Amtrel Mechanism of Action

Pharmacology: Pharmacodynamics: When given single-dose or multidose of benazepril ≥10 mg for 24 hrs, 80-90% suppression of ACE activity can be reached. After giving 10 mg for 4 hrs, the vasopressor response of extrinsic angiotensin I can be suppressed by 60-90%. When benazepril is given to mild to moderate hypertensive patients, blood pressure is lowered when measuring blood pressure in both seated and standing postures, and compensatory tachycardia will not occur. Patients with a loss of salt or body fluids might experience postural hypotension, but this condition is uncommon (see Hypotension under Warnings). For patients with high or low salt intake, no significant difference is found in the antihypertensive effects of benazepril. In healthy subjects, single-dose of benazepril will cause increase in renal blood flow, but the glomerular filtration rate is unaffected.
When giving antihypertensive patients therapeutic dosage of amlodipine, vascular dilation results. Both recumbent and standing blood pressure may be reduced and long-term use does not result in tachycardia or significant changes in plasma catecholamine concentration. Correlation between plasma concentration and efficacy may be observed in both young and old patients. Like other calcium-ion blockers, when treating patients with normal ventricular functions with amlodipine, hematodynamic measurements of heart functioning during rest and exercise indicate mild increases, but no significant effects on dP/dt, left ventricular diastolic pressure or body fluids are found. In hemodynamic studies, amlodipine with a dosage within the therapeutic limit was given to humans or animals, even with simultaneous administration of β-blockers, amlodipine will not produce negative muscular constriction. In both animals and humans, amlodipine will not affect function of the S-A node and atrioventricular conduction. In clinical trials, when patients with hypertension or angina were given amlodipine and β-blockers, no adverse reactions were observed in the electrocardiograms.
In 6 double-blind, placebo-controlled clinical studies examining >950 patients that received the amlodipine and benazepril formula, found that blood pressure can be lowered with 1 hr after taking Amtrel. The lowest point can be achieved within 2-8 hrs. A single-dose of Amtrel can maintain the blood-pressure lowering effects for 24 hrs. When taking benazepril 10-20 mg combined with amlodipine 2.5-10 mg, seated blood pressure (systolic/diastolic) can be reduce by 10-25/6-13 mmHg after 24 hrs.
The combination therapy can be effective for both Blacks and non-Blacks. In non-Blacks, both ingredients may lower blood pressure. In Blacks, however, the major antihypertensive effects come from amlodipine. In a placebo-controlled clinical trial, comparing the blood-pressure lowering effects of the combination formula (amlodipine and benazepril) and individual ingredient given separately, with non-Blacks as the subjects, results indicated that the formulated agent had additive antihypertensive effects, while synergistic effects were observed in few patients.
With long-term use, the maximum reduction of blood pressure usually occurs 1-2 weeks after Amtrel is administered. The blood pressure reduction can be maintained for at least 1 year. Sudden stoppage of Amtrel will not result in rapid increase of blood pressure.
Mechanism of Action: Contraction of the vascular smooth muscle and the myocardium requires specific ionic channels that transport calcium ions into the cells. Amlodipine is a calcium-ion inhibitor, which suppresses calcium ion from moving through the cell membrane into vascular smooth muscle or myocardium. However, this suppression is selective and is more effective with the smooth muscle than when compared to myocardium. Also, serum calcium-ion concentration will not be affected by amlodipine. In normal physiological pH, amlodipine is an ionic metabolite (pKa=8.6). Its binding and removal rate with calcium ion-channel receptors are gradual. Thus, its exerted effects are also gradual. Amlodipine is a peripheral vascular dilator and can directly act on vascular smooth muscles to cause lowered peripheral vascular resistance and reduced blood pressure.
In humans and animals, benazepril and benazeprilat can suppress ACE, and ACE can convert angiotensin I to angiotensin II, which is a vascular constricting substance. Angiotensin II can stimulate the adrenal cortex to secrete aldosterone. Suppression of ACE can reduce the plasma concentration of angiotensin II, causing reduced vasoconstrictive activity and decreased secretion of aldosterone. The latter substance can cause a microscopic increase of potassium concentration in the blood. After 56 weeks of treatment involving benazepril and amlodipine in hypertensive patients, the blood potassium concentration increased to 0.2 mEq/L. Removal of the negative feedback of angiotensin on renin may cause plasma renin to increase. In an animal study, benazepril had no suppressive effects on the vasopressor response of angiotensin II. Also, it did not affect the hemodynamics of neurotransmitters eg, acetylcholine, epinephrine or norepinephrine. The general belief of the antihypertensive mechanism of benazepril is the suppression of the renin-angiotensin-aldosterone system. Therefore, even in hypertensive patients with low renin level, benazepril still can reduce their blood pressure.
Pharmacokinetics: According to international clinical studies, the rate of absorption of benazepril and amlodipine formula in the body is not significantly different than taking them individually. In terms of individual administration, absorption will not be affected by food in the gastrointestinal tract. There are currently no reports of the effects of food on absorption of the formula. After taking Amtrel, plasma benazepril concentration peaks in 0.5-2 hrs and cleavage of the ester group (mainly occurs in the liver) occurs to be converted to its active metabolite (benazeprilat). The plasma concentration of the metabolite benazeprilat reaches its peak level in 1.5-4 hrs. Level of absorption for benazepril is at least 37%. The plasma concentration of amlodipine peaks in 6-12 hrs and its level of absorption is approximately 64-90%.
The volume distribution of amlodipine and benazeprilat is 21 L/kg and 0.7 L/kg, respectively. In the circulation, about 93% of amlodipine are bound to plasma proteins. The binding ratio of benazeprilat is slightly higher than amlodipine. In vitro studies found that the protein-binding level of benazeprilat was not affected by concentration, age and liver function.
Suppression of ACE activity is much higher in benazeprilat compared to benazepril and almost all benazepril are metabolized to become benazeprilat. Only small amounts of the original substance are found in the excreted urine; about 20% of benazeprilat are found, 8% are benazeprilat glucuronide and 4% are benazepril glucuronide. Amlodipine is mostly metabolized in the liver, and 10 % of the original structure and 60% of its metabolites are found in the urine. In patients with liver dysfunction, due to lowered clearance rate of amlodipine, the area under the plasma concentration-time curve (AUC) is increased by about 40-60%. Thus, dosage should be appropriately adjusted (see Dosage & Administration). Patients with renal dysfunction will not affect the pharmacokinetics of amlodipine.
The half-life for effective removal of benazeprilat and amlodipine is appproximately 10-11 hrs and 2 days, respectively. The 2 drugs can reach stable blood concentrations with 1 administration of Amtrel per day for 1 week. Removal of benzaprilat from the plasma is mainly through the kidneys. In normal individuals, however, bile removal accounts for 11-12% of total elimination of benazepril. For patients with renal dysfunction [creatinine clearance (CrCl) <30 mL], time for benazeprilat to reach its peak concentration and time to reach stability may both be prolonged (see Dosage & Administration). For patients with liver dysfunction, the pharmacokinetics of benazeprilat remains unchanged. Age will not affect the pharmacokinetics of benazepril and benazeprilat, while the removal rate of amlodipine will be lower in the elderly, causing peak blood concentration, half-life of removal and AUC to increase approximately 35-70%. Therefore, in the elderly, the dosage might need to be adjusted.