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LOTREL (AMLODIPINE, BENAZEPRIL): CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in 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.
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. Hypertensive patients treated with benazepril and amlodipine for up to 56 weeks had elevations of serum potassium up to 0.2 mEq / l.
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
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 Lotrel remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but
such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor
binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg dose, pressor responses to exogenous angiotensin I were inhibited by 60%-90%.
Administration of benazepril 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.
The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.
In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Plasma concentrations correlate with
effect in both young and elderly patients.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In
hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta blockers to humans.
Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
The rate and extent of absorption of benazepril and amlodipine from Lotrel are not significantly different, respectively, from the rate and extent of absorption of benazepril and amlodipine from individual tablet formulations. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from Lotrel have not been studied.
Following oral administration of Lotrel (Amlodipine Besylate, Benazepril HCl), peak plasma concentrations of benazepril are reached in 0.5-2 hours. Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5-4 hours. The extent of absorption of benazepril is at least 37%.
Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of Amlodipine with Benazepril (Lotrel); the extent of absorption is 64%-90%.
The apparent volumes of distribution of amlodipine and benazeprilat are about 21 l / kg and 0.7 l / kg, respectively. Approximately 93% of circulating amlodipine is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat's degree of protein binding should be unaffected by age, by
hepatic dysfunction, or.over the therapeutic concentration range.by concentration.
Benazeprilat has much greater ACE-inhibitory activity than benazepril, and the metabolism of benazepril to benazeprilat is almost complete. Only trace amounts of an administered dose of benazepril can be recovered unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 8% as benazeprilat glucuronide, and 4% as benazepril glucuronide.
Amlodipine is extensively metabolized in the liver, with 10% of the parent compound and 60% of the metabolites excreted in the urine. In patients with hepatic dysfunction, decreased clearance of amlodipine may increase the areaunder-the-plasma-concentration curve by 40%-60%, and dosage reduction may be required. In patients with renal impairment, the pharmacokinetics of amlodipine are essentially unaffected.
Benazeprilat's effective elimination half-life is 10-11 hours, while that of amlodipine is about 2 days, so steady-state levels of the two components are achieved after about a week of once-daily dosing. The clearance of benazeprilat from the plasma is primarily renal, but biliary excretion accounts for 11%-12% of benazepril elimination in normal subjects. In
patients with severe renal insufficiency (creatinine clearance less than 30 ml / min), peak benazeprilat levels and the time to steady state may be increased. In patients with hepatic impairment, on the other hand, the pharmacokinetics of benazeprilat are essentially unaffected.
Although the pharmacokinetics of benazepril and benazeprilat are unaffected by age, clearance of amlodipine is decreased in the elderly, with resulting increases of 35%-70% in peak plasma levels, elimination half-life, and area-under-theplasma-concentration curve. Dose adjustment may be required.
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