Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diltiazem (DT), a potent slow channel blocker, has been found to be clinically useful for treatment of coronary vasospasm, hypertension, and tachyarrhythmias. Nevertheless, only limited data are available on the hemodynamic and electrophysiologic effects of DT. Atrial, His, right ventricular apex, aortic, and Swan-Ganz thermodilution catheters were used in 10 anesthetized dogs, and recordings were made during control period and after each of four infusions of DT (0.01, 0.02, 0.04, and 0.08 mg/kg/min) each lasting 30 minutes. Results showed that heart rate, pulmonary capillary wedge pressure, stroke volume, and HV interval did not change significantly. However, two dogs had second-degree AV block and a third had escape junctional rhythm during DT 0.08 mg/kg/min. Mean aortic pressure (AP), corrected sinus node (SN) recovery time, and systemic vascular resistance (SVR) were significantly reduced, whereas AH interval, AV functional and effective refractory periods were prolonged by DT. AV nodal refractory periods and AH interval were the only parameters significantly affected at DT 0.02 mg/kg/min. SN recovery time was significantly shortened at DT 0.04 mg/kg/min, whereas AP and SVR tell significantly at DT 0.08 mg/kg/min. DT had significant electrophysiologic effects at low doses, whereas hemodynamics were significantly altered only at high doses. Further, major electrophysiologic effects were on the AV node with lesser effects on SN function. Therefore, at a dose when antiarrhythmic effects are evident, the safety of diltiazem is corroborated by lack of adverse hemodynamic effects.
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PMID:Electrophysiologic and hemodynamic actions of diltiazem: disparate temporal effects shown by experimental dose-response studies. 721 68

Recently it has been recognized that coronary vasospasm plays a significant role in precipitating myocardial ischemic pain in a significant minority of individuals with coronary atherosclerosis (approximately 27-35% of patients with angina pectoris at rest). In these individuals normal physiological vasoconstrictor stimuli appear to trigger a spasm of the large epicardial coronary vessels; evidence suggests that it may be caused by the release of increased amounts of calcium from augmented sarcolemmal storage sites. The calcium entry blockers are remarkably effective in preventing coronary spasm by reducing intracellular calcium, but by different mechanisms. Verapamil appears to reduce intracellular and, more specifically, sarcolemmal calcium stores directly. Diltiazem appears to reduce intracellular calcium by stimulating the sarcolemmal sodium-potassium pump and reducing intracellular sodium, and by this mechanism. potentiating passive sodium-calcium exchange. The effects of the calcium entry blockers on myocardial contractility, cardiac pacemaker and conduction tissue, and regional vascular smooth muscle are also different. This makes some of these agents more suitable than others for therapy of other clinical problems such as chronic stable angina pectoris, supraventricular tachycardia, hypertension, hypertropic cardiomyopathy, and protection of the ischemic myocardium during cardiac surgery.
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PMID:Clinical use of calcium entry blockers. 730 98

Vascular selective calcium antagonists (CAs) show an improved tolerance and a reduced incidence of adverse cardiac effects, especially in treatment of hypertension. The effects of seven well-known CAs on contractions of single isolated rat myocytes were studied and compared with their effects on stimulated 45Ca2+ uptake of rat aortic smooth muscle cells (A7r5 cell line). In the latter test system, the order of potency to inhibit 45Ca2+ uptake was as follows (pIC25, -logM): isradipine (9.2), felodipine (8.7), nifedipine (8.5), nisoldipine (8.5), nicardipine (8.1), verapamil (6.7), and diltiazem (6.5). The potencies for inhibition of ventricular myocyte contraction at 0.5 Hz were (pIC25): isradipine (6.9), nisoldipine (6.7), felodipine (6.6), nicardipine (6.5), nifedipine (6.5), verapamil (5.3), and diltiazem (4.8). Thus, the order of vascular selectivity (i.e., the ratios of IC25 cardiocytes/IC25 A7r5 cells) was: isradipine (184), felodipine (128), nifedipine (107), nisoldipine (63), diltiazem (48), nicardipine (43), and verapamil (23). When ventricular cells were stimulated at 1 Hz, the order of selectivity was changed: Diltiazem was the least selective. Verapamil, diltiazem, and felodipine showed a highly frequency-dependent negative inotropic effect, whereas the effects of the other dihydropyridines were less affected by the frequency of stimulation. CAs show different degrees of vascular selectivity and different frequency-dependent profiles, and vascular selectivities are also dependent on experimental conditions. Selectivity is thus not necessarily related to chemical classes of drugs (e.g., dihydropyridines) or to different binding sites at the channel protein but could instead be due to varying dissociation rates from the respective binding sites at the channel in its different voltage-dependent states.
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PMID:Vascular selectivity of seven prototype calcium antagonists: a study at the single cell level. 750 31

A double-blind, three-period, crossover trial used 24-hour ambulatory blood pressure monitoring to compare diltiazem controlled diffusion (CD) 300 mg with placebo. Patients with hypertension (N = 43) were randomly assigned to one of four crossover treatment sequences of three treatment periods each. Ambulatory blood pressure was obtained at the end of each 4-week treatment period. Diltiazem CD significantly decreased diastolic and systolic blood pressure at bihourly ambulatory blood pressure evaluations (p < 0.05, all). However, when all ambulatory blood pressure monitoring data were combined into one statistical model, blood pressure reductions were quantifiably similar to those in the overall bihourly analysis, but with a consistent 24-hour antihypertensive effect for both diastolic and systolic blood pressure relative to that with placebo (i.e., parallel blood pressure profiles) and with increased precision. Mean +/- SE changes in diastolic and systolic blood pressure across the 24-hour dosing interval were -5.6 +/- 0.4 mm Hg and -7.6 +/- 0.5 mm Hg, respectively (p < 0.001, both). Therefore, by using a crossover design with ambulatory blood pressure monitoring, we showed diltiazem CD to reduce blood pressure consistently throughout a 24-hour dosing interval in comparison with placebo in patients with hypertension.
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PMID:Three-period crossover trial with ambulatory blood pressure monitoring for evaluating antihypertensive therapy. 757 95

Diltiazem (DTZ) is a calcium channel blocker widely used in the treatment of angina and hypertension. DTZ undergoes extensive metabolism yielding several metabolites, some of which are active like N-desmethyldiltiazem (MA), desacetyldiltiazem (M1) and N-desmethyl,desacetyldiltiazem (M2). Due to the nature of its biotransformation, several organs should have the ability to metabolize DTZ, however it is still assumed that the liver is the only organ implicated in its elimination. In this study, the fate of DTZ, MA and M1 was assessed in several organs that could contribute to their biotransformation. To this purpose, DTZ (48.2 microM) was incubated in the 10,000 x g supernatant of homogenates of rabbit tissues for 60 min at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolites were assayed by HPLC. The elimination rate constant of DTZ in 10,000 x g supernatants varied between the organs: liver 334 +/- 45, proximal small intestine 69 +/- 11, distal small intestine 25 +/- 3, lungs 15 +/- 6 and kidneys 8 +/- 6 (10(-4) min-1). The metabolism of DTZ in the liver generated large amounts of MA but no M1, and in the small intestine, modest amounts of both metabolites. When MA (50.0 microM) or M1 (53.7 microM) were incubated in liver homogenates, the estimated elimination rate constant were 166 +/- 23 and 468 +/- 53 (10(-4) min-1), respectively. The rate of degradation of the metabolites in the small intestine was much slower.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism of diltiazem in hepatic and extrahepatic tissues of rabbits: in vitro studies. 759

Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained-release formulation (Mono-Tildiem LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained-release formulation. The influence of these factors was investigated over two different open, randomized, cross-over studies in 12 healthy volunteers. Although a significant decrease in Tmax and an increase in Cmax occurred when diltiazem sustained-release was administered with food intake, AUC0-48, and therefore the fraction absorbed, were not modified either by concurrent food intake or by different times of administration. The minor modifications of pharmacokinetic parameters of diltiazem sustained release observed were unlikely to induce any clinical consequence.
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PMID:Pharmacokinetic and bioavailability of diltiazem sustained-release: influence of food and time of administration. 762 34

Diltiazem is a calcium antagonist used in angina pectoris and hypertension. There is little information concerning the slow-release (SR) formulation in the literature. The pharmacokinetics of diltiazem SR (120 mg) have been assessed over a 36h period in healthy volunteers after single- (SD) and multiple-dose (MD) administrations. Cmax, AUC0-36, and AUC0-infinity were significantly increased at steady state compared to the extrapolated SD values, suggesting accumulation of the drug. Renal and cardiovascular parameters have also been assessed at intervals of 3-6h during baseline (B) and following single and multiple doses of diltiazem SR. Diuresis over a 24 h period was increased, but not significantly, by the administration of diltiazem SR i.e. 1782 ml (MD) and 1915 ml (SD), versus 1626 ml (B). Natriuresis and creatinine clearance were slightly decreased by diltiazem SR, compared to B values; this might be due to the relatively short period over which steady state was maintained (five days) and the effects of norepinephrine and angiotensine II on renal vasculature and the pharmacokinetics of diltiazem SR. No increase in the systolic blood pressure occurred after the administration of diltiazem SR; diastolic blood pressure and PR interval were decreased and increased respectively by diltiazem SR. These results do not appear to be clinically significant. Finally, no relation was found between the pharmacokinetics and pharmacodynamics of diltiazem. This may be attributed to the absence of clinically significant effects in healthy volunteers, the presence of active metabolites, the pharmacokinetics of the SR formulation and/or the accumulation of the drug at steady state.
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PMID:Pharmacokinetics and pharmacodynamics of a slow-release formulation of diltiazem after the administration of a single and repeated doses to healthy volunteers. 788 Sep 83

The safety and efficacy of an extended-release form of diltiazem HCl (diltiazem XR) in patients 55 years or older with mild-to-moderate essential hypertension were examined in a multi-center, double-blind, randomized, placebo-controlled, parallel-group study involving 350 patients with supine diastolic blood pressure (DBP) between 95 mm Hg and 114 mm Hg. Patients were randomized to a once-daily dose of diltiazem XR (240 mg) or placebo; 261 patients received diltiazem XR and 89 received placebo. After 4 weeks, the dose was doubled (to 480 mg) in patients whose supine DBP was > 90 mm Hg, and treatment was continued for another 4 weeks. Diltiazem XR consistently reduced blood pressure (BP) in the study population. At end-point, the mean reduction in supine DBP was 8.65 mm Hg in the diltiazem XR group and 2.75 mm Hg in the placebo group (P < 0.0001). Subgroup analysis confirmed the efficacy of diltiazem XR in men, women, patients between the ages of 55 and 64 years, patients 65 years or older, and non-black patients. Other BP values (supine systolic, standing diastolic, and standing systolic) also were significantly reduced in patients treated with diltiazem XR. BP reduction (supine DBP < or = 90 mm Hg or by > or = 10 mm Hg) was achieved in 58% of patients receiving diltiazem XR compared with 27% of patients receiving placebo. Decreases in apical heart rate were minimal and similar in both groups. No significant differences were noted in adverse events in the diltiazem XR and placebo groups: 36.4% of patients in the diltiazem XR group and 37.1% in the placebo group had no adverse experiences, and 63.6% and 62.9%, respectively, had at least one adverse event. Physical examination findings and laboratory values were clinically unremarkable and comparable in the diltiazem XR and placebo groups. Diltiazem XR given once daily at doses of 240 mg and 480 mg was safe and effective in lowering blood pressure in mature and elderly patients with mild-to-moderate hypertension.
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PMID:Blood pressure control with diltiazem XR, a novel extended-release formulation of diltiazem HCl, in mature and elderly hypertensive patients. 806 17

The effects of diltiazem, Ca ion channel blocker, on arterial blood gases were evaluated in 50 patients (G-I: 24 patients undergoing abdominal surgery, G-II: 26 patients undergoing non-abdominal surgery). Diltiazem hydrochloride was administered to prevent intraoperative hypertension as a bolus (5 mg) followed by a continuous infusion (5-10 micrograms.kg-1.min-1). Arterial blood gases were analyzed just before, as well as 5 and 15 min after the administration of diltiazem. In G-I, arterial blood oxygen tension decreased significantly (P < 0.001) from 210.8 +/- 42.4 to 197.7 +/- 50.2 mmHg 5 min after infusion, and to 193.2 +/- 53.4 mmHg 15 min after; while there was no significant difference in G-II. Diltiazem infusion may deteriorate oxygenation in patients undergoing abdominal surgery, and therefore oxygenation should be carefully monitored.
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PMID:[Effects of diltiazem hydrochloride on blood gases]. 807 48

Today calcium antagonists (Ca-antagonists) are widely used agents in the management of various diseases of the circulatory system. More than 20 years ago the Ca-antagonists of the so-called 1st generation (Verapamil, Diltiazem, Nifedipine) were introduced for treatment of angina pectoris and later of essential hypertension. In the last decade an increasing number of agents structurally related to dihydropyridines were developed for the treatment of hypertension and/or coronary heart disease or cerebral disorders; the main target was to reduce side effects and to guarantee once or at least twice daily administration. Therefore the Ca-antagonists of the so-called 2nd generation (e.g. Amlodipine, Felodipine, Isradipine, Nitrendipine, Nicardipine, Nimodipine, Nisoldipine) tend to longer elimination-half-lives; Amlodipin is an exception with an elimination-half-life of 30 hours on the average. Apart from elimination rates, however, the biopharmaceutical and pharmacokinetic characteristics of all Ca-antagonists are similar: they are highly cleared drugs and are relatively highly protein bound. As they are subject to significant hepatic first-pass-metabolism old age and hepatic disease will increase their plasma-concentrations. Renal impairment affects little their pharmacokinetics since the fraction eliminated unchanged by the kidneys is small. For most agents, plasma-concentration-response relationships have been described. With exception of nicardipine a linear pharmacokinetic in all Ca-antagonists was demonstrated. Drugs and food affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. With regard to the acute pharmacodynamic effects the Ca-antagonists show similar qualitative effects, though there are quantitative differences. Orally administered dihydropyridine-derivatives induce acute hypotensive effects, whereas the other compounds show clinically relevant hypotensive effects only when administered chronically per os or less pronounced when given as intravenous infusion.
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PMID:[Principles of the pharmacokinetics and pharmacodynamics of calcium antagonists]. 813 31


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