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Pharmacokinetics of Calcium Antagonists
Abstract
Calcium antagonists are a biochemically heterogeneous group of drugs that share the property of blocking the entry of calcium into cells by voltage-operated channels in cardiac and smooth muscle. They are useful in the management of angina pectoris and hypertension. The drugs available at present include nifedipine, verapamil, and diltiazem. All three drugs have similar pharmacokinetic properties of low and variable bioavailability, high first-pass metabolism, short elimination half-life, and active metabolites. The pharmacokinetics of calcium antagonists are relevant, because in individual patients the intensity and duration of the pharmacological effect is related to the level of drug in plasma. Amlodipine is a new dihydropyridine calcium antagonist in advanced clinical development. It has a completely different pharmacokinetic profile. It is water soluble and photostable, and has a long half-life of 35-50 h. Amlodipine is slowly absorbed, its absolute bioavailability is high, and it is extensively metabolized in the liver. The long half-life is associated with a prolonged (greater than 24 h) duration of pharmacodynamic action. Amlodipine, because of its novel pharmacokinetics, may offer practical advantages over existing calcium antagonists in the long-term treatment of cardiovascular disease.
... Nifedipine along with amlodipine, are among the most studied of Ca 2+ channels blockers, and both belong to the dihydropyridine subgroup of LTCC antagonists. Relative to nifedipine, a fast and short-acting LTCC antagonist with a plasma half-life of 1.2 h, amlodipine is slow and longer acting, more extensively bound to plasma protein, with a larger volume of distribution, more gradual elimination, with a half-life of over 30 h [130][131][132][133][134]. We have evaluated the antiemetic efficacy of both nifedipine and amlodipine (Figure 2) by assessing mean emesis frequency and the percentage of shrews vomiting, and demonstrated that both LTCC blockers [45,46] behave as broad-spectrum antiemetics when delivered systemically against diverse specific emetogens, including FPL 64176 (10 mg/kg, i.p.), the peripherally-acting and non-selective 5-HT 3 R agonist 5-HT (5 mg/kg, i.p.), the peripherally/centrally-acting and more selective 5-HT 3 R agonist 2-Methyl-5-HT (5 mg/kg, i.p.), the dopamine D 2 R-preferring agonist quinpirole (2 mg/kg, i.p.), the non-selective dopamine D 2 R agonist apomorphine (2 mg/kg, i.p.), the nonselective cholinergic agonist pilocarpine (2 mg/kg, i.p.), the M 1 -preferring cholinergic agonist McN-A343 (2 mg/kg, i.p.), and the selective neurokinin NK 1 R agonist GR73632 (5 mg/kg, i.p.). ...
... Nifedipine appears to be more potent than amlodipine against vomiting caused by FPL64176, 5-HT, 2-Methyl-5-HT, GR73632, quinpirole and McN-A343. These potency disparities could be explained in terms of their pharmacokinetic and pharmacodynamic differences [130][131][132][133][134][135][136][137][138][139]. ...
... Лерканидипин -новый длительно действующий АК из группы дигидропиридинов -обладает высокой сосудистой селективностью; фармакологические исследования продемонстрировали его медленный и постепенно нарастающий антигипертензивный эффект без отрицательного инотропного действия [13]. Мы исследовали эффективность и переносимость лерканидипина у пожилых пациентов с легкой и умеренной АГ. ...
... У пожилых пациентов даже с легкой и умеренной АГ часто имеют место сопутствующие заболевания (ишемическая болезнь сердца с сердечной недостаточностью, поражения периферических сосудов, почечная недостаточность, метаболические нарушения), которые могут ограничивать использование лекарственных препаратов [16,17], способных повреждать функцию сердца или почек, нарушать липидный или углеводный обмен, усугублять сопутствующие заболевания или способствовать прогрессированию атеросклероза. Как и другие новые АК [18], лерка-нидипин продемонстрировал высокую сосудистую селективность при отсутствии негативного инотропного эффекта [13]. Большинство подобных препаратов благоприятно действуют на клеточные механизмы формирования атеросклероза [19], а также улучшают функцию почек [20][21][22]. ...
Цель. Оценить эффективность лерканидипина (антагониста кальция из группы дигидропиридинов) у пожилых больных артериальной гипертонией (АГ). Материал и методы. В многоцентровое рандомизированное двойное слепое плацебо-контролируемое исследование включены 144 больных в возрасте 60-85 лет, разделенных на группы, получавших лерканидипин в дозе 10 мг или плацебо в течение 4 нед. При недостаточной антигипертензивной эффективности исходную дозу лерканидипина увеличивали (вплоть до 30 мг один раз/день в течение 12 нед). Результаты. Диастолическое артериальное давление (АД) под действием лерканидипина в дозе 10 мг снижалось в большей степени (-10,3 мм рт.ст.), чем под действием плацебо (-6,1 мм рт.ст.; p<0,05). Доля больных, положительно ответивших на прием лерканидипина, также была выше, чем при приеме плацебо (59,1% и 37,8 %, соответственно; p<0,05). При увеличении дозы препарата до 20 мг доля больных, положительно ответивших на лечение, возросла до 69,4%; увеличение дозы до 30 мг потребовалось лишь небольшому числу пациентов. Частота сердечных сокращений и лабораторные показатели на фоне лечения не менялись. Процент больных с побочными эффектами был одинаковым в обеих группах. Заключение. Прием лерканидипина один раз в день значительно снижает АД у пожилых пациентов с легкой и умеренной АГ . Эффект сохраняется в течение 24 ч и не сопровождается рефлекторной тахикардией. Препарат хорошо переносится и, учитывая его фармакологические и фармакодинамические особенности, может быть рекомендован, особенно пожилым пациентам.
... Due to its unique structural features including the replacement of the nitro substituent in nifedipine with a chlorine and a side chain with a basic substituent, amlodipine molecules exist primarily in the ionized form at physiologic PH (Abernethy, 1991). Therefore, relative to nifedipine, a short-acting LTCC antagonist with a plasma half-life of 1.2 h (Burges and Moisey, 1994); amlodipine is longer acting, more extensively bound to plasma protein, with a larger volume of distribution, more gradual elimination, with a half-life of over 30 h (Abernethy, 1991;Burges, 1991;Burges and Moisey, 1994;Reid et al., 1988;Toal et al., 2012). Amlodipine also slowly associates with and dissociates from L-type calcium channel in a manner 2-3 orders of magnitude slower than other dihydropyridines (Burges et al., 1989;Burges and Moisey, 1994). ...
... Moreover, 3.5 h after incubation, amlodipine appears to be twice potent as nifedipine (IC50: 1.9 nM for amlodipine; 4.1 nM for nifedipine), while nifedipine reached to its maximal effect within 30 min (Burges et al., 1989;Burges and Moisey, 1994). In addition, peak plasma levels occurs 6-12 h after oral dosing of amlodipine (Reid et al., 1988). We have evaluated the antiemetic efficacy of nifedipine and amlodipine by assessing mean emesis frequency and the percentage of shrews vomiting, and demonstrated that both LTCC blockers (Darmani et al., 2014; Zhong et al., 2014a) behave as broad-spectrum antiemetics when delivered systemically against diverse specific emetogens, including FPL 64176 (10 mg/kg, i.p.), the peripherally-acting and non-selective 5-HT 3 R agonist 5-HT (5 mg/kg, i.p.), the peripherally/centrally-acting and more selective 5-HT 3 R agonist 2-Me-5-HT (5 mg/kg, i.p.), the dopamine D 2 R-preferring agonist quinpirole (2 mg/kg, i.p.), the non-selective dopamine D 2 R agonist apomorphine (2 mg/kg, i.p.), the nonselective cholinergic agonist pilocarpine (2 mg/kg, i.p.), the M 1 -preferring cholinergic agonist i.p.), and the selective tachykinin NK 1 R agonist GR73632 (5 mg/kg, i.p.). ...
Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca(2+))-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca(2+) signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca(2+) elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca(2+) channel (LTCC) agonist FPL 64176 and the intracellular Ca(2+) mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca(2+) involvement in the emetic process; discuss the relationship between Ca(2+) signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca(2+)-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca(2+)-signaling blockers/inhibitors in the treatment of nausea and vomiting.
... 5 Antagonistas do cálcio e β-bloqueadores são drogas freqüentemente utilizadas no tratamento da hipertensão arterial pois apresentam alta eficácia antihipertensiva. 6,7 Entre os antagonistas do cálcio a eficácia anti-hipertensiva é maior para aqueles pertencentes ao grupo dos derivados dihidropiridínicos. 7 Os antagonistas do cálcio do grupo dos dihidropiridínicos, além de bons hipotensores, revertem adequadamente a hipertrofia cardíaca e têm um perfil neutro em relação aos metabolismos glicídico e lipídico. ...
... 6,7 Entre os antagonistas do cálcio a eficácia anti-hipertensiva é maior para aqueles pertencentes ao grupo dos derivados dihidropiridínicos. 7 Os antagonistas do cálcio do grupo dos dihidropiridínicos, além de bons hipotensores, revertem adequadamente a hipertrofia cardíaca e têm um perfil neutro em relação aos metabolismos glicídico e lipídico. 9 Entretanto, em decorrência da potente vasodilatação arterial que acarretam, ocorre uma estimulação simpática secundária levando a taquicardia com queixa freqüente pelo paciente de palpitação. ...
... 5 Antagonistas do c?lcio e ?-bloqueadores s?o dro- gas freq?entemente utilizadas no tratamento da hiper- tens?o arterial pois apresentam alta efic?cia anti- hipertensiva. 6,7 Entre os antagonistas do c?lcio a efi- c?cia anti-hipertensiva ? maior para aqueles perten- centes ao grupo dos derivados dihidropirid?nicos. ...
... maior para aqueles perten- centes ao grupo dos derivados dihidropirid?nicos. 7 Os antagonistas do c?lcio do grupo dos dihi- dropirid?nicos, al?m de bons hipotensores, revertem adequadamente a hipertrofia card?aca e t?m um perfil neutro em rela??o aos metabolismos glic?dico e lip?dico. ...
... The chromatography was performed on an ACQUITYTM UPLC system (Waters Corp, USA) [15,16] with cooling auto sampler and column oven enabling temperature control of the analytical column. Phenomenex, Lux 3u Cellulose-2 (150 × 4.6) mm column was employed. ...
High Performance Liquid Chromatographic tandem mass spectrometric method for the estimation of Carbocisteine in human plasma has been developed and validated using Carbocisteine 13 C 3 as internal standard. Sample preparation process was accomplished by solid phase extraction technique. The processed sample was chromatographed and analyzed on Luna 5u HILIC 200 A (150 x 4.6 mm) column using mobile phase [Acetone-M: Buffer-1(40:60% v/v)] and diluent as [Acetone-M: Water (90:10% v/v)] .Carbocisteine was chromatographed and analyzed by MS Detector. The analytical method described is valid the determination of Carbocisteine (over a range of 52.27 µg/ml to 5301.83 µg/ml) using as Carbocisteine 13 C 3 internal standard in human plasma. Signal from the detector were captured in a computer and processed using MassLynx SCN 4.1 v software. This method was found suitable to analyze human plasma samples for the application in pharmacokinetic and BA/BE studies.
... The chromatography was performed on an ACQUITYTM UPLC system (Waters Corp, USA) [15,16] with cooling auto sampler and column oven enabling temperature control of the analytical column. Phenomenex, Lux 3u Cellulose-2 (150 × 4.6) mm column was employed. ...
... The chromatography was performed on an ACQUITYTM UPLC system (Waters Corp, USA) [15,16] with cooling auto sampler and column oven enabling temperature control of the analytical column. Phenomenex, Lux 3u Cellulose-2 (150 × 4.6) mm column was employed. ...
... Amlodipine (Figure 1), a dihydropyridine calcium antagonist, is prescribed for the management of hypertension, chronic stable angina pectoris and Prinzmetal's variant angina (5). Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and blood pressure (6)(7)(8). ...
A simple, rapid and sensitive method was established for the simultaneous determination of telmisartan and amlodipine in dog plasma by a HPLC-MS-MS analysis. The plasma sample preparation was a simple deproteinization by the addition of three volumes of methanol/acetonitrile mixture followed by centrifugation. The analytes and internal standard diphenhydramine were separated on a Zorbax SB-C18 column with a mobile phase of acetonitrile : water (45 : 55, v/v) at a flow rate of 0.2 mL/min with an operating temperature of 25°C. Detection was carried out by electrospray ionization in positive-ion multiple reaction monitoring mode. The calibration plots in dog plasma were linear over the ranges of 0.5-2,000 ng/mL for telmisartan and 0.5-500 ng/mL for amlodipine. The lower limit of quantification was 0.5 ng/mL for two analytes. The intra- and interday precisions (RSD%) were within 9.0%. The average recoveries of analytes were >85.0%. The method was successfully applied to the pharmacokinetic study of the two compounds after oral administration of telmisartan-amlodipine combination preparation to dogs.
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... As already mentioned the slow onset of action involves both a slow rate of absorption due to a prolonged hepatic transfer time [23] and a slow rate of association with the Ca 2+ calcium complex [22]. Its relatively high bioavailability is largely due to a slow rate of degradation by the liver [29] resulting, in turn, in a slow rate of elimination [25]. Some calcium antagonists, it should be recalled, undergo extensive first pass hepatic metabolism, resulting in a relatively low bioavailability. ...
Calcium antagonists are now widely used in the management of patients with a variety of cardiovascular disorders, including angina pectoris and hypertension. The prototype of the group - the phenylalkylamine-based verapamil - lacked tissue specificity within the cardiovascular system. Its introduction triggered the search for other calcium antagonists with improved tissue selectivity and resulted in the introduction of a variety of dihydropyridine based compounds including nifedipine, nisoldipine, nitrendipine and felodipine. These drugs exhibited improved tissue selectivity relative to verapamil, but possessed unfavourable pharmacokinetic profiles resulting in short duration of action, short plasma half-lives and rapid onset of action. The resultant unfavourable side effects limited the efficacy of these compounds and although the introduction of slow release formulations attenuated some of the problems encountered during their use the search for a tissue selective calcium antagonist with an intrinsically favourable pharmacokinetic profile continued, resulting in the development of amlodipine. Although a dihydropyridine, amlodipine differs from its predecessors in having a strongly ionized side-chain and an ability to insert directly into membranes lipid bilayers. This therefore provides the prototype of a third generation of calcium antagonists characterised by possessing a favourable pharmacokinetic profile (slow onset and prolonged duration of action coupled with a long plasma half-life) due to its own molecular structure. For purposes of classification verapamil can be regarded as the prototype of the first generation of calcium antagonists, nifedipine as the prototype of the second generation (improved tissue selectivity) whilst amlodipine is the prototype of a third generation (retained tissue selectivity with an intrinsically favourable pharmacokinetic profile). Clinically amlodipine is an effective blood pressure lowering agent in hypertensives, where it also reverses left ventricular hypertrophy. Surprisingly amlodipine's safety extends to its long-term use in hypertensives with severely compromised left ventricular function - including chronic heart failure associated with non-ischaemic, dilated cardiomyopathy.
... Experimental studies have shown that amlodipine reduces blood pressure gradually and at the same time does not cause tachycardia. The prophylactic use of amlodipine protects the cardiomyocytes from the ischemic calcium overload resulting after reperfusion and protects the endothelium from ischemic damage (11). This medicine is relatively well tolerated and has no adverse effects on carbohydrate and lipid metabolism. ...
Background. Identification of activity properties of new synthesized compounds is important to help choose the adequate research methodology. The goal of this experimental research was to determine the relationship between the chemical structure of 25 compounds of 1,4-dihydropyridine derivatives and their effects on the contraction force of guinea pig papillary muscles and the action potential (AP) duration.
Methods. AP recordings were obtained with standard microelectrodes that were made from borosilicate glass capillaries, filled with 2.5 M KCl and connected to the high-input impedance amplification system. 1.0 Hz stimulation frequency was used. The contraction of papillary muscles was recorded by using a force transducer. Both signals (inotropic response and AP) were digitised by an A/D converter and registered by a computer specialised program.
Results. The results have shown that most of 1,4-dihydropyridine derivatives possessed the negative inotropic action and had the negligible impact on the AP duration.
It was identified that 1,4-dihydropyridine compound OSI 9719 (2-propoxyethyl-4-difloemethoxyphenyl-2-methyl-5-nitro-1,4-dihydropyridine-3carboxylate) had a prolonged duration of AP and simultaneously increased the force of contraction (p
... Amlodipine, a dihydropyridine, is a long acting vasoselective calcium antagonist with a plasma half-life of 35-50 hours. It is extensively metabolized in the liver and mostly excreted by the kidneys (Reid et al. 1988). The normal daily dose of amlodipine is 2.5-10 mg. ...
... Amlodipine was chosen to be the most suitable drug to ensure full smooth muscle relaxation in the coronary artery since it is a long lasting L-type calcium channel blocker [9]. Furthermore, another advantage of amlodipine is its endothelium independent capability of SMC administration which means it can diffuse into the SMCs from any direction [10]. ...
... Amlodipine is a dihydropyridine calcium channel blocker [3][4] used in the management of hypertension and angina pectoris 5 . It is reported that Benazepril was identified by HPLC [6][7][8][9] , spectrophotometry [10][11][12][13][14][15][16] , and with Benazeprilat by liquid chromatography-mass spectrometry 2,17 , and gas chromatography-mass spectrometry 18 . ...
A selective, sensitive, rapid, and reproducible liquid chromatographyelectro spray ionization tandem mass method has been developed and subsequently validated for the simultaneous determination of Amlodipine (AML), Benazepril (BENZ), and its active metabolite Benazeprilat (BENZT) in spiked human plasma, using Moexipril (MOX) as an internal standard (IS). Various modes were tried and the Multiple Reaction Monitoring (MRM) mode was found the most suitable one. The three analytes and Moexipril (IS) were extracted from human plasma by simple protein precipitation using acetonitrile as the precipitating solvent. The stationary phase used was a C18 Sunfire column while water and acetonitrile at 0.1 % formic acid (30:70, v/v) was used as a mobile phase. The flow rate used was 0.8 mL/min. FDA guidelines were followed for the method validation. The linearity range was found to be 10-200 ng/mL for Amlodipine, 0.5-100 ng/mL for Benazepril and 5-200 ng/mL for Benazeprilat and the correlation coefficient was more than 0.9980 for each analyte. The equation of the calibration curve was: y=0.0068x - 0.0072 (r2=0.9981, n=3) for Amlodipine, y=0.6098x - 0.135 (r2 = 0.9988, n=3) for Benazepril and y=0.0173x - 0. 0312 (r2=0.9987, n=3) for Benazeprilat. Results for accuracy and precision showed satisfactory results. Also the method was compared with reported HPLC method and no significant difference was found.
... Amlodipine is slowly and almost completely absorbed from the gastrointestinal tract 5,6 . Peak plasma concentrations are reached at 6-9 h of post dose 8,9 . ...
The aim of this study was to investigate the physicochemical properties of amlodipine besylate tablets. Tablets containing 5 mg of amlodipine besylate were prepared using Generally Regarded as Safe (GRAS) excipients. Preformulation studies were carried out using Fourier Transform Infrared (FTIR) spectroscopy and High Performance Liquid Chromatography (HPLC). Dissolution studies were performed to assess biowaiver criteria for Biopharmaceutical Classification System (BCS) Class I drug. Both the test and reference products conformed to pharmacopoeial requirements for physical parameter of tablets. FTIR studies revealed that there was no interaction between drug and excipients used in the test product. The percentage of drug remaining in the samples, subjected to the accelerated condition, complied the range specified in the United States Pharmacopeia (USP) monograph of amlodipine besylate. The dissolution of both the products was found to be more than 85 % in pH 1.2 buffer at the interval of 15 min. However, in pH 4.5 and pH 6.8 buffer media, only test product released more than 85 % drug, whereas the reference product did not. Mathematical analysis suggested that the release profiles obtained from the test and reference products in pH 4.5 and pH 6.8 buffer media were dissimilar. The finding of this study suggests that, under the tested conditions, the test product is better than the leading foreign brand available in Nepal. Prescribing pattern could be tailored based on the pharmaceutical quality of the product as well as cost of therapy to ensure better pharmacotherapy and patient compliance INTRODUCTION: Cardiovascular diseases are increasing rapidly in the developing world 1 . Hypertension is one among the most important modifiable risk factors for cardiovascular disease 2 , it affects approximately one billion people in the worldwide 3 . Treatment of high blood pressure can reduce cardiovascular mortality and morbidity 4 .
... Amlodipine (Fig. 1), a dihydropyridine calcium antagonist, is prescribed for the treatment of angina and hypertension. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and blood pressure [4][5][6]. ...
A rapid and sensitive liquid chromatography–tandem mass spectrometric (LC–MS/MS) assay method has been developed and fully validated for the simultaneous quantification of telmisartan and amlodipine in human plasma. Carbamazepine was used as an internal standard. Analytes and the internal standard were extracted from human plasma by solid-phase extraction technique using Waters Oasis® HLB 1 cm3 (30 mg) extraction cartridge. The reconstituted samples were chromatographed on a Hypurity advance C18 column (50 mm×4.6 mm, 5 μm) using a mixture of acetonitrile–5 mM ammonium acetate buffer (pH-4.0) (50:50, v/v) as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r≥0.99) over the concentration range of 2.01–400.06 ng/mL for telmisartan and 0.05–10.01 ng/mL for amlodipine. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The proposed method was found to be applicable to clinical studies.
... The active substance of this investigation, nifedipine (Nf), is a calcium antagonist and is used for the treatment of hypertension. It is a poorly water-soluble drug with a low bioavailability and a short half-life of 2 h [1]. Thus, nifedipine has to be administered two or three times per day. ...
... Oral doses of 5 to 10 mg QD are effective in the treatment of mild to moderate hypertension and stable angina pectoris. [7][8][9][10] Amlodipine is well tolerated and does not appear to cause some of the undesirable effects often associated with other cardiovascular agents. It has a long elimination half-life and a large volume of distribution. ...
A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric assay method has been developed and fully validated for simultaneous quantification of losartan and its active metabolite, losartan carboxylic acid, and amlodipine in human plasma. Irbesartan was used as an internal standard.
The analytes were extracted from human plasma samples by solid-phase extraction technique using Oasis HLB cartridges, (Waters Corporation, Mumbai, India). The reconstituted samples were chromatographed on a C18 column by using an 85:15, v/v mixture of methanol and 0.1% v/v formic acid as the mobile phase at a flow rate of 1.0 mL/min. A detailed validation of the method was performed as per the FDA guidelines.
The calibration curves obtained were linear (r ≥ 0.99) over the concentration range of 0.5-1000 ng/mL for losartan and for its active metabolite losartan acid and 0.05-10.1 ng/mL for amlodipine. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits.
A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies.
... Similar to most other calcium blocking agents of the dihydropyridine class, a racemic mixture of AML is used for therapeutic purposes. However, it has been reported that the vasodilatation effect of AML can be ascribed to its S-enantiomer (Kungys et al., 2003;Zhang et al., 2002;Cooper et al., 1995;Abernethy, 1992;Meredith and Elliott, 1992;Elliott et al., 1992;Reid et al., 1988). As reported before, S-AML is mostly associated with AML antihypertensive effects, while R-AML is thought to be responsible for nitric oxide-mediated vasodilatation, which is associated with adverse effects, including peripheral edema and facial flushing (Goldman et al., 1992;Zhang et al., 2002). ...
A rapid, simple, specific and sensitive LC-MS/MS method has been developed and validated for the enantiomeric quantification of amlodipine (AML) isomers [R-amlodipine (R-AML) and S-amlodipine (S-AML)] with 200 μL of human plasma using R-AML-d4 and S-AML-d4 as corresponding internal standards as per regulatory guidelines. A simple liquid-liquid extraction process was used to extract these analytes from human plasma. The total run time was 3.5 min and the elution of R-AML, S-AML, R-AML-d4 and S-AML-d4 occurred at 1.62, 2.51, 1.63 and 2.53 min, respectively. This was achieved with a mobile phase consisting of 0.2% ammonia-acetonitrile (20:80, v/v) at a flow rate of 1 mL/min on a Chiralcel OJ RH column. A linear response function was established for the range of concentrations 0.1-10 ng/mL (r >0.998) for each enantiomer. The intra- and inter-day precision values for both enantiomers met the acceptance criteria. Both enantiomers were stable in a set of stability studies, viz. bench-top, auto-sampler, freeze-thaw cycles and long-term. The current assay was successfully applied to a pharmacokinetic study to quantitate AML enantiomers following oral administration of 10 mg AML tablet to humans. Copyright © 2013 John Wiley & Sons, Ltd.
Background. Graft spasm remains challenging in CABG (coronary artery bypass grafting) surgery. We investigated the inhibitory effect of a dihydropyridine calcium antagonist amlodipine on the vasoconstriction mediated by potassium chloride (KCl), human urotensin-II (hU-II), and U46619 in human internal mammary artery (IMA) from patients undergoing CABG. Methods. Isolated IMA rings (n ؍ 78, taken from 42 patients) were studied in organ baths in two ways: the relaxing effect of amlodipine on vasoconstrictor-induced precontraction by KCl, hU-II, and U46619 and the depressing effect of amlodipine on the contraction. Results. Amlodipine caused full relaxation in KCl-contracted (98.0% ؎ 2.1%), in hU-II-contracted (98.5% ؎ 2.4%), and in U46619-contracted (96.3% ؎ 1.3%) IMA rings (n ؍ 8) with 15.5-fold higher potency to KCl than to
A rapid, simple, sensitive and specific LC-MS/MS method has been developed and validated for the simultaneous estimation of amlodipine (AML), benazepril (BEN) and benazeprilat (BNT) using eplerenone and torsemide as internal standards (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Sample preparation involves both extraction and precipitation techniques. The reconstituted samples were chromatographed on Acquity UPLC BEH C18 (50mm×2.1mm, 1.7μm) column by pumping 0.1% formic acid and acetonitrile in a gradient mode at a flow rate of 0.45ml/min. A detailed validation of the method was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 0.1-5ng/ml for AML; 5-1200ng/ml for both BEN and BNT. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A run time of 2.5min for each sample made it possible to analyze more than 300 human plasma samples per day. The developed assay method was successfully applied to a bioequivalence study in human volunteers.
Für die Praxis stehen Kalziumantagonisten vom Dihydropyridin-, Verapamil- und Diltiazemtyp mit sehr unterschiedlichen pharmakokinetischen Eigenschaften zur Verfügung. Der Zeitpunkt der maximalen Plasmaspiegel nach oraler Einnahme reicht von 0,5–1 h bis zu 8–9 h. Die Plasmahalbwertszeiten liegen zwischen 2–3 h und 35–50 h. Einige Kalziumantagonisten liegen sowohl in rasch resorbierbarer als auch in retardierter Form vor.
Introduction:
Angina pectoris is a common presenting symptom of underlying coronary artery disease or reduced coronary flow reserve. Patients with angina have impaired quality of life; and need to be treated optimally with antianginal drugs to control symptoms and improve exercise performance. A wide range of antianginal medications are approved for the treatment of angina, and often more than one class of antianginal drugs are used to adequately control the symptoms. This expert opinion highlights the likely cardiac adverse effects of available antianginal drugs, and how to minimize these in individual patients and especially during combination treatment.
Areas covered:
All approved antianginal drugs, including the older and newly approved medications with different mechanism of action to the older drugs as well as some of the unapproved herbal medications. The safety profiles and potential cardiac side effects of these medications when used as monotherapy or as combination therapy are discussed and highlighted.
Expert opinion:
Because of the different cardiac safety profiles and possible side effects, we recommend selection of initial drug or adjustment of therapy based on the resting heart rate; blood pressure, hemodynamic status; and resting left ventricular function, concomitant medications and any associated comorbidities.
Background: Amlodipine, a dihydropyridine calcium channel blocker, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers. However, its calcium channel blocking activity is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than the S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic characteristics and safety profiles of the newly developed S-amlodipine formulation, composed of different additives, with those of the previously developed formulation. Methods: This randomized, double blind, two periods, two sequence crossover study was conducted in 24 healthy male volunteers at Seoul National University Hospital Clinical Trials Center. All subjects were randomly assigned to one of two sequence groups: (1) a single dose of the new S-amlodipine formulation (5 mg, 2.5mg/tablet) in the first study period, followed by a single dose of the reference S-amlodipine formulation (5 mg, 2.5mg/tablet) in the second study period, or (2) vice versa. A 14 day-washout separated the study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected just before study drug administration and at predefined time points up to 168 hours post dose. Safety profiles including hematology, biochemistry, electrocardiography, and urinalysis were assessed throughout the study. Pharmacokinetics of the two formulations were characterized using noncompartmental model and compared between the formulations. Results: The pharmacokinetic profiles of S-amlodipine were comparable between the formulations. The mean [SD] values for Cmax in reference and test formulation (3.4 [0.8] ug/L vs 3.3 [0.88] ug/L, respectively) and AUC from time 0 to the last available measurement (AUC last) (159.2 [45.6] ug*h/L vs 160.6 [48.9] ug*h/L, respectively) were similar. The calculated 90% confidence interval of the corresponding ratios of log-transformed C max and AUC last, were 0.90~1.03 and 0.93~1.08, respectively. Neither formulation caused any serious adverse events. Conclustions: Both formulations were safe and well tolerated in tested dose, 5 mg of S-amlodipine. This study provides evidence for similar pharmacokinetic characteristics of the newly developed formulation of S-amlodipine to a previously prescribed formulation in healthy Korean male volunteers.
Background: This randomized, single-blind, two-sequence, two-period crossover study in 24 healthy volunteers with a 2-week washout interval compared pharmacokinetics of two salt forms of amlodipine formulations, the newly developed formulation (amlodipine orotate, Orodipine,® Dong-A Pharmaceutical Company, Limited., Korea) to increase the dissolution rate at higher gastric pH conditions and the original formulation (amlodipine besylate, Norvasc,® Pfizer Incorporated, Korea). Methods: Plasma samples were obtained over 144 h after a single oral dose of 10 mg amlodipine, two tablets for each formulation. Plasma amlodipine concentrations were analyzed by combined liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization (ESI) using multiple reaction monitoring (MRM). From the amlodipine plasma concentration versus time curves, the amlodipine pharmacokinetic parameters were determined by non-compartmental method. Results: Mean of area under the plasma amlodipine concentration-time curve from time 0 to time infinity (AUC0-∞) of Orodipine® was 336 ng·h/mL (coefficient of variation (CV) = 31.3%) and that of Norvasc® was 329 ng·h/mL (CV = 38.3%). Mean of maximum observed plasma amlodipine concentration (Cmax) of Orodipine® was 6.89 ng/mL (CV = 25.8%) and that of Norvasc® was 6.46 ng/mL (CV = 32.0%). The percent ratios of 90% confidence intervals of Orodipine®/Norvasc® were 99̃124% for Cmax and 94̃118% for AUC0∞, and the means of terminal elimination half-life (t1/2β) of amlodipine were 44.0 h (CV = 17.5%) for Orodipine® and 42.6 h (CV = 16.7%) for Norvasc® respectively. Conclusion: Since amlodipine orotate and amlodipine besylate showed similar pharmacokinetic characteristics, alteration of the salt form did not affect the pharmacokinetics of amlodipine.
Background: Amlodipine is a dihydropyridine calcium antagonist used for the treatment of hypertension and angina. Amlodipine adipate is a newly developed salt formulation of amlodipine. The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of amlodipine adipate with those of conventional amlodipine besylate in healthy subjects. Methods: The study was conducted as a single blinded, block dose randomized, two-way crossover design. Twenty-four subjects were enrolled, twelve subjects each for the 5 mg dose group and the 10 mg dose group. Subjects were administered single oral dose of amlodipine adipate and amlodipine besylate, in a randomized sequence, with two weeks washout period between the two treatments. Serial blood samples were collected till 120 hours after drug administration. Plasma concentrations of amlodipine were analyzed by liquid chromatography tandem mass spectrometry. Individual pharmacokinetic parameters were calculated by noncompartmental methods and the pharmacokinetic parameters were analyzed by analysis of variance. Ambulatory blood pressure and computerized impedance cardiography were measured till 24 hours after drug administration. The pharmacodynamic parameters were analyzed by repeated-measures analysis of variance. Results: In the 5 mg dose group, the ratios of AUClast and Cmax of amlodipine adipate to amlodipine besylate were 0.93 and 0.89, respectively. In the 10 mg dose group, the ratios of AUClast and Cmax of amlodipine adipate to amlodipine besylate were 1.01 and 1.09, respectively. Regarding pharmacodynamic results, there were no significant differences in systolic blood pressure, diastolic blood pressure, pulse rate, or in change of total peripheral resistance between amlodipine adipate and amlodipine besylate at doses of both 5 mg and 10 mg. Conclusions: We concluded that amlodipine adipate and amlodipine besylate showed similar pharmacokinetic and pharmacodynamic characteristics.
Synopsis Amlodipine belongs to the dihydropyridine class of calcium channel blockers. Both short and long term studies indicate that amlodipine effectively lowers mild to moderately elevated blood pressure and relieves symptoms of angina pectoris. In comparative studies, its antihypertensive efficacy is similar to that of other established agents such as β-blockers, diuretics, ACE inhibitors and other calcium channel blockers (including the dihydropyridines); limited comparative data are, however, available in patients with angina pectoris. Amlodipine may offer potential in patients with congestive heart failure. Vasodilator adverse events such as oedema, headaches, and flushing are commonly observed with amlodipine. The drug does not appear to cause postural hypotension, reflex tachycardia or cardiac conduction disturbances. Comparative studies suggest that amlodipine is at least as well tolerated as other standard agents. Thus, amlodipine provides an attractive therapeutic option for the treatment of hypertension, and offers potential for patients with angina pectoris. Its beneficial effects in patients with congestive heart failure require confirmation in future studies.
Synopsis
Amlodipine, a basic dihydropyridine derivative, inhibits the calcium influx through ‘slow’ channels in peripheral vascular and coronary smooth muscle cells, thus producing marked vasodilation in peripheral and coronary vascular beds. Short to medium term clinical trials indicate that amlodipine is effective as both an antianginal agent in patients with stable angina pectoris and an antihypertensive agent in patients with mild to moderate hypertension. In small comparative studies amlodipine was at least as effective as ‘standard’ agents, including atenolol, verapamil, hydrochlorothiazide or captopril in hypertension, and diltiazem or nadolol in angina pectoris
Amlodipine is well tolerated, and does not appear to cause some of the undesirable effects often associated with other cardiovascular agents (e.g. adverse changes in serum lipid patterns, cardiac conduction disturbances, postural hypotension). The most common adverse effects associated with amlodipine therapy —oedema and flushing - are related to the vasodilatory action of the drug, and are generally mild to moderate in severity
Thus, amlodipine seems to provide a useful alternative to other agents currently available for the treatment of essential hypertension and chronic stable angina pectoris, with certain pharmacodynamic and tolerability properties thai should be advantageous in many patients
Pharmacodynamic Properties
Amlodipine, like other calcium entry blockers, inhibits the ‘slow’ channel influx of calcium into cardiac and vascular tissue. Its main site of action is the peripheral vasculature, although it also produces vasodilation in coronary vascular beds. Indeed, in patients with essential hypertension, intra-arterial infusions of amlodipine markedly increase forearm blood flow and reduce forearm vascular resistance, effects indicative of a peripheral arterial vasodilatory action. In vitro, amlodipine has been shown to inhibit potassium-induced contractions in human coronary artery preparations and, in several animal models, has dramatically increased coronary blood flow and reduced coronary vascular resistance. In humans, amlodipine has no significant effects on the sinoatrial or atrioventricular node
In patients with mild to moderate essential hypertension amlodipine has a sustained and gradual onset of antihypertensive effect. Medium term once-daily dosage regimens of 2.5 to 10mg produce reductions in mean systolic and diastolic blood pressures of about 10 to 18% in most studies. Moreover, in these patients amlodipine increases renal blood flow and glomerular filtration rate, and reduces renovascular resistance; plasma renin activity and aldosterone and cate-cholamine levels are not significantly affected. In addition, urine volume and urinary sodium excretion are unchanged, factors which suggest that amlodipine has no long term effect on sodium homeostasis
In animal models and in vitro studies using human cardiac tissue, high concentrations of amlodipine, which exceed clinically effective concentration ranges, have a weak negative inotropic effect. However, after short term administration to patients with coronary artery disease no significant cardiodepression occurs
As well as markedly reducing peripheral vascular resistance, and therefore afterload, amlodipine increases cardiac output and reduces stroke work. In addition to its ability to reduce afterload, amlodipine increases myocardial oxygen supply, reduces demand and improves exercise capacity in patients with symptomatic myocardial ischaemia
Animal studies have demonstrated a cardioprotective effect for amlodipine — in both in vivo and in vitro models of ischaemia-reperfusion; reductions in tissue calcium content and increases in shortening fraction have been noted after reperfusion
Amlodipine has demonstrated several other actions which warrant further study. These include antiatherosclerotic, antithrombotic and antihypertrophic actions. Indeed, amlodipine inhibits in vitro collagen synthesis in aortic strips from spontaneously hypertensive rats (SHRs), which may indicate antiatherosclerotic potential. It also stimulates LDL receptor binding in human fibroblasts in vitro, an effect which, if produced in vivo, may retard atherogenesis through intracellular accumulation of LDL and a reduced accumulation of cholesterol in arterial walls. With reference to an antithrombotic action, amlodipine has been shown to reduce platelet aggregation in patients with essential hypertension and, in terms of antihypertrophic effects, regression of myocardial hypertrophy has been noted in SHRs
Pharmacokinetic Properties
After oral administration amlodipine is slowly and almost completely absorbed; peak plasma concentrations are attained within 6 to 12 hours. Amlodipine has a relatively high oral bioavailability of 60 to 65%, which is not influenced by food. Moreover, amlodipine appears to have a linear pharmacokinetic profile, with strong positive correlations between oral dosage, and Cmax and AUC0–72. In healthy volunteers, steady-state plasma concentrations are achieved after 7 once-daily oral doses, without evidence of accumulation. Amlodipine has a large volume of distribution of 21 L/kg, and is more than 95% bound to plasma proteins
Unlike verapamil, diltiazem and nifedipine, amlodipine does not undergo extensive and variable presystemic metabolism, although it is extensively and slowly metabolised by the liver. The initial biotransformation is oxidation of the dihydropyridine ring to produce the pyridine analogue, usually followed by oxidative deamination of the basic 2-aminoethoxymethyl side chain. In fact, this metabolic pathway leads to the production of more than 75% of the urinary metabolites of amlodipine, none of which are conjugated. None of the amlodipine metabolites have significant pharmacological activity
In comparison with other calcium entry blockers amlodipine has a relatively long elimination half-life of 35 to 45 hours, which permits once-daily administration. Less than 10% of an orally administered dose of amlodipine is excreted unchanged; 60% of a dose is recovered in the urine and 20 to 25% in the faeces after either oral or intravenous administration. The latter indicates that amlodipine and its metabolites are excreted in the bile and/or across the gut wall
In patients with hepatic cirrhosis, and in the elderly, amlodipine elimination is significantly reduced and some degree of accumulation is noted; elimination half-life is prolonged and AUC is increased. Although in the elderly this may simply be a reflection of large intersubject variability, relevant dosage adjustments should be made in both patient groups. The pharmacokinetic profile of amlodipine does not appear to be significantly altered in patients with renal impairment
Therapeutic Efficacy
In patients with chronic stable angina pectoris amlodipine improves both subjective symptoms [i.e. nitroglycerin (glyceryl trinitrate) consumption and angina attack frequency] and objective symptoms (ST segment deviation, exercise duration and time to angina onset). A few small well designed comparative trials have shown the antianginal efficacy of amlodipine to be similar to that of diltiazem and nadolol, but its relative efficacy needs confirmation in larger comparative studies. Amlodipine also improves subjective symptoms in patients with vasospastic angina
Several short to medium term trials have shown amlodipine, in oral regimens of 2.5, 5 and 10mg once daily, to significantly reduce supine and standing systolic and diastolic blood pressures in a dose-dependent manner in patients with essential hypertension. Amlodipine 5 to 10mg once daily also significantly reduces mean ambulatory blood pressure throughout a 24-hour dose interval in hypertensive patients. These antihypertensive effects are achieved without accompanying reflex tachycardia or postural hypotension. In a few small but well designed medium term comparative trials the antihypertensive efficacy of amlodipine was slightly better than that of verapamil and similar to that of hydrochlorothiazide, captopril and atenolol. However, as is the case in angina pectoris, amlodipine’s relative efficacy in hypertension needs to be further assessed in larger comparative studies
Tolerability
Amlodipine is generally well tolerated during short term therapy (i.e. ⩽ 6 months) in patients with essential hypertension or angina pectoris. Pooled results from 40 double-blind placebo-controlled trials show that 529/1775 (29.8%) amlodipine vs 268/1213 (22.1%) placebo recipients experienced adverse effects; 1.1 vs 0.7% of patients withdrew from treatment. The main amlodipine-induced side effects (oedema and flushing) occur as a result of vasodilation and are thought to be dose-dependent. However, amlodipine-induced oedema is usually mild or moderate in severity and is rarely troublesome to patients. Again on the basis of pooled data from 40 studies, 9.8% of amlodipine vs 2.3% of placebo recipients had oedema, which was considered definitely related to treatment in 4.3 vs 0.4% of patients
Other adverse effects reported occasionally and considered to be possibly related to amlodipine therapy include muscle cramps, frequency of micturition/nocturia, coughing, impotence, asthma, epistaxis, nervousness and conjunctivitis. However, these reactions are infrequent and few have been severe enough to warrant stopping treatment
Comparative trials suggest that amlodipine is at least as well tolerated as atenolol, nadolol, verapamil, diltiazem and hydrochlorothiazide. However, pharmacodynamic data suggest that amlodipine may have a more favourable adverse effect profile than /5-blockers, thiazide diuretics and possibly some other calcium antagonists — for example, it does not appear to impair cardiac function or to cause postural hypotension, and reflex tachycardia occurs in only a small proportion of patients
Dosage and Administration
In patients with essential hypertension or angina pectoris, amlodipine should be initiated at a dosage of 5mg once daily orally and increased to 10mg once daily, if the desired therapeutic response has not been achieved after 2 weeks
A simple, specific, accurate, and stability-indicating reversed-phase high-performance liquid chromatography method was developed for simultaneous estimation of irbesartan and amlodipine besylate in pharmaceutical formulations. The chromatographic separation was achieved on a Zorbax CN column using a mixture of 1 mM potassium dihydrogen phosphate (pH 3.0) and acetonitrile (70:30, v/v) as the mobile phase at a flow rate of 0.9 mL/min. Detection was carried out at 240 nm. The calibration curves were linear (R 2 ≥ 0.99) over a concentration range of 6–42 µg/mL for irbesartan and 2–14 µg/mL for amlodipine besylate. The retention times of irbesartan and amlodipine besylate were 9.6 and 7.6 min, respectively. For stability studies, irbesartan and amlodipine besylate stock solutions were subjected to acid, alkali hydrolysis, chemical oxidation, and dry heat degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention times and resolution. To elucidate structures of degradation products, the LC-MS method was used. The proposed method was successfully validated in accordance to the ICH guidelines acceptance criteria.
The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.
The effect of sustained-release (SR) diltiazem 300 mg on 24-hour ambulatory blood pressure (BP), heart rate (HR), and left ventricular mass was evaluated in 35 elderly patients aged 75 to 84 years with mild-to-moderate essential hypertension, defined as sitting systolic blood pressure (SBP) >160 mm Hg and diastolic blood pressure (DBP) >90 mm Hg but <110 mm Hg, After a 4-week placebo washout period, patients were treated with SR diltiazem 300 mg once daily for 6 months. At the end of the placebo period and after 1, 3, and 6 months of treatment, BP was measured in both the sitting and standing positions, an electrocardiogram and an M-mode echocardiogram were performed, and ambulatory BP was monitored noninvasively. SR diltiazem significantly lowered both sitting and standing SEP and DBP at trough levels. Ambulatory BP monitoring confirmed consistent antihypertensive activity throughout the 24-hour dosing interval, without affecting the circadian BP profile. A statistically but not clinically significant decrease in HR was observed. Echocardiographic measurements demonstrated a significant reduction in left ventricular mass index (LVMI) (18%) and in left ventricular wall thickness (posterior mall, 19%; interventricular septum, 17%) versus placebo, with no change in fractional shortening or diastolic filling time. The treatment was well tolerated, and no serious side effects mere reported. The results of this study suggest that once-daily administration of SR diltiazem 300 mg was well tolerated and effective in reducing both sitting and standing BP as well as ambulatory BP and LVMI in elderly patients with hypertension, without causing deterioration in cardiac function.
Objective: The aim of the present study was to assess the effects on blood pressure, platelet aggregation, and insulin sensitivity of lacidipine and nifedipine gastrointestinal therapeutic system (GITS) given once daily in a parallel-group, double-blind, randomized study of patients with mild to moderate hypertension. Methods: Twenty patients (12 men, 8 women) with mild to moderate hypertension aged 45 to 56 years (average age, 50 ± 2.3 years) were included. They received placebo for 4 weeks and were then randomly divided into 2 groups of 10 patients each. Nifedipine GITS 30 mg and lacidipine 4 mg were given for 16 weeks. Blood pressure and heart rate were measured at the clinic in the supine, sitting, and standing positions 24 ± 1 hours after the last dose. At the end of the placebo and active phases the following procedures were performed: a platelet aggregation test; determination of platelet malondialdehyde production; and determination of tolerance to 100 g of glucose by measuring plasma insulin. Results: Both drugs significantly reduced systolic and diastolic blood pressures to the same level; however, observable differences in the rate of reduction were noted. In week 1, systolic blood pressure decreased 15.15% in the nifedipine GITS group and 6.54% in the lacidipine group. Heart rate was increased slightly but significantly in the standing position in the nifedipine GITS group only. Neither of the drugs reduced platelet aggregation ex vivo, however, both modified malondialdehyde production, indicating an effect at the arachidonic acid metabolic pathway. Conclusions: The effects of the drugs on the metabolism of carbohydrates were inconclusive. However, a tendency for lacidipine to improve insulin sensitivity and for nifedipine GITS to have the opposite effect was observed.
This multicenter, randomized, double-blind, placebo-controlled study was performed to assess the efficacy and tolerability of lercanidipine, a new dihydropyridine calcium antagonist, for treatment of elderly hypertensive patients. A total of 144 patients aged 60-85 years were enrolled and randomly allocated to lercanidipine 10 mg or placebo for 4 weeks. The starting dose was then titrated up to 30 mg q.d. in non-responders during the following 12 weeks. The diastolic blood pressure (DBP) decrease induced by lercanidipine 10 mg (-10.3 mm Hg) was significantly greater than the DBP reduction observed after placebo (-6.1 mm Hg; p<0.01), and the percentage of patients responding to the active treatment was significantly greater than the corresponding percentage in the placebo group (59.1 vs. 37.8%, respectively; p<0.05). Dose titration to 20 mg increased the response rate to 69.4%, and only a few patients required titration to 30 mg. Heart rate and laboratory test parameters did not change with treatment. The percentage of patients reporting adverse events was similar in the placebo and active groups. Lercanidipine given once a day significantly reduces blood pressure levels in elderly subjects with mild to moderate hypertension. The effect persists for 24 h and does not induce reflex tachycardia. The drug is well-tolerated and because of its pharmacologic and pharmacodynamic properties may be particularly indicated in the treatment of elderly hypertensive patients.
The efficacy and tolerability of lercanidipine, a new dihydropyridine calcium antagonist, were assessed in comparison with atenolol in a randomized, double-blind, multicenter trial in patients with mild to moderate essential hypertension. After 3 weeks of placebo run-in, 217 eligible patients were divided into two parallel groups receiving either lercanidipine 10 mg or atenolol 50 mgonce a day. Systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) were measured at weeks 4, 8, 12, and 16 of treatment, 24 ± 2 h after the last dose. After the first 4 weeks of treatment, in non-responder patients (DBP >90 mm Hg or reduction < 10 mm Hg compared to baseline) lercanidipine was initially tritated up to 20 mg and atenolol up to 100 mg. Then, after 8 weeks in patients still unresponsive, the two study drugs were combined. After 4 weeks, BP was significantly (p < 0.01) reduced in both treatment groups compared to control values: lercanidipine DBP -10.26 mm Hg, SBP -12.09 mm Hg; atenolol DBP -11.98 mm Hg, SBP -14.69 mm Hg. The changes observed in the lercanidipine group were not significantly different from those observed in the atenolol group. HR did not change in the lercanidipine group, whereas it significantly decreased in the atenolol group. After the first 4 weeks, patients with normalized DBP included 64.7% in the lercanidipine group and 75.5% in the atenolol group. By doubling the dose of the drug in the nonresponding patients, the percentage of normalized patients in the lercanidipine and atenolol groups increased to 82.2 and 85.7% respectively. Adverse events reported included 10.2% and 8.3% in the lercanidipine group receiving 10 and 20 mg respectively, whereas they were 7.2% and 4.1% in the atenolol group receiving 50 and 100 mg, respectively. The severity of the events was generally mild or moderate. The efficacy of lercanidipine and of atenolol in lowering blood pressure in mild to moderate essential hypertension is similar. However, unlike atenolol, lercanidipine is devoid of any effects on HR. The few adverse events observed with lercanidipine treatment confirmed the good tolerability profile of this new calcium antagonist.
The purpose of the present study was to evaluate the efficacy and tolerability of lercanidipine vs. placebo in patients with mild to moderate essential hypertension. A randomized, double-blind, placebo-controlled study was conducted in 132 patients (mean age 54.7 ± 8.6 years; 58 men and 74 women) recruited from seven centers, allocated to three parallel groups, and treated respectively with placebo, 10 mg, and 20 mg of lercanidipine in a single daily dose. Patients were randomized at the and of a placebo runin period of 3 weeks if their diastolic blood pressure (DBP) was ≥95 ≤115 mm Hg and were followed for 16 weeks of double-blind treatment, with a visit every 4 weeks. At each visit, patients classified as non-responders (DBP >90 mm Hg or reduced by less than 10 mm Hg compared to baseline values) had the dose of lercanidipine titrated up in steps of 10 mg daily. The maximal dose of lercanidipine was 40 mg per day. A total of 116 patients completed the first 4 weeks of the study and were considered eligible for the efficacy evaluation. There were 16 drop-outs during the first 4 weeks, eight voluntary withdrawals and eight because of adverse effects. After the first 4 weeks of treatment, 53.7% of the patients in the 10 mg lercanidipine and 62.9% in the 20-mg lercanidipine groups normalized blood pressure (DBP ≤90 mm Hg), whereas this occurred in only 15% of the patients receiving placebo. The percentage of patients classified in the same period as responders was 22.5% with placebo, 65.9% with 10 mg lercanidipine, and 85.7% with 20 mg lercanidipine. Comparison between placebo and 10and 20-mg lercanidipine revealed highly significant differences (p <0.01) for both responder and normalized patients. Concerning tolerability, neither the heart rate nor the laboratory test parameters exhibited significant changes compared to baseline values. The adverse effects reported during the study were 9.0%, 5.1%. and 17.1% in the placebo, 10-mg, and 20-mg lercanidipine groups, respectively. We conclude that lercanidipine is an effective and well-tolerated antihypertensive agent for which the most appropriate dose regimen is 10 mg once a day.
The long-term tolerability and antihypertensive effect of lercanidipine, a new calcium-entry blocker, was evaluated in this open, multicenter study. A total of 355 mild to moderately hypertensive patients (184 men and 171 women) aged 56.1 ± 8.3 years were selected after 2 weeks of wash-out and 3 weeks of placebo run-in and were enrolled for the 1-year treatment phase. The initial dose of lercanidipine 10 mg q.d. was increased every 4 weeks in non-responding patients up to 30 mg q.d. Then, if further BP reduction was needed, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, or a β-blocker was added to lercanidipine monotherapy. A total of 295 patients completed the study. After 4 weeks of treatment, lercanidipine 10 mg caused a significant reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (-12.2 and -9.7 mm Hg, respectively; p < 0.001), which led to normalized DBP values in 49.1% of patients. The therapeutic response was consolidated by dose titration to 20 mg during the following 4 weeks and then was continued unmodified until the end of the study. Only a few patients required a dose increase to 30 mg, and even fewer needed a combination with other drugs. No tachycardia was observed at any dose. No clinically relevant changes in laboratory tests were recorded during the treatment period. There was, however, a significant decrease in the number of patients with glucose, total cholesterol, and creatinine plasma levels outside the normal range. Only 16 patients discontinued the study because of side effects. Lercanidipine therefore appears to be a useful alternative in long-term treatment of essential hypertension.
The solubilities of nifedipine and nitrendipine in supercritical CO2 were measured by a static-analytical method in the pressure range from 100 to 300 bar at temperatures of 60, 80, and 100 degrees C. The mole fraction solubility of nifedipine at 300 bar and 100 degrees C is 7.1 x 10(-5), and that for nitrendipine is 10.6 x 10(-5). The difference in the solubilities of both compounds is small due to the similar chemical structure and physical properties. The applicability and limitations of three density-based models used to correlate the results are discussed.
A new group of drugs with antiepileptic efficacy, but lacking sedative side effects, would be an exciting therapeutic prospect. Theoretical considerations and results with experimental seizure models put forward the possibility that calcium antagonists may represent such an advance. The phenylalkylamine, verapamil, and the benzothiazepine, diltiazen, are not under serious consideration as antiepileptic drugs, since they are known to inhibit oxidative metabolism, in particular that of carbamazepine. The most promising drugs have been flunarizine and, more recently, the dihidropyridines, nimodipine and nifedipine. Controlled clinical trials in refractory epilepsy support antiepileptic efficacy for flunarizine, although these have not been unanimous. On the debit side, the drug is sedative and can prodcue extrapyramidal reactions and depression. Accordingly, its usage is likely to remain sporadic, although it may be beneficial in individual cases. Nimodipine and nifedipine are not implicated in central nervous system side effects, but are powerful vasodilators. These dihidropyridines undergo flow-dependent hepatic metabolism, and so concomitant treatment with enzyme-inducing antiepileptic drugs will reduce their bioavailability and accelerate their elimination. On conventional dosing, concentrations are low. Early clinical trials with nimodipine and nifedipine suggest that these pharmacokinetic disadvantages rule out their suitability for administration to the majority of patients with treated epilepsy. Another likely candidate is amlodipine, which is active in animal seizure models and which has an elimination half-life exceeding 24 h in man. It has not yet been studied in human epilepsy. At present, therefore, no calcium antagonist seems set to establish itself as a useful antiepileptic drug. The dihidropyridine group still looks most promising, but the breakthrough may come from a different class of compounds with a more suitable pharmacokinetic profile.
In the present study, the ability of the pig to discriminate the in-vivo release characteristics of two 60 mg sustained release nifedipine formulations, an experimental formulation (Faulding) and Procardia XL (Pfizer), under both fasting and fed conditions was assessed. These forms had previously been evaluated in humans, where an alteration in the release profile of the experimental formulation was noted following administration with food. 12 Large White female pigs (mean weight 38 kg) were divided into two groups and each group was orally administered one of the two products under both fasting and fed conditions. The mean area under the plasma concentration-time curve was not significantly different between the formulations under both conditions. The mean maximum observed plasma concentration (Cmax) was significantly higher for the experimental formulation when compared against Procardia XL under both fasting (P<0.05) and fed (P<0.05) conditions. Peak concentrations were achieved at approximately 6 h for the experimental formulation and 12 h for Procardia XL. The time for which the plasma concentration exceeded 75% of Cmax was approximately 2.5-fold greater for Procardia XL than for the experimental formulation. There were no significant food effects on the relative bioavailability nor release profiles of the two formulations. The results obtained suggest that the pig may be a useful model in differentiating the release profiles of nifedipine formulations for the fed state in humans as results were similar to the human-fed study, but dissimilar to the human-fasted study.
Amlodipine, a potent long-acting dihydropyridine calcium antagonist, was compared with placebo in a parallel, randomized, double-blind study in 134 patients with chronic stable angina pectoris maintained on betaadrenergic blocking agents. After a single-blind, two-week placebo period, patients were randomized to receive either amlodipine (2.5, 5, and 10 mg) or placebo once daily for four weeks. The effects of amlodipine on maximal exercise time, work, time to angina onset, and subjective indices including angina frequency, nitroglycerin tablet consumption, and patient and investigator ratings were assessed. Each dose of amlodipine produced increases in exercise time and calculated total work accomplished compared to baseline. Improvements at 5 and 10 mg were significantly greater than placebo which produced no significant change (p<0.05). Qualitative improvements in the severity of angina were produced by amlodipine at 5 and 10 mg daily assessed by patient-rating questionnaires (p<0.05). Reductions in angina frequency attacks per week and weekly nitroglycerin tablet consumption occurred but were not statistically significant when compared with placebo. Adverse effects observed during amlodipine treatment prompted discontinuation of treatment in only 2 out of 100 patients. Three patients discontinued treatment for reported lack of efficacy. No laboratory abnormalities prompted treatment discontinuation and minor side effects of dizziness, nausea, headache, and fatigue were observed infrequently. The results of this controlled, large-scale multicenter trial suggest that amlodipine significantly increased exercise capacity and was well tolerated when added to the antianginal regimen of patients remaining symptomatic while receiving beta-blocking agents.
The movement of calcium into neurons may be the common denominator for the triggering and propagation of seizure activity. We report results of the first double-blind, placebo-controlled, crossover trial with the dihidropyridine calcium antagonist nifedipine (NFD) as adjuvant therapy in refractory epilepsy. Twenty-two students (12 male, 10 female, age 17-22 years) attending Lingfield Hospital School received NFD retard and matched placebo for 8 weeks in 2 doses (20 and 40 mg b.i.d. each for 4 weeks) with a washout period of 8 weeks between treatment phases. In the 20 students who completed the trial, fewer partial seizures (p < 0.05) were documented during the first 2 weeks of NFD administration. Similarly, fewer seizure days (p < 0.05) were reported in the first month of active treatment. This response was not sustained into the second month of the trial. Blind scoring of EEGs suggested a small improvement with NFD (p < 0.05). More patients reported headache when receiving NFD (p < 0.02) than placebo, but heart rate and erect and supine blood pressure remained unaffected. Mean maximum NFD concentrations were 13.1 ± 10.4 ng/ml. A weak correlation was noted between total (p < 0.05) and partial (p = 0.025) seizure numbers and NFD concentrations following 8 weeks of treatment. This study does not support important anticonvulsant efficacy for NFD as adjuvant therapy for refractory epilepsy at doses appropriate for the treatment of angina or hypertension. Further trials are recommended using higher doses of NFD in less severely affected patients.
The selectivity of action of the clinically available calcium channel antagonists depends on a number of factors: 1) Mode of calcium mobilization—intracellular and extracellular sources. 2) Class and subclass of calcium channel involved. 3) Pharmacokinetic considerations, including distribution and interactions with cell membranes. 4) State-dependent interactions—voltage- and frequency-dependent interactions. 5) Pathologic state of tissue and channel regulation. These factors will be illustrated with particular reference to the 1,4-dihydropyridine series of ligands. The Ca2+ channel antagonists may be placed in several classes according to their rates of onset and offset of action, and the overall cardiovascular activity of an agent can profoundly alter its hemodynamic response. Additionally, third-generation agents such as lacidipine and lercenadipine partition extensively into plasma membranes according to membrane composition. Calcium mobilization through the L-type channel is the dominant target of the available antagonists: hence, systems that rely dominantly or exclusively on other mobilization processes are insensitive. Renal afferent and efferent arterioles that regulate glomerular flow and resistance are sensitive to the powerful vasoconstrictive effects of angiotensin II; however, only the processes in the afferent arteriole are sensitive to the Ca2+ channel antagonists. An important and subtle process for conferring tissue selectivity of action is derived from state-dependent interactions between channel and drug, whereby, according to the modulated-receptor hypothesis, drugs may exhibit preferential affinity for or access to different states of the channel—resting, open, or inactivated. Transitions between these states are determined by membrane potential and biochemical factors, including channel phosphorylation. The 1,4-dihydropyridine series exhibit significant and structure-dependent voltage-dependent interactions, which reflect a preferential interaction with open and/or inactivated channel states. The differential pharmacology of the L-type Ca2+ channel is a further determinant of tissue selectivity. The cardiovascular system expresses three different α1 subunits—CaV1.2A–C—and although a detailed pharmacological comparison is not yet available, there is sufficient evidence to indicate important differences. Thus, the 1,4-dihydropyridine nisoldipine interacts differentially with recombinant channels derived from cardiac and vascular smooth muscle. A number of disease states, both clinical and experimental, have been associated with changes in Ca2+ channel expression and function, although the causal relationship is often not established. Thus, in cardiac hypertrophy and failure the majority of studies reveal a reduction in L-type channel number or function. Drug Dev. Res. 58:5–17, 2003. © 2003 Wiley-Liss, Inc.
Graft spasm remains challenging in CABG (coronary artery bypass grafting) surgery. We investigated the inhibitory effect of a dihydropyridine calcium antagonist amlodipine on the vasoconstriction mediated by potassium chloride (KCl), human urotensin-II (hU-II), and U46619 in human internal mammary artery (IMA) from patients undergoing CABG.
Isolated IMA rings (n = 78, taken from 42 patients) were studied in organ baths in two ways: the relaxing effect of amlodipine on vasoconstrictor-induced precontraction by KCl, hU-II, and U46619 and the depressing effect of amlodipine on the contraction.
Amlodipine caused full relaxation in KCl-contracted (98.0% ± 2.1%), in hU-II-contracted (98.5% ± 2.4%), and in U46619-contracted (96.3% ± 1.3%) IMA rings (n = 8) with 15.5-fold higher potency to KCl than to hU-II (effective concentration causing 50% of maximal response [EC(50)]: -8.17 ± 0.28 vs -6.98 ± 0.01 log M, p < 0.001) and 19.5-fold that to U46619 (EC(50): -8.17 ± 0.28 vs -6.88 ± 0.08 log M, p < 0.001). Pretreatment of IMA with plasma concentrations of amlodipine (-6.6 log M) significantly depressed subsequent contraction to KCl (from 20.8 ± 2.5 mN to 7.6 ± 3.0 mN, p = 0.004) and hU-II (from 14.1 ± 4.2 mN to 3.8 ± 2.0 mN, p = 0.026), but did not significantly affect the contraction to U46619.
We conclude that in human IMA amlodipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Thus, use of amlodipine in CABG patients is favored in treating and preventing graft spasm.
A simple and validated liquid chromatographic–mass spectrometric method (LC-MS) for amlodipine in human plasma was quantifi ed using LC-MS (ESI). Chromatography was performed on a C<sub>18</sub> analytical column, the mobile phase used was Acetonitrile-10mM Ammonium acetate in the ratio of 90:10%v/v and the retention times were 0.829 and 1.281 min for azithromycin (Internal standard) and amlodipine respectively. The ionization was optimized using ESI (+) and enhanced selectivity was achieved. The method is validated as per FDA guidelines. The analyte was shown to be stable over the timescale of the whole procedure. The pharmacokinetic parameters such as peak plasma concentration (C<sub>max</sub>), Time to peak Concentration (t<sub>max</sub>), Area under the plasma concentration-time curve (AUC<sub>0-t</sub> & AUC<sub>0-∞</sub>), elimination rate constant (K<sub>eli</sub>), Elimination half-life (t<sub>½</sub>) were calculated. Log transferred values were compared by Analysis ofVariance (ANOVA) followed by classical 90% confidence interval for C<sub>max</sub> AUC0-t.and AUC<sub>0-∞</sub> and was found to be within the range. These results indicated that the Test and Reference formulation is bioequivalent.
The potential use of calcium antagonists in the treatment of hypertension and ischemic heart disease in elderly patients creates a requirement for pharmacokinetic information that is specific for that age group. This study describes the pharmacokinetics of amlodipine after single oral doses of 5 mg in 16 elderly subjects, mean age 72 years, age range 65-85 years. The principal findings were that the mean elimination half-life was 48 h and that peak plasma drug concentrations were not observed until 7 h after dosing. In comparison with data obtained from a group of young subjects, mean age 26 years, there were significant differences in pharmacokinetics. The terminal elimination half-life of 48 h in the elderly was significantly longer than that of 35 h in the young subjects and there was a correspondingly greater area under the curve in the elderly, by approximately 50%. These findings are consistent with an age-related reduction in drug clearance.
The pharmacokinetics of amlodipine was studied in 27 subjects with renal function ranging from normal to dialysis-dependent. Amlodipine (as a single 5-mg capsule) was administered once daily for 14 days and its plasma concentrations were measured by gas chromatography during and after treatment. Renal impairment had little or no effect on the pharmacokinetics of amlodipine. The elimination half-life was of the order of 50 h, similar to previously observed values, and did not vary with differences in renal function. Steady-state predose concentrations were observed after the ninth dose. Accumulation of amlodipine to steady-state levels was not significantly different from that expected on theoretical grounds and did not significantly change with renal function. These results suggest that once-daily administration of amlodipine is suitable for all degrees of renal function and that dosage adjustment is not necessary in renal impairment.
The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged.
The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value.
Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance. The combined use of calcium antagonists and β-adrenoceptor antagonists may be hazardous because of the additive negative inotropic and chronotropic effects of these classes of compounds.
The acute and long-term hypotensive effects of low doses of nifedipine, and the correlation between the fall in the blood pressure (BP) and the plasma nifedipine concentration, were investigated in patients with essential hypertension. The oral administration of nifedipine 5 mg rapidly decreased BP from 163 +/- 22/101 +/- 10 to 127 +/- 12/82 +/- 9 mmHg (mean +/- SD; p less than 0.001), and increased heart rate from 72 +/- 8 to 76 +/- 6 beats/min (p less than 0.05), plasma renin activity rose from 1.2 +/- 0.6 to 1.4 +/- 0.8 ng/ml/h (p less than 0.05), and plasma nifedipine concentration was 75.6 +/- 22.0 ng/ml 30 min after administration (n = 7). The nifedipine concentration was significantly correlated both with the fall in BP (r = 0.410, p less than 0.02, n = 31) and the rise in the heart rate (r = 0.412, p less than 0.02, n = 31). Treatment with nifedipine 5 mg t.d.s. alone or in combination either with propranolol 10 mg t.d.s., or thiazide 1 tablet daily, or propranolol and thiazide, controlled BP in 36 patients during the 22 week study period. During the long-term nifedipine therapy, the plasma nifedipine level was significantly correlated with the fall in systolic (r = 0.577, p less than 0.01, n = 20) and diastolic (r = 0.595, p less than 0.01, n = 20) BP. It was concluded that the plasma nifedipine concentration could be correlated with the fall in BP, and that low doses of nifedipine, either as monotherapy or in combination, were effective in the acute and long-term treatment of patients with essential hypertension.