
In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or Injection Mapryl was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy.
In patients with mild to moderate heart failure, Mapryl retarded progressive cardiac dilatation/enlargement and failure, as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction.
Clinical data have shown that Mapryl reduced the frequency of ventricular arrhythmias in patients with heart failure, although the underlying mechanisms and clinical significance are not known.
Pharmacokinetics:
Oral Mapryl is rapidly absorbed, with peak serum concentrations of Mapryl occurring within one hour. Based on urinary recovery, the extent of absorption of Mapryl from oral Mapryl is approximately 60%.
Following absorption, oral Mapryl is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Similar peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of Mapryl. Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact Mapryl. Except for conversion to enalaprilat, there is no evidence for significant metabolism of Mapryl. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of oral Mapryl. The effective half-life for accumulation of enalaprilat following multiple doses of oral Mapryl is 11 hours. The absorption of oral Mapryl is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of Mapryl are similar for the various doses in the recommended therapeutic range.
Studies in dogs indicate that Mapryl crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of oral Mapryl in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C Mapryl. Radioactivity was found to cross the placenta following administration of 14C Mapryl to pregnant hamsters.
How should I take Mapryl?
Take Mapryl exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
You may take Mapryl with or without food.
Shake the oral suspension (liquid) well just before you measure a dose. Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.
Your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested.
You may have very low blood pressure while taking this medication. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.
If you need surgery, tell the surgeon ahead of time that you are using Mapryl. You may need to stop using the medicine for a short time.
If you are being treated for high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.
Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.
Store the liquid medicine in the refrigerator, do not freeze. Throw away any Mapryl liquid not used within 60 days.
Mapryl administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results.
Mapryl can be taken with or without food.
Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking Mapryl. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.
Your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.
If you need surgery, tell the surgeon ahead of time that you are using Mapryl. You may need to stop using the medicine for a short time.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.
Store the liquid medicine in the refrigerator, do not freeze. Throw away any unused liquid after 30 days.
Mapryl pharmacology
Mechanism of Action
Mapryl, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE 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. The beneficial effects of Mapryl in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with Mapryl tablets alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with Mapryl tablets plus a thiazide diuretic, there was essentially no change in serum potassium. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Mapryl remains to be elucidated.
While the mechanism through which Mapryl lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Mapryl is antihypertensive even in patients with low-renin hypertension. Although Mapryl tablets was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to Mapryl monotherapy than non-black patients.
Pharmacodynamics
Hypertension
Adults
Administration of Mapryl tablets to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure, usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients.
In most patients studied, after oral administration of a single dose of Mapryl, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval.
In some patients achievement of optimal blood pressure reduction may require several weeks of therapy.
The antihypertensive effects of Mapryl have continued during long-term therapy. Abrupt withdrawal of Mapryl has not been associated with a rapid increase in blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of Mapryl, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
When given together with thiazide-type diuretics, the blood pressure lowering effects of Mapryl are approximately additive.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving Mapryl tablets. In this study, there was no evidence of a blunting of the antihypertensive action of Mapryl.
Pediatric Patients
In a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of Mapryl daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of Mapryl daily. Mapryl administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of Mapryl was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, Mapryl was generally well tolerated.
Heart Failure
In trials in patients treated with digitalis and diuretics, treatment with Mapryl resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. Hemodynamic effects were observed after the first dose, and appeared to be maintained in uncontrolled studies lasting as long as four months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year.
Pharmacokinetics
The pharmacokinetics of Mapryl
Oral Solution were shown to be similar to that of Mapryl® tablets under fasted conditions. A high-fat meal reduced the Cmax of Mapryl and enalaprilat by 46% and 36%, respectively. The exposure, as measured by AUC, to enalaprilat was reduced by 23%. The time to peak concentrations (Cmax) was delayed by 20 minutes for Mapryl and 62 minutes for enalaprilat. The trough plasma concentrations of Mapryl (from 6 to 12 hours) and enalaprilat (from 16 to 36 hours) are similar between fasted and fed administrations.
Adults
Following oral administration of Mapryl tablets, peak serum concentrations of Mapryl occur within about one hour. Based on urinary recovery, the extent of absorption of Mapryl is approximately 60%. Mapryl absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, Mapryl is hydrolyzed to enalaprilat, which is a more potent angiotensin-converting enzyme inhibitor than Mapryl; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of Mapryl. Excretion of Mapryl is primarily renal.
Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or Mapryl. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact Mapryl. There is no evidence of metabolites of Mapryl, other than enalaprilat.
The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of Mapryl is 11 hours.
The disposition of Mapryl and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases, and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of Mapryl is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at the rate of 62 mL/min.
Pediatric Patients
A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg Mapryl. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total Mapryl and enalaprilat in 24 hours was 68% of the administered dose. Conversion of Mapryl to enalaprilat was in the range of 63-76%. The overall results of this study indicate that the pharmacokinetics of Mapryl in hypertensive children aged 2 months to ≤16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults.
In the above pediatric study, Mapryl was given as tablets and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, Mapryl was administered in a suspension formulation.
Studies in dogs indicate that Mapryl crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of Mapryl in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C-Mapryl. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
References
- DailyMed. "ENALAPRIL MALEATE; HYDROCHLOROTHIAZIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- DailyMed. "GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Enalapril: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Mapryl are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Mapryl. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
