amlodipine Norvasc
Haemodynamic and electrophysiological effects of amlodipine, a new long-acting calcium antagonist.

Vetrovec GW, Dailey S, Kay G, Epstein A, Plumb V.

Medical College of Virginia, Richmond 23219.

Patients with stable angina pectoris received an intravenous bolus injection of 10 mg amlodipine followed by a second 10-mg bolus, 30 min later, if no haemodynamic compromise occurred. Systolic and diastolic blood pressures were significantly reduced and cardiac output increased. Left ventricular function was unaltered. Amlodipine did not affect the electrophysiological parameters studied; sinus node recovery time and the pacing rate to Wenckebach heart block did not significantly change from baseline. Amlodipine is a powerful arterial vasodilator with no negative inotropic effects. Cardiac electrophysiological function is not affected by amlodipine.

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amlodipine Norvasc
Liquid chromatography assay for amlodipine: chemical stability and pharmacokinetics in rabbits.

Yeung PK, Mosher SJ, Pollak PT.

College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, Nova Scotia, Canada.

Amlodipine is a long acting dihydropyridine calcium antagonist recently introduced for the treatment of angina and hypertension. In order to document its stability in vitro and to develop a pharmacokinetic model in rabbits, a new reversed-phase liquid chromatography (LC) assay with UV detection was developed. The method utilized a C18 column (250 x 4.6 mm i.d.) with a mobile phase composed of a mixture of methanol 0.04 M ammonium acetate-acetonitrile (38:38:24, v/v/v) containing 0.02% triethylamine (final pH 7.1). Under these conditions, the retention times of amlodipine and the internal standard desipramine were 10.6 and 12.9 min, respectively. Using 1 ml of plasma, sensitivity of the assay was 2.5 ng ml-1 at which the RSD was 11%. The standard curve was linear from 2.5 to 100 ng ml-1 (r2 = 0.990), and the mean RSD at this concentration range was 6.8%. The pharmacokinetic model was developed in rabbits which provides results similar to those in dogs, but at less expense. The assay was also applied to a stability study comparing amlodipine and nifedipine in pH 3 and pH 7 ammonium acetate buffers and in methanol. Amlodipine was considerably more stable than nifedipine under all conditions. Finally the assay was applied to a pharmacokinetic study in rabbits (n = 6) after a single 1 mg kg-1 intravenous dose. The mean half-life (t1/2) of amlodipine was 6.5 h, the systemic clearance (CL) was 4.8 l h-1 kg-1 and the apparent volume of distribution at steady state (Vdss) was 30.2 l kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
Haemodynamic and radionuclide effects of amlodipine in coronary artery disease.

Silke B, Verma SP, Zezulka AV, Sharma S, Reynolds G, Jackson NC, Guy S, Taylor SH.

University Department of Cardiovascular Studies, General Infirmary, Leeds.

1. The haemodynamic and radionuclide effects of a new long-acting slow-calcium channel blocking agent, amlodipine, were evaluated in 32 patients with coronary artery disease. 2. Haemodynamic measurements in 24 patients were made at rest and 10 to 15 min after 20 mg i.v. amlodipine. Amlodipine significantly reduced systemic arterial blood pressure and vascular resistance index with an increased heart rate and augmented cardiac index. Cardiac stroke volume index rose and stroke work fell without change in pulmonary artery occluded pressure (PAOP). 3. The exercise effects were determined by comparison of measurements during 4 min of supine bicycle exercise at a fixed workload before and after drug treatment. During dynamic exercise, amlodipine reduced systemic arterial pressure and vascular resistance index. Exercise cardiac index, stroke volume index and heart rate were higher. The left ventricular filling pressure was significantly reduced. 4. Radionuclide parameters were studied in 16 patients at rest and on exercise; ejection fraction was unaltered following amlodipine. 5. Pre-therapy haemodynamic values correlated with response following amlodipine for resting mean blood pressure, systemic vascular resistance and exercise PAOP. 6. Thus, the immediate impact of amlodipine in stable coronary artery disease was to reduce left ventricular afterload and thereby improve cardiac pumping performance.

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amlodipine Norvasc
Effects of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamics in relation to disposition.

Abernethy DR, Gutkowska J, Winterbottom LM.

Division of Clinical Pharmacology, Brown University, Providence, RI 02908.

Pharmacodynamics and disposition of amlodipine, a dihydropyridine calcium antagonist, were compared between elderly and young patients with hypertension. Elderly (mean +/- SD; age, 68 +/- 3 years) and young (35 +/- 5 years) patients received single intravenous amlodipine doses followed by oral administration once daily for a total of 12 weeks. After intravenous administration, elderly patients had prolonged elimination half-life values (58 +/- 11 versus 42 +/- 8 hours; p less than 0.01) caused by decreased clearance (19 +/- 5 versus 25 +/- 7 L/hr; p less than 0.01). After a 3-months oral treatment washout period, half-life tended to be prolonged in the elderly patients (69 +/- 20 hours for the elderly patients versus 53 +/- 14 hours for the young patients; difference not significant) and was not markedly different from the short-term intravenous measurement. Both systolic and diastolic blood pressure were significantly decreased from baseline throughout the treatment period, with greater decreases in elderly patients for both systolic and diastolic pressure. When amlodipine plasma concentration was correlated to change in mean blood pressure after short-term intravenous doses, elderly patients had a greater decrease than young patients at a given drug concentration. However, after long-term oral administration, elderly and young patients had comparable decreases in mean blood pressure at a given drug concentration, and the increased antihypertensive effect in the elderly was associated with somewhat higher amlodipine plasma concentration. Amlodipine administered once daily is an effective antihypertensive agent in elderly patients and young patients with essential hypertension.

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amlodipine Norvasc
Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.

Burges RA, Gardiner DG, Gwilt M, Higgins AJ, Blackburn KJ, Campbell SF, Cross PE, Stubbs JK.

Amlodipine was twice as potent as nifedipine at inhibiting Ca2+-induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by amlodipine (IC50 19.4 nM), whereas the potency of nifedipine was little changed (IC50 7.1 nM). This difference may be explained by a modulated receptor hypothesis, similar to that described for cardiac muscle, in which block of vascular calcium channels by dihydropyridines is enhanced at depolarized membrane potentials, such voltage-dependence only being apparent with a slow-acting drug such as amlodipine. Recovery from amlodipine block of K+-responses in rat portal vein after drug washout was also very slow. Amlodipine and nifedipine blocked phenylephrine-induced contractions of the rat aorta with potencies similar to those against depolarisation-induced responses. Negative inotropic potencies of amlodipine and nifedipine in perfused guinea pig hearts were approximately one-tenth those against Ca2+-induced contractions in rat aorta. Amlodipine caused complete block of guinea pig papillary muscle single-cell slow action potentials at a concentration (5 microM) that had no effect on upstroke velocity of normal, fast potentials but reduced the duration of the plateau phase.

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amlodipine Norvasc
Natriuretic activity of amlodipine, diltiazem, and nitrendipine in saline-loaded anesthetized dogs.

Carter AJ, Gardiner DG, Burges RA.

Pfizer Central Research, Sandwich, Kent, England.

The natriuretic effects of amlodipine, diltiazem, and nitrendipine were compared in anesthetized dogs receiving a continuous saline load. Doses of all agents were selected that caused similar degrees of coronary vasodilation (approximately 50% of maximum) but that had only minimal peripheral vasodilator effect. Bolus doses of either saline, amlodipine, or diltiazem were administered intravenously. Because of its short duration of action, nitrendipine was given by infusion for 2 h and its effects were compared with infused vehicle [5% polyethylene glycol (PEG 300)]. Bolus amolodipine (105 micrograms/kg) and infused nitrendipine (1 micrograms/kg/min) had a similar hemodynamic profile of action: Both drugs caused a sustained reduction of coronary vascular resistance (CVR) (131.1 to 77.9 and 124.9 to 76.7 dyn/s/cm-5 at 2 h, respectively), but only slightly reduced systemic vascular resistance, with no significant change in blood pressure. Diltiazem (150 micrograms/kg) caused an initial transient reduction of CVR (141.9 to 77.0), followed by a secondary, more sustained action (100.1 at 180 min). Cumulative sodium excretion, measured 1 h after saline, amlodipine, and diltiazem, was 1.96, 5.11, and 5.74 mEq, respectively, increasing to 4.05, 13.19 (p less than 0.05), and 13.09 (p less than 0.05) at 2 h. Significant increases were maintained for up to 3.5 h. A similar pattern was observed with urine volume. Cumulative sodium excretion was 10.05 and 8.27 mEq for vehicle and nitrendipine, respectively, at the end of the 2-h infusion (NS), increasing to 15.88 and 13.73 mEq 60 min later (NS). Nitrendipine did not increase urine volume in comparison with its vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
The effect of amlodipine on hypertension-induced cardiac hypertrophy and reperfusion-induced calcium overload.

Nayler WG.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.

Amlodipine is a long-acting dihydropyridine-based calcium antagonist developed for use on a once-a-day basis. Experiments were undertaken to establish whether the chronic administration of amlodipine prevents the rise in blood pressure in spontaneously hypertensive rats (SHR), and whether it attenuates cardiac hypertrophy caused by hypertension. The experiments were performed in spontaneously hypertensive rats, and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. Amlodipine was given orally to provide a daily intake of 10 mg kg-1 day-1. The rats were 8 weeks old at the start of the therapy. In the SHR, but not in the WKY or SD rats, the blood pressure was reduced (p less than 0.01) after 30 weeks in the rats receiving amlodipine but not in the placebo-treated rats. At the same time the heart-to-body-weight ratio was reduced in the amlodipine-treated SHR but not in the SD or WKY rats. This same amlodipine regimen (10 mg kg-1 day-1 orally) or amlodipine i.v. (0.25 mg/kg, 5 h before excising the hearts) improved functional recovery (p less than 0.01) of hearts "stunned" by 10 min ischemia and attenuated (p less than 0.05) calcium ion gain on reperfusion after 30 to 60 min ischemia. These results indicate that prophylactic therapy with amlodipine lowers blood pressure in hypertensive rats, prevents hypertension-induced hypertrophy, and exerts a cardiac-protective effect during short periods of ischemia.

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amlodipine Norvasc
Block of heart calcium channels by amlodipine: influence of drug charge on blocking activity.

Kass RS, Arena JP, DiManno D.

Department of Physiology, University of Rochester School of Medicine and Dentistry, New York.

Changes in pH0 were used to to vary the ratio of neutral to ionized amlodipine (acid dissociation constant = 10(-8.6). The behavior of neutral and charged drug blockade of calcium channel current (ICa) was tested in the context of the modulated receptor hypothesis. ICa was recorded at room temperature from enzymatically isolated guinea pig ventricular cells using the whole-cell arrangement of the patch-clamp technique. When amlodipine was predominantly charged (pH0 = 7.4), trains of pulses that induced multiple channel openings enhanced block, but inhibition of ICa was also promoted by depolarizing changes in holding potential. Neutral amlodipine (pH0 = 10.0), blocked ICa at depolarized membrane potentials without channel openings. This form of the drug resembled other previously described neutral dihydropyridine (DHP) blockers in its voltage dependence. Recovery from block by ionized drug molecules was very slow and incomplete, whereas block by neutral molecules was always reversible at hyperpolarized membrane potentials. We conclude that amlodipine, like other DHP calcium channel blockers, preferentially blocks calcium channels in depolarized cells. At pH0 7.4 amlodipine molecules gain access to the DHP receptor more readily when channels open, but channel openings are not required for this interaction. Recovery from block by ionized drug is almost irreversible, suggesting that channel openings are needed for this process or that the ionized drug stabilizes the calcium channel in a nonconducting state.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2467128&dopt=Abstract amlodipine Norvasc