Actions of Xenam in details
The mechanism of action of Xenam has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the rennin angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.
Xenam prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by Xenam. In animal studies, Xenam did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action.
ACE is identical to ''bradykininase'', and Xenam may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E 2 may also have a role in the therapeutic effect of Xenam.
Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.
How should I take Xenam?
Take Xenam 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.
Xenam is usually taken 1 hour before meals. Follow your doctor's instructions.
Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking Xenam. This can lead to very low blood pressure, electrolyte disorders, or kidney failure.
Drink plenty of water each day while you are taking Xenam.
Your blood pressure will need to be checked often, and you may need frequent blood tests.
This medication can cause false results with certain medical tests. Tell any doctor who treats you that you are using Xenam.
If you need surgery, tell the surgeon ahead of time that you are using Xenam. 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.
Xenam 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.
Xenam is usually taken 1 hour before meals. Follow your doctor's instructions.
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 Xenam. 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 Xenam. 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.
Xenam pharmacology
Mechanism of Action
The mechanism of action of Xenam has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the rennin angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.
Xenam prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by Xenam. In animal studies, Xenam did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action.
ACE is identical to ''bradykininase'', and Xenam may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E 2 may also have a role in the therapeutic effect of Xenam.
Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.
Pharmacokinetics
After oral administration of therapeutic doses of Xenam, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; Xenam therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of Xenam and Xenam-cysteine disulfide.
Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged Xenam is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of Xenam occurs.
Pharmacodynamics
Administration of Xenam results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of Xenam and glomerular filtration rate is usually unchanged.
Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of Xenam. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of Xenam and thiazide-type diuretics are additive. In contrast, Xenam and beta-blockers have a less than additive effect.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of Xenam has not been associated with a rapid increase in blood pressure.
In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output, and increased exercise tolerance time (ETT) have been demonstrated. These hemodynamic and clinical effects occur after the first dose and appear to persist for the duration of therapy. Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics and digitalis show no tolerance to beneficial effects on ETT; open studies, with exposure up to 18 months in some cases, also indicate that ETT benefit is maintained. Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal.
The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 2,231 patients (age 21 to 79 years) who survived the acute phase of myocardial infarction and did not have active ischemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤40%, but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half of the patients had symptoms of heart failure in the past. Patients were given a test dose of 6.25 mg oral Xenam and were randomized within 3 to 16 days post-infarction to receive either Xenam or placebo in addition to conventional therapy. Xenam was initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg t.i.d. About 80% of patients were receiving the target dose at the end of the study. Patients were followed for a minimum of two years and for up to five years, with an average follow-up of 3.5 years.
Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and Xenam groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the Xenam group (119/74 vs. 125/77 mmHg at 1 yr).
Therapy with Xenam improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular death was 21% (P=0.014). Xenam treated subjects had 22% (P=0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving Xenam developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2056 placebo; 2036 Xenam).
Xenam was well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics.
In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18 to 49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤ 2.5 mg/dL, were randomized to placebo or Xenam (25 mg t.i.d.) and followed for up to 4.8 years (median 3 years). To achieve blood pressure control, additional antihypertensive agents (diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for patients in both groups.
The Xenam group had a 51% reduction in risk of doubling of serum creatinine (P<0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or transplantation) or death (P<0.01). Xenam treatment resulted in a 30% reduction in urine protein excretion within the first 3 months (P<0.05), which was maintained throughout the trial. The Xenam group had somewhat better blood pressure control than the placebo group, but the effects of Xenam on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Xenam was well tolerated in this patient population. In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20-200 µg/min) were randomized to placebo or Xenam (50 mg b.i.d.) and followed for up to 2 years. Xenam delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P<0.05). Xenam also reduced the albumin excretion rate. However, the long term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established.
Studies in rats and cats indicate that Xenam does not cross the blood-brain barrier to any significant extent.
References
- DailyMed. "CAPTOPRIL: 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. "Captopril: 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).
- EPA DSStox. "Captopril: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Xenam 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 Xenam. 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
