amlodipine Norvasc
Pharmacokinetics and pharmacodynamics of amlodipine.

Abernethy DR.

Division of Clinical Pharmacology, Brown University, Providence, R.I.

Amlodipine is a low-clearance, dihydropyridine calcium antagonist. The slow rate of elimination (elimination half-life of 40-60 h) confers several pharmacokinetic characteristics that are not seen with other calcium-antagonist drugs. It has high oral bioavailability (60-80%) and accumulates to a steady-state with once-daily administration over a period of 1-1 1/2 weeks. Fluctuation of plasma drug concentration between doses is between 20 and 25% when once-daily dosing is used. Onset of effect is gradual after oral administration which is due, in part, to an intermediate rate of drug absorption (peak plasma drug concentration occurs 6-8 h after dosing) and perhaps also to the physicochemical characteristics of the drug-cell membrane-receptor interaction. The pharmacodynamic profile of the drug in hypertensive patients is consistent with the disposition of the drug. After single doses, blood pressure decreases gradually over 4-8 h and may slowly return to baseline over 24-72 h. No change in heart rate is noted after the dose as the onset is gradual and physiological reflexes are not activated. During chronic, oral, once-daily dosing blood pressure is decreased from pretreatment baseline with little fluctuation over the 24-hour dose interval. Discontinuation of amlodipine treatment results in a slow return of blood pressure to baseline over 7-10 days, with no evidence of a 'rebound' effect. Amlodipine is a low-clearance, dihydropyridine calcium antagonist which is effective for the treatment of hypertension and angina pectoris with once-daily dosing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1534713&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Long-term haemodynamic effects of amlodipine at rest and during exercise in essential hypertension.

Lund-Johansen P, Omvik P, White W, Digranes O, Helland B, Jordal O, Stray T.

Medical Department, University of Bergen School of Medicine, Haukeland Sykenhus, Norway.

Haemodynamic responses at rest and during exercise were studied in 18 patients with essential hypertension following long-term treatment with amlodipine. Patients underwent a 2-week placebo run-in period followed by a mean duration of 11 months' treatment with amlodipine 5-10 mg (mean dose 9 mg) once daily. Blood pressure was measured intra-arterially, cardiac output by dye dilution and heart rate by electrocardiogram. Amlodipine produced a mean reduction in systolic and diastolic arterial pressure of 27 and 16 mm Hg, respectively, at rest and after exercise. At rest sitting, mean systolic and diastolic arterial pressures were reduced by 16 and 14% (p less than 0.01), respectively, from initial mean values of 182.4/111.2 mm Hg. This reduction in blood pressure was associated with a marked reduction in the total peripheral resistance index of 19% (p less than 0.001). Similar responses were observed at rest supine and during exercise. No significant changes were seen in heart rate. Stroke index showed a small increase at rest and during exercise together with a trend towards an increase in cardiac index after treatment with amlodipine. Ambulatory blood pressure monitoring was carried out in 10 patients after the placebo run-in and at the end of the study. Amlodipine showed effective blood pressure control throughout the 24 h after one daily dose. The incidence of side effects was low (ankle oedema in 2 patients).

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amlodipine Norvasc
The influence of amlodipine and verapamil on ion and water transport in the nephron, skin and urinary bladder of amphibians.

Natochin YuV, Goncharevskaya OA, Johns EJ, Monin YuG, Shakhmatova EI.

Sechenov Institute of Evolutionary Physiology and Biochemistry, Leningrad, U.S.S.R.

1. The addition of amlodipine or verapamil into the lumen of the newt distal tubule led to the decrease of reabsorption of Na, Cl, Ca and of fluid. 2. The application of amlodipine to the outside of the frog skin caused large increases in potential difference (PD) and short circuit (SCC) similar to what is seen with Co2+. If both amlodipine and Co2+ were applied simultaneously to the outer surface the increases in PD and SCC were additive. 3. Verapamil added to the outer surface of the skin caused a reduction in PD which could be overcome by subsequent addition of amlodipine. 4. After addition of amlodipine to serosal or mucosal surfaces of the frog urinary bladder, the ability of vasopressin to increase osmotic permeability was markedly attenuated. 5. It is likely that the calcium channel blockers used here not only affect intracellular calcium levels by inhibiting entry through calcium channels, but they may also alter calcium dependent processes within the plasma membranes which modulate sodium transfer across epithelia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1676947&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effect of an L-type calcium channel blocker on the hemodynamics of orbital arteries in dogs.

Kallberg ME, Brooks DE, Komaromy AM, Miyabayashi T, Bradshaw PT.

Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville 32610-0126, USA.

PURPOSE: (1) To determine the effect of the l-type calcium channel blocker amlodipine on color Doppler ultrasound-determined vascular resistance and blood flow velocities in the distal retrobulbar arteries of dogs; (2) to determine any effect of blood pressure and PCO2 rate on such color Doppler-determined circulatory measurements. METHODS: Color Doppler imaging measurements of the short posterior ciliary artery, long posterior ciliary artery, and ophthalmic artery of normal eyes of 10 dogs were obtained under isofluorane anesthesia before and 1 week after oral amlodipine administration. Mean systemic arterial blood pressure and PCO2 were monitored. RESULTS: The mean resistive index decreased significantly in the short posterior ciliary artery (P = 0.0347), in the long posterior ciliary artery (P = 0.0092), and ophthalmic artery (P = 0.0004) following systemic amlodipine administration. The end diastolic velocity increased significantly in the long posterior ciliary artery (P = 0.0368) and ophthalmic artery (P < 0.0001). The peak systolic velocity increased significantly in the ophthalmic artery (P = 0.0256). Mean systemic arterial blood pressure was significantly negatively associated with resistive index (P < 0.0001) and significantly associated with the log of the end diastolic velocity (P < 0.0001). CONCLUSIONS: Systemically administered amlodipine increases color Doppler imaging-determined blood flow velocity and decreases vascular resistive index in the ophthalmic artery, short posterior ciliary artery and long posterior ciliary artery of normal dogs. Changes in systemic arterial blood pressure can significantly affect the measurement of color Doppler imaging parameters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12753616&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
(-)[3H]amlodipine binding to rat cardiac membranes.

Nayler WG, Gu XH.

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

Amlodipine is a newly developed long-acting dihydropyridine-based calcium antagonist. To characterize the binding properties of this compound, saturation binding studies were undertaken, using (-)[3H]amlodipine and rat cardiac membrane fragments. (-)[3H]Amlodipine bound to a single population of high-affinity binding sites with a KD of 1.68 +/- 0.12 nM, a Bmax of 0.34 +/- 0.08 pmol/mg protein, and a Hill coefficient approaching unity. Binding required up to 5 h to reach asymptote, and was pH- and temperature-sensitive. The specific binding was totally inhibited by (-) amlodipine and (-) D600 (IC50 values of 9.20 +/- 5.56 and 6.58 +/- 6.57 nM, respectively) and only partially inhibited by (+) PN 200-110, (-) Bay K 8644, (+) D600, and d-cis diltiazem (IC50 values of 60 +/- 10, 160 +/- 20, 250 +/- 40, and 200 +/- 30 nM, respectively). These results indicate that in addition to its ability to bind to the dihydropyridine and benzothiazepine recognition sites in rat cardiac membrane fragments, (-)[3H]amlodipine also binds strongly to the recognition sites for the phenylalkylamine-based calcium antagonists. The results also show that the inhibition of (-)[3H]amlodipine binding by D600 is stereospecific with (-) greater than (+)D600. Dissociation of bound (-)[3H]amlodipine was slowed under acidotic (pH 6.0) and accelerated under alkalotic (pH 10.0) conditions.

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amlodipine Norvasc
The hemodynamic effects of lacidipine in anesthetized dogs: comparison with nitrendipine, amlodipine, verapamil, and diltiazem.

Quartaroli M, Gambini F, Tarter G, Micheli D, Trist DG, Gaviraghi G.

Glaxo Research Laboratories, Verona, Italy.

The hemodynamic effects of lacidipine in anesthetized, open-chest dogs were compared with those of nitrendipine, amlodipine, verapamil and diltiazem. Lacidipine administered intravenously induced dose-related, long-lasting reductions in systemic and coronary vascular resistance with corresponding increases in aortic flow and coronary blood flow. The hypotensive effect (ED25 for mean blood pressure reduction = 0.006 mg/kg) was still significant 120 min after administration with all doses tested. Nitrendipine was equipotent with lacidipine in reducing the mean blood pressure (ED25 = 0.005 mg/kg), but its effect was shorter acting (significant effect at 120 min only with the highest dose tested). Amlodipine caused a marked and long-lasting hypotension though at higher doses than lacidipine (ED25 = 0.50 mg/kg). Short-lasting hypotensive responses were also detected with verapamil (ED25 = 0.1 mg/kg) and diltiazem (ED25 = 0.12 mg/kg). A reflex increase in heart rate was observed with lacidipine, nitrendipine, and amlodipine, whereas verapamil and diltiazem showed a dose-related bradycardia. No effect on AV conduction was observed with lacidipine and nitrendipine, whereas amlodipine, verapamil, and diltiazem produced second- to third-degree AV block at the highest doses tested. Lacidipine and nitrendipine caused a reflex increase in contractile index at all doses, whereas amlodipine was more similar to verapamil since a marked decrease in contractile index was detected at the highest dose. Diltiazem was practically devoid of negative inotropic effect.

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amlodipine Norvasc
Hemodynamic profile of Ro 40-5967 in conscious rats: comparison with diltiazem, verapamil, and amlodipine.

Veniant M, Clozel JP, Hess P, Wolfgang R.

Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Ro 40-5967 is a new calcium antagonist that binds to the same site as verapamil but that has been shown to have a much lesser negative inotropic effect than verapamil. The goal of the present study was to assess the hemodynamic profile of Ro 40-5967 not only in comparison with verapamil but also with diltiazem and amlodipine. For this purpose, hemodynamic parameters were assessed in conscious normotensive rats by measuring mean arterial pressure (MAP), left ventricular (LV) dP/dtmax, and heart rate. Dose-response curves were obtained with intravenous injection of the four drugs. Despite similar decreases in arterial pressure, the effects of the four drugs on left ventricular contractility and heart rate were different. Verapamil and diltiazem were markedly negative inotropic. Amlodipine decreased left ventricular contractility only at the highest dose. Ro 40-5967 was less negative inotropic than amlodipine. Verapamil, diltiazem, and Ro 40-5967 did not alter heart rate or slightly decreased it. In contrast, amlodipine induced a reflex tachycardia. In conclusion, because of its very low negative inotropism and its lack of reflex tachycardia, Ro 40-5967 seems to have a unique hemodynamic profile among calcium antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1725005&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vascular injury: mechanisms and manifestations.

Nayler WG.

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

Abnormalities in regulatory mechanisms for calcium handling play a key role in cell death and tissue necrosis. In the cardiovascular system this applies to the vasculature and the myocardium alike. In the aged population, where hypertension is a known risk factor, manifestations of vascular injury include atherogenesis and stroke. The newly developed dihydropyridine-based calcium antagonist amlodipine was used in investigations to determine whether calcium antagonists with sustained activity, in addition to lowering blood pressure, slow the development of atherogenesis in rabbits receiving high cholesterol diets, or reduce mortality in stroke-prone hypertensive rats. To establish whether this drug protects the vasculature against excessive atheroma formation in the presence of high cholesterol intake, rabbits were given 2% cholesterol in addition to their normal food intake and either 0, 1, or 5 mg/kg/day amlodipine orally for either 8 or 12 weeks. One day after the conclusion of the treatment protocol, the thoracic aorta was excised, assayed for calcium or cholesterol concentrations, and stained to identify sudanophilic-positive lesions. Amlodipine caused a time- and dose-dependent reduction in lesion formation, calcium overload, and cholesterol level. In the second series of experiments, amlodipine (5 mg/kg/day) was added to the diets of stroke-prone hypertensive rats. Treatment was initiated at age 5 weeks and continued for 30 weeks. During the treatment period, systolic blood pressure was reduced in the amlodipine-treated rats (166 +/- 9 mm Hg) versus those treated with placebo (248 +/- 12 mm Hg) (p less than 0.001). A significant reduction in mortality was observed in the amlodipine-treated rats (p less than 0.001), with 93% surviving versus only 26% in the placebo group at the end of the 30-week treatment period. Concomitantly, cardiac hypertrophy was attenuated in the treated group compared with the placebo group (heart-to-body weight ratios of 4.5 +/- 0.01 vs 5.8 +/- 0.6, respectively [p less than 0.01]). These results extend the evidence that calcium antagonists provide vascular protection in animal models. This finding may become increasingly important in the management of an aging hypertensive population.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1826808&dopt=Abstract amlodipine Norvasc