[Calcium channel blockers scare].
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Antihypertensive Agents↗
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"Accidental ingestion of sustained release calcium channel blockers in children".
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Calcium Channel Blockers↗
Safety of calcium channel blockers in cardiovascular disease.
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Calcium Channel Blockers↗
Calcium-channel blockers: effects on cerebral blood flow and potential uses for acute stroke.
Current research suggests that ischemia induces a massive shift of calcium from the extracellular fluid to the intracellular space. This is associated with a precipitous decrease in the concentration of adenosine triphosphate, the energy source required to drive the ion pumps of the calcium channels that maintain intracellular calcium homeostasis. The result is a further increase in free intracellular calcium, leading to calcium overload and thus to cell catabolism and cell necrosis. Treatment with calcium-channel blockers may therefore offer a new approach to arresting and, possibly, preventing destruction of cerebral tissue in stroke victims. Animal studies using nimodipine, a calcium antagonist with marked vasodilator effects, have shown that this agent prevents both spasm of the isolated rabbit basilar artery, produced either by depolarization or by receptor stimulation, and postischemic impairment of cerebral blood flow (CBF), which may be a major contributor to neuronal damage. In patients with acute ischemic stroke, intravenous nimodipine therapy caused a dose-dependent increase in hemispheric CBF. These data prompted us to conduct a prospective, single-blind, randomized trial of 60 patients to determine whether nimodipine treatment would reduce neurologic deficits in patients with acute ischemic stroke. The 29 treated patients were given standard dextran therapy supplemented with daily 120 mg doses of nimodipine, and the 31 control subjects received dextran therapy alone. Mathew scale neurologic scores indicated decreased consciousness and impaired cerebral function in both treated and control groups; however, cerebral deficits were significantly smaller in patients who received nimodipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Does combination therapy with a calcium channel blocker and an ACE inhibitor have additive effects on blood pressure reduction?
Reports in the medical literature have suggested that the effects on blood pressure (BP) of calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors are additive. Most reports have provided neither a definition of 'additive' nor the necessary information to determine whether the effects are additive. In this review of the medical literature, the effects of combination therapy were defined as additive if the sum of the mean reductions in BP following monotherapy with a CCB and an ACE inhibitor was not significantly different from the mean reduction in BP of combination therapy. The review generally showed that combination therapy is more effective than treatment with either monotherapy alone, based on mean decreases in either diastolic or systolic BP. The studies provided no clear evidence that the effects of combination therapy were either additive or less than additive.
Adult↗
Calcium channel blockers: association with myocardial infarction, mortality, and cancer.
The purpose of this study was to review the results of trials assessing the association between the use of calcium channel blockers (CCBs) and mortality, myocardial infarction (MI), and cancer. Possible mechanisms of such relationships are discussed and recommendations regarding the use of CCBs made. Since 1995, 10 controversial studies have been published that associate the use of CCBs with an increased risk of mortality, MI, and cancer; these findings have caused widespread anxiety and frustration among patients and physicians. For health care professionals to properly advise patients, the facts surrounding this controversy should be reviewed. To do this, we reviewed and assessed English-language clinical studies, abstracts, editorials, and review articles pertaining to the use of CCBs and mortality, MI, and cancer in humans. The designs of ongoing prospective, randomized studies are discussed. Based on current published studies, the US Food and Drug Administration has agreed to a label warning against off-label use of short-acting nifedipine in patients with hypertension, acute MI, or nonvasospastic unstable angina. Practitioners should exercise caution when prescribing CCBs, especially to high-risk patients (e.g., those with congestive heart failure or clinical or subclinical coronary artery disease). When possible, long-acting CCBs should be used.
Animals↗
Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.
Animals↗
Design and discovery of RWJ 22108--a novel bronchoselective calcium channel blocker.
A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.
Animals↗
Differential and interactive effects of calcium channel blockers and cholesterol content of the diet on jejunal uptake of lipids in rabbits.
The present study was undertaken to determine the effects of two classes of calcium channel blockers (CCB), nisoldipine (N) and verapamil (V), on the jejunal uptake of lipids in rabbits. The uptake of cholesterol and long-chain fatty acids into rabbit jejunum was examined after 6 and 36 min of exposure to N or V in vitro ("acute" studies), and after 3-wk feeding of N or V ("chronic" studies). Animals were fed either a low (0.08%) cholesterol diet (LCD) or a high (2.8%) cholesterol diet (HCD), with or without N or V added. Acute in vitro exposure of the jejunum to N or V did not affect the uptake of cholesterol or palmitic acid in rabbits fed LCD or HCD. The effect of N or V feeding depended upon the cholesterol content of the diet; adding N or V to LCD increased cholesterol uptake while adding N or V to HCD enhanced or lowered cholesterol uptake, respectively. Both N and V increased the uptake of stearic acid in LCD. N in HCD had no effect on fatty acid uptake, whereas V lowered the uptake of stearic and linoleic acids and increased the uptake of oleic acid. These changes in lipid uptake were not due to variation in the animals' food intake, body weight gain, or intestinal mucosal surface area. The chronic administration of N or V results in an intestinal adaptative process that alters the jejunal uptake of lipids, the direction of which is influenced by the class of CCB, and by the cholesterol content of the diet. (ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention.
We investigated whether protection from coronary heart disease (CHD) and stroke conferred by angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) in hypertensive or high-risk patients may be explained by the specific drug regimen. We extracted summary statistics regarding CHD and stroke from 28 outcome trials that compared either ACEIs or CCBs with diuretics, beta-blockers, or placebo for a total of 179,122 patients, 9509 incident cases of CHD, and 5971 cases of stroke. CHD included myocardial infarction and coronary death. In placebo-controlled trials, ACEIs decreased the risk of CHD (P<0.001), and CCBs reduced stroke incidence (P<0.001). There were no significant differences in CHD risk between regimens based on diuretics/beta-blockers and regimens based on ACEIs (P=0.46) or CCBs (P=0.52). The risk of stroke was reduced by CCBs (P=0.041) but not by ACEIs (P=0.15) compared with diuretics/beta-blockers. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by metaregression. Examined covariates were the reduction in systolic blood pressure (BP), drug treatment (ACEIs versus CCBs), their interaction term, sex, age at randomization, year of publication, and duration of treatment. Prevention of CHD was explained by systolic BP reduction (P<0.001) and use of ACEIs (P=0.028), whereas prevention of stroke was explained by systolic BP reduction (P=0.001) and use of CCBs (P=0.042). These findings confirm that BP lowering is fundamental for prevention of CHD and stroke. However, over and beyond BP reduction, ACEIs appear superior to CCBs for prevention of CHD, whereas CCBs appear superior to ACEIs for prevention of stroke.
Angiotensin-Converting Enzyme Inhibitors↗
Calcium-channel blocker withdrawal in a pregnant woman.
We present a case report of a woman for whom a topical mucosal ulcer drug was prescribed and the pharmacist erroneously dispensed a calcium channel blocker (CCB), resulting in toxicities from the drug and withdrawal symptoms when attempts were made to stop the CCB. The pharmacology and toxicology of CCBs are discussed, particularly in relation to the adverse experiences of the case.
Adult↗
Effect of voltage-dependent calcium channel blockers on ethanol-induced beta-endorphin release from hypothalamic neurons in primary cultures.
The voltage-dependent calcium channel (VDCC) has been shown to mediate calcium entry into neurons that regulates neurotransmission in many neuronal cells. Four major types of VDCCs (three high-voltage-activated L-, N-, and P-types and one low-voltage-activated T-type) have been identified in neurons. Involvement of the VDCC in ethanol-stimulated beta-endorphin (beta-EP) release from hypothalamic neurons has not been studied. In the present study, the role of VDCC on basal and ethanol-induced beta-EP release was determined by using rat fetal hypothalamic cells in primary cultures. Treatments with a 50 mM dose of ethanol for 3 hr increased immunoreactive beta-EP (IR-beta-EP) release from hypothalamic cells maintained in cultures for 9 days. Ethanol-induced IR-beta-EP release was inhibited by a P/Q-type channel blocker omega-agatoxin TK (0.1-1 microM), an N-type channel blocker omega-conotoxin (0.1-1 microM), an L-type blocker nifedipine (1-10 microM), and a T-type blocker flunarizine (1-10 microM). The minimal effective doses of these blockers that blocked the ethanol response produced no significant effects on basal release of IR-beta-EP; neither did these doses of the blockers produce any significant effects on cell viability. These results suggest that ethanol-stimulated IR-beta-EP release is regulated by extracellular calcium involving P-, N-, L- and T-type channels.
Animals↗
Long-term treatment of hypertension with the calcium channel blocker diltiazem.
A group of 48 patients with essential mild to moderate hypertension were treated with the calcium-channel blocker diltiazem (90-270 mg/day) for one year. Adequate blood pressure control was achieved in all patients. No tolerance developed during the one-year treatment period. The drug is almost free from side effects. Very few patients develop fluid retention, which can be controlled by adding a diuretic.
Diltiazem↗
Effects of the calcium channel blocker nifedipine on epiphyseal growth plate and bone turnover: a study in rabbit.
The potential effects of a calcium channel blocker (nifedipine) on epiphyseal growth plate and bone remodeling have been investigated in growing rabbits. The treated group received 6 mg/kg/day nifedipine twice daily by gavage for 10 weeks. An untreated group was used as control; with this dose, neither toxic effects nor decrease in the body weight have been observed. No modifications of blood phosphocalcic parameters have been found. In the treated group there is a significant lower cancellous bone volume, lower osteogenesis, shorter labeled perimeters, and lower mineral apposition rate than in the control group. Epiphyseal growth plate thickness is lower than in the untreated animals and considerable morphological changes are observed in the growth zone compared with the control group. A decrease in the growth of humerus length was found. In conclusion, nifedipine affects bone physiology, especially with consequences on bone growth. These effects appear to be quantitatively important, and there is the possibility of bone side effects on therapeutic use in humans, especially in young subjects.
Animals↗
Effect of gallopamil, a calcium channel blocker, on carbachol- and histamine-induced bronchoconstriction in sheep.
We compared the in vivo effectiveness of the calcium channel blockers, gallopamil and verapamil, in inhibiting carbachol- and histamine-induced bronchoconstriction in conscious sheep. In 13 sheep, specific lung resistance (SRL) was measured before and after aerosol challenge with histamine (50 breaths; 5% solution) and carbachol (10 breaths; 2.5% solution), without and with pretreatment with intravenous and aerosolized gallopamil and verapamil. Histamine increased mean SRL by 213%. Intravenous (20 micrograms/kg) and aerosolized (5 mg) gallopamil markedly inhibited the histamine-induced bronchoconstriction. Mean SRL increased by 19% and 23%, respectively, whereas 2.5 mg of aerosolized gallopamil partly inhibited the histamine-induced response with SRL increasing by 115% (p less than 0.05). Carbachol increased mean SRL by 380%. Pretreatment with 2.5 mg of aerosolized gallopamil had no effect on carbachol-induced bronchoconstriction, whereas intravenous and 5 mg of aerosolized gallopamil partly attenuated the carbachol response; mean SRL increased by 204% and 177%, respectively (p less than 0.05). Intravenous (150 micrograms/kg) and aerosolized (10 mg and 20 mg) verapamil did not prevent either histamine- or carbachol-induced bronchoconstriction. These results indicate that gallopamil (parenteral and aerosol) attenuates carbachol- and histamine-induced bronchoconstriction, is more potent than verapamil, and may be of therapeutic potential.
Aerosols↗
Adverse effect of the calcium channel blocker nitrendipine on nephrosclerosis in rats with renovascular hypertension.
The effect of a 6-week treatment with the calcium channel blocker nitrendipine or the angiotensin converting enzyme inhibitor enalapril on blood pressure, albuminuria, renal hemodynamics, and morphology of the nonclipped kidney was studied in rats with two-kidney, one clip renovascular hypertension. Six weeks after clipping of one renal artery, hypertensive rats (178 +/- 4 mm Hg) were randomly assigned to three groups: untreated hypertensive controls (n = 8), enalapril-treated (n = 8), or nitrendipine-treated (n = 10). Sham-operated rats served as normotensive controls (128 +/- 3 mm Hg, n = 8). After 6 weeks of treatment, renal hemodynamics (glomerular filtration rate and renal plasma flow) were measured in the anesthetized rats. Renal tissue was obtained for determination of glomerular size and sclerosis. Enalapril but not nitrendipine reduced blood pressure significantly. After 6 weeks of therapy, glomerular filtration rate was not different among the studied groups. Renal plasma flow increased, but albumin excretion and glomerulosclerosis did not change after enalapril treatment. In contrast, in the nitrendipine-treated group albuminuria increased from 12.8 +/- 2 progressively to 163 +/- 55 compared with 19.2 +/- 9 mg/24 hr in the hypertensive controls. Furthermore, glomerulosclerosis index was significantly increased in the nitrendipine-treated group compared with the hypertensive controls (0.38 +/- 0.1 versus 0.13 +/- 0.04). In addition, glomerular size was higher in the nitrendipine-treated group (14.9 +/- 0.17 10(-3) mm2) but lower in the enalapril-treated group (11.5 +/- 0.15 10(-3) mm2) compared with the hypertensive controls (12.1 +/- 0.17 10(-3) mm2).(ABSTRACT TRUNCATED AT 250 WORDS)
Albuminuria↗
[Effect of the calcium channel blocker nicardipine on intraocular pressure and aqueous humor dynamics in rabbit].
The effects of nicardipine hydrochloride (NH), a calcium channel blocker, on the intraocular pressure (IOP) and aqueous humor dynamics were studied in the rabbit eye. Thirty micrograms/kg of NH administered intravenously by bolus injection into an ear vein significantly lowered IOP for 5 to 30 minutes. But topical administration of NH significantly increased IOP, as compared with the fellow control eye at 15 and 30 minutes. This increased IOP was a dose-dependent response; the maximum effect was 4.3 +/- 0.6 mmHg at 15 minutes after administration of 0.1%NH. Severe hyperemia was observed at the limbus for 3 hours after topical administration. The aqueous flow rate after topical application of 0.1%NH showed no significant difference between treated and fellow control eye. However, the coefficient of aqueous outflow after topical application of 0.1%NH was significantly decreased (0.08 +/- 0.01 microliters/min/mmHg: p < 0.05) as compared with fellow control eye (0.13 +/- 0.02 microliters/min/mmHg). The penetration level of 0.1%NH into the aqueous humor of the rabbit eye was 0.22 +/- 0.13 micrograms/ml, 30 minutes after topical administration. Systemic NH decreased IOP, but topical NH increased IOP by increasing resistance of aqueous outflow.
Animals↗
[The effect of the calcium channel blockers cinnarizine and flunarizine on the duration of hexobarbital-induced sleep i rats].
The effect of the calcium channel blockers cinnarizine (20 mg/kg) and flunarizine (10 mg/kg) on hexobarbital sleeping time in rats has been studied. We have found that cinnarizine when applied intraperitoneally once 1 h or 4 h before hexobarbital and repeatedly for 5 days once daily prolongs sleeping time significantly. When cinnarizine has been introduced simultaneously with phenobarbital (60 mg/kg) for 5 days once daily the sleeping time that was expected to be shortened by phenobarbital only has been obtained to return to control values. Flunarizine has not been found to affect sleeping time significantly either alone or in the presence of phenobarbital. Latencies have not been altered by any of both agents.
Animals↗