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Brand Names: Hyperdix, Hyperium
Generic name: Rilmenidine
Hyperdix exerts its antihypertensive activity by binding selectively to imidazoline I1 receptors. Through the reduction of sympathetic nervous system overactivity, Hyperdix offers optimal efficacy and clinical and biological acceptability for each and every hypertensive patient.
Hypedix decreases blood pressure (systolic and diastolic blood pressure) to a similar extent to that of reference drugs such as diuretics, ß-blockers, ACE inhibitors, or calcium channel blockers.
Beyond blood pressure control, Hyperdix provides protection against the main complications of hypertension, thanks to the reduction of the sympathetic overdrive:
Hyperdix reduces left ventricular hypertrophy (LVH) significantly (-14%) over 1 year. This reduction in LVH is accompanied by an improvement in diastolic filling function and arterial compliance.
Hyperdix does not interfere with carbohydrate and lipid metabolism, or renal function.
Hyperdix prevents occurrence of adrenaline-induced arrhythmia, as has been shown under experimental conditions in dogs in whom arrhythmias are easily provoked.
These clinical advantages can be explained by its innovative and physiological mode of action. The usefulness of this mechanism of action is due to the fact that imidazoline I1 receptors are located at the heart of the main mechanisms of blood pressure regulation:
in the medullary vasopressor center, which via the sympathetic nervous system, governs the immediate neuronal regulation of blood pressure,
in the proximal convoluted tubule of the kidney, which is the site of deferred regulation of blood pressure.
This explains why Hyperdix acts, via imidazoline I1 receptors, on all of the physiological mechanisms concerned with the immediate neuronal and deferred renal regulation of blood pressure.
Thus, at the medullary level, Hyperdix rapidly decreases the sympathetic hyperactivity which is manifested, among other effects, as a decrease in vascular peripheral resistance. At the renal level, Hyperdix brings about a long-term decrease in the excessive water/sodium reabsorption present in hypertensive patients. This explains why Hyperdix has an effective antihypertensive action in the long term, regardless of the type of hypertension, without development of pharmacological tolerance.
Furthermore, by virtue of its selectivity of action at imidazoline I1 receptors, which are directly involved in blood pressure regulation, Hyperdix acts specifically on blood pressure regulation without affecting other bodily functions. Thus the antihypertensive effect of Hyperdix is accompanied by exceptional safety.
Recommended Dosage: 1 tab/day as a single morning administration. If results are not adequate after 1 month of treatment, the dosage may be increased to 2 tabs/day, given in divided doses (1 tab in the morning and in the evening) before meals.
As a result of its good clinical and biological acceptability, Hyperdix may be administered to both the elderly and diabetic hypertensive patients.
In patients with renal failure, no dosage adjustment is necessary in principle when the creatinine is >15 mL/min.
Treatment may be continued indefinitely.
Should be taken on an empty stomach (Take before meals.).
Severe depression and severe renal failure (creatinine clearance <15 mL/min), as a precaution in the absence of currently available studies.
Therapy should never be interrupted suddenly; the dosage should be reduced gradually.
As with all antihypertensive agents, regular medical monitoring is required when Hyperdix is administered to patients with a recent history of cardiovascular disease (stroke, myocardial infarction).
Alcohol consumption should be avoided during treatment. In patients with renal failure, no dosage adjustment is necessary if creatinine clearance is >15 mL/min.
Effects on the Ability to Drive or Operate Machinery: Double-blind placebo controlled studies have not shown Hyperdix to have any effect on alertness at therapeutic doses (1 or 2 daily administrations of 1 mg). If these doses are exceeded, or if Hyperdix is combined with other drugs capable of reducing alertness, vehicle drivers or machine operators should be warned of the possibility of drowsiness.
Use in pregnancy: As with all new compounds, administration of Hyperdix should be avoided in pregnant women, although no teratogenic or embryotoxic effects have been observed in animal studies.
Use in lactation: Hyperdix is excreted in breast milk, and its use is therefore not recommended during lactation.
Use in children: In the absence of documented experiments in this area, Hyperdix is not recommended for prescription to children.
Combination with MAOIs is not recommended; combination with tricyclic antidepressants requires prudence, as the antihypertensive activity of Hyperdix may be partly antagonized.
No cases of massive absorption have been reported. Likely symptoms in such an eventuality would be marked hypotension and lowered alertness. In addition to gastric lavage, sympathomimetic agents may also be required. Hyperdix is only slightly dialyzable.
At a dose of 1 mg given as a single daily administration during controlled trials, the incidence of side effects was comparable to that observed with placebo. At a dose of 2 mg/day of Hyperdix, controlled comparative studies versus clonidine (0.15-0.3 mg/day) or α2-methyldopa (500-1000 mg/day) demonstrated that the incidence of side effects was significantly lower with Hyperdix than with either clonidine or α-methyldopa.
Side effects are rare, not severe and transient at therapeutic doses: Asthenia, palpitations, insomnia, drowsiness, fatigue on exercise, epigastric pain, dryness of the mouth, diarrhea, skin rash; and exceptionally, cold extremities, postural hypotension, sexual disorders, anxiety, depression, pruritus, edema, cramps, nausea, constipation, hot flushes.
Each tablet contains rilmenidine dihydrogen phosphate 1.544 mg equivalent to rilmenidine base 1 mg.
Hyperdix, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. It shows greater selectivity for I1-imidazoline receptors than for cerebral α2-adrenergic receptors, distinguishing it from reference α2-agonists.
Pharmacology: Rilmenidine acts to limit the sympathetic outflow at the target organ level, which represents an interesting approach in treating hypertension and probably cardiovascular diseases. Rilmenidine acts selectively for I1 imidazoline receptors at RVLM in brain stem. In the periphery, I1 imidazoline receptors can also be detected in the kidney, platelets and adrenal chromaffin cells. Rilmenidine has high affinity to I1 imidazoline sites and has shown to increase urine flow rate secondary to an increase in sodium excretion. As a consequence of such a receptor selectivity, rilmenidine demonstrated a dissociation between antihypertensive activity and central nervous system side effect. This pharmacologic profile is exemplified in clinical studies. Preclinical and clinical studies have shown that sympatho-inhibition evidenced by a decrease in plasma norepinephrine concentration and possibly a natriuretic effect are the basis of the antihypertensive activity of rilmenidine.
Pharmacokinetics: Rilmenidine does not interact with food. It is weakly bound to plasma proteins (<10%). The weak involvement of protein-binding minimizes the risk of pharmacokinetic interactions with any drug co-administered with antihypertensive agents. Rilmenidine is mainly excreted through the kidney. The unchanged compound (urinary fraction of rilmenidine) is approximately 65%, and no metabolite plasma levels are detected. Metabolism is poorly involved in the elimination process. This allows the assumption that no hepatic first-pass effect occurs after oral administration, as confirmed by the absolute bioavailability.
After acute administration, the linearity of the pharmacokinetics is demonstrated within the 0.5- to 2-mg range. After repeated administration, the linear disposition of rilmenidine with dose is confirmed.
Elderly: The elimination rate is reduced, as demonstrated by a prolongation of elimination half-life, an increase in mean resident time and a decreased total apparent clearance. When considering the extent of renal elimination in clearance of rilmenidine, which involves both glomerular filtration and tubular secretion, the physiologic decrease in glomerular filtration rate in the elderly is likely to be involved in the reduction of observed clearance. The fall in clearance is responsible for the rise in terminal elimination half-life. These modifications in the biodisposition of rilmenidine in the elderly do not require an adaptation of dosage regimen.
Renal Failure Patients: In patients with severe renal failure (creatinine clearance <15 mL/min), rilmenidine can be given at a dose of 1 mg every other day, because at that dose, the accumulation ratio is similar after respected and single administration.
Patients with Hepatic Failure: The modifications of rilmenidine disposition after administration are weak. Variations in absorption and distribution confirm that rilmenidine has a minimal first-pass effect. No adaptation of dosage regimen is required in hepatic insufficiency. Monitoring of rilmenidine plasma levels in long-term clinical studies has never shown any accumulation.
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