Massive verapamil overdose complicated by noncardiogenic pulmonary edema

We describe two cases of pulmonary edema, bradycardia, and hypotension associated with massive verapamil overdose. A noncardiogenic etiology of the pulmonary edema was indicated in one patient by normal thermodilution cardiac output and pulmonary artery occlusion pressure, and in the other patient by a normal echocardiogram. We hypothesize that calcium channel blocker overdose predisposes patients to develop pulmonary edema.     

Fatal intoxication with amlodipine

Although poisoning with calcium channel blocking agents is frequent, to our knowledge no cases involving amlodipine have been published. We describe here a case of amlodipine intoxication, in which protracted hypotension did not respond to vasopressor therapy alone. After the addition of continuous calcium chloride and glucagon infusion, blood pressure was restored and vasopressor therapy could be tapered off substantially. When calcium and glucagon were interrupted because of severe hypercalcemia and hyperglycemia, the patient developed irreversible hypotension and died. Either glucagon or calcium or both, and to some extent vasopressors, seem to have constituted effective treatment of hypotension in this case.     

Paediatric rheumatology: clinical practice review. Physiotherapy and occupational therapy for juvenile chronic arthritis: custom and practice in five centres in the UK, USA and Canada

Calcium channel blockers can block calcium signals that trigger cell differentiation and apoptosis, which are important mechanisms of cancer growth regulation. To ascertain whether calcium channel blocker use was associated with an increased risk of cancer, 750 hypertensive persons age > or = 71 years, with no history of cancer at baseline, were followed from 1988 through 1992. The patients were using either beta-blockers, angiotensin converting enzyme inhibitors or calcium channel blockers (verapamil, nifedipine, and diltiazem; mainly of the short-acting variety). Compared to beta-blockers (n = 424, 28 events), after adjusting for age, gender, race, smoking, body mass index, and number of hospital admissions not related with cancer, the relative risks of cancer (95% confidence interval) for angiotensin converting enzyme inhibitors (n = 124, 6 events) and calcium channel blockers (n = 202, 27 events) were 0.73 (0.30 to 1.78) and 2.02 (1.16 to 3.54), respectively. These findings indicate that calcium channel blocker therapy might increase the risk of cancer. New data are needed in patients using modern calcium channel blocker agents with more gradual absorption. This report should encourage further study of cancer outcomes in elderly patients who are vulnerable to cancer and who are receiving calcium channel blockers.     

Radiofrequency catheter ablation of multiple haemodynamically unstable ventricular tachycardias in a patient with surgically repaired tetralogy of Fallot

A 55-year-old man was admitted following an overdose of sustained-release verapamil (calcium channel blocker) and ordinary-release atenolol (beta-1 blocker). At admission, there was extreme bradycardia (20-25 beats min-1) and hypotension (systolic arterial pressure 40-50 mm Hg). To counteract the cardiovascular depression, prenalterol, dopamine, dobutamine, isoprenaline, adrenaline and noradrenaline were used. A satisfactory state was obtained with adrenaline, noradrenaline and dopamine infused at high rates. Cardiac output was then more than 101 min-1, with a very low total peripheral resistance. The infusion of the adrenergic agonists could be interrupted on day 3. Prolonged ventilator treatment was necessary but the patient recovered without sequelae. Treatment options for similar cases are outlined.     

Felodipine use in pregnancy. Report of three cases

BACKGROUND: Calcium channel blockers are effective agents for the management of chronic hypertension and are being used with increasing frequency. If their safety and efficacy during pregnancy can be documented, women can be counseled to continue their antihypertensive agent during pregnancy. To our knowledge, the use of felodipine, a calcium channel blocker of the dihydropyridine group, during pregnancy has not been described. CASES: We report three cases of felodipine use in pregnancy by women with chronic hypertension. CONCLUSION: In women with severe hypertension (diastolic blood pressure > 100 mm Hg) who require pharmacologic treatment of it during pregnancy, felodipine appears to be an acceptable option.     

Analysis of the electroencephalogram in growing calves by use of power spectrum and cross correlation

Electromechanical dissociation (EMD) occurred in a 20-year-old woman 48 hours after an overdose of atenolol, despite intensive treatment of the beta-blocker poisoning (gastric lavage, charcoal, glucagon, epinephrine, atropine, correction of electrolyte abnormalities, administration of fluids, cardiac pacing, and mechanical ventilation). Administration of calcium chloride during EMD repeatedly restored blood pressure. Therefore it may have a role to play in management of atenolol overdose.     

Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses' Health Study

BACKGROUND: In several observational studies, patients prescribed calcium channel blockers had higher risks of cardiovascular diseases and mortality than those prescribed other antihypertensive medications. We explored these associations in the Nurses' Health Study. METHODS AND RESULTS: A total of 14 617 women who reported hypertension and regular use of diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, or a combination in 1988 were included in the analyses. Cardiovascular events and deaths were ascertained through May 1, 1994. We documented 234 cases of myocardial infarction. Calcium channel blocker monodrug users had an age-adjusted relative risk (RR) of myocardial infarction of 2.36 (95% CI, 1.43 to 3.91) compared with those prescribed thiazide diuretics. Women prescribed calcium channel blockers had a higher prevalence of ischemic heart disease. After adjustment for these and other coronary risk factors, the RR was 1.64 (95% CI, 0.97 to 2.77). Comparing the use of any calcium channel blocker (monodrug and multidrug users) with that of any other antihypertensive agent, the adjusted RR was 1.42 (95% CI, 1.01 to 2.01). An association between calcium channel blocker use and myocardial infarction was apparent among women who had ever smoked cigarettes (covariate-adjusted RR, 1.81; 95% CI, 1.20 to 2.72) but not among never-smokers (RR, 0.94; 95% CI, 0.48 to 1.84). CONCLUSIONS: In analyses adjusted only for age, we found a significant elevation in RR of total myocardial infarction among women who used calcium channel blockers compared with those who did not. After adjustment for comorbidity and other covariates, the RR was reduced. Whether the remaining observed elevated risk is real, or a result of residual confounding by indication, or chance, or a combination of the above cannot be evaluated with certainty on the basis of these observational data.     

Alpha 1-blocker combination therapy for hypertension

Combination therapy is a cost-effective and rational approach to treatment of severe hypertension and of mild to moderate hypertension that is refractory to monotherapy. The method has several advantages, most notably improved tolerability and enhanced antihypertensive efficacy. Long-term prospective studies are needed to confirm that such agents as calcium channel blockers, ACE inhibitors, and alpha 1 blockers reduce end-organ damage more effectively than do older antihypertensive drugs. However, scientific evidence strongly suggests that reducing risk factors for end-organ damage reduces heart, brain, kidney, and large-artery injury. Alpha 1 blockers appear to be a particularly suitable choice for use in combination regimens. The only class of agents that should be avoided in combination with alpha 1 blockers is central alpha agonists; all other agents act in an additive or synergistic fashion. Unlike diuretics and beta blockers, alpha 1 blockers do not adversely affect serum lipid, glucose, or insulin levels. In fact, alpha 1 blockers may improve these measurements and also counteract the adverse effects of other antihypertensive agents on them. Alpha1-blocker therapy may bring about regression of LVH, and it does not have deleterious effects on disorders that often coexist with hypertension (e.g., gout, chronic obstructive lung disease, peripheral ischemia).     

Interactions of cyclosporin A and amlodipine: blood cyclosporin A levels, hypertension and kidney function

The introduction of cyclosporin A has led to improved survival of allografts in humans. However, the use of cyclosporin A is associated with an increased prevalence of hypertension in kidney transplant recipients. Renal vasoconstriction and enhancement of tubular reabsorption contribute to this hypertensive effect. Concomitant treatment with calcium channel blockers blocks or ameliorates most of these adverse effects. This paper reviews the short-term effects of the calcium channel blocker amlodipine on plasma levels of cyclosporin A and its interaction with blood pressure and kidney function.     

A potential role for glucagon in the treatment of drug-induced symptomatic bradycardia

Nine cases of symptomatic bradycardia are presented in which treatment with intravenous glucagon was administered when atropine failed to improve the patient's condition significantly. Although the cause often was not obvious at presentation, all nine subjects took oral medications that could have contributed to the development of symptomatic bradycardia. Eight of nine patients demonstrated clinical improvement 5 to 10 min after glucagon administration, which was consistent with its peak clinical action. Beta-blockers, calcium channel blockers, and digoxin were ultimately thought to have contributed to the majority of these presentations. This report suggests that glucagon may have a role in the treatment of symptomatic bradycardia, particularly in the presence of beta-adrenergic blockade and perhaps calcium channel blockade. Furthermore, the results in these cases suggest that future clinical trials should not be limited to drug-induced symptomatic bradycardia.     

Use of digoxin, diuretics, beta blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers in older patients in an academic hospital-based geriatrics practice

OBJECTIVE: To investigate the prevalence of and indications for digoxin use and the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension in an academic hospital-based geriatrics practice. DESIGN: A retrospective analysis of charts from 528 unselected older patients, seen from June 1995 through July 1996 at an academic hospital-based geriatrics practice, was performed to investigate the prevalence of digoxin use and indications for digoxin use, the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension. SETTING: An academic hospital-based, primary care geriatrics practice staffed by fellows in a geriatrics training program and full-time faculty geriatricians. PATIENTS: A total of 416 women and 112 men, mean age 81 +/- 8 years (range 58 to 101), were included in the study. MEASUREMENTS AND MAIN RESULTS: Ninety-two of the 528 patients (17%) were taking digoxin. Recorded indications for digoxin were atrial fibrillation with or without congestive heart failure (CHF) in 39% of patients, CHF with sinus rhythm and abnormal left ventricular ejection fraction (LVEF) in 18% of patients, a clinical assessment of CHF with sinus rhythm and no recorded measurement of LVEF in 20% of patients, paroxysmal atrial fibrillation in 14% of patients, and coronary artery disease (CAD) in 9% of patients. Of 121 patients with previous myocardial infarction, 23 (19%) were prescribed beta blockers, and 54 (45%) were taking calcium channel blockers. Of 173 patients with CAD, 41 (24%) were treated with beta blockers, and 79 (46%) were taking calcium channel blockers. LVEF was not recorded in the charts of 90 of 121 patients (74%) with prior myocardial infarction and of 125 of 173 patients (72%) with CAD. Of 480 older patients with hypertension, 154 (37%) were treated with diuretics, 55 (13%) were treated with beta blockers, 160 (38%) were treated with ACE inhibitors, and 197 (47%) were treated with calcium channel blockers. CONCLUSIONS: In 528 older patients seen in an academic hospital-based geriatrics practice, the prevalence of digoxin use was 19%. Appropriate indications for digoxin were documented clearly in the charts of 53 of 92 patients (57%). Calcium channel blockers were used more often than beta blockers in patients with previous myocardial infarction or CAD. Calcium channel blockers were the most frequently used antihypertensive drugs.     

The Bcl-xL and Bax-alpha control points: modulation of apoptosis induced by cancer chemotherapy and relation to TPCK-sensitive protease and caspase activation

Calcium channel blockers are used as neuroprotective agents, as glutamate antagonists. However, it has been found that calcium channel blockers may compromise neuronal survival after long-term exposure. To explore the mechanisms of the toxicity of calcium channel blockers on neurons, we studied the morphological characteristics and biochemical changes of cultured cortical neurons treated with verapamil, a calcium channel blocker. We now report that cerebral cortical cultures exposed to verapamil for 48 h undergo neuronal degeneration in both concentration-dependent and time-dependent fashion, possibly partially through the activation of apoptosis. On the other hand, it was found that Ginkgo biloba extract (EGb761) attenuated verapamil-induced neuronal injury, suggesting the possibility of using verapamil combined with EGb761 clinically. Furthermore, both B-50 immunoactivity (BIA) and the concentration of intracellular calcium in single neurons ([Ca2+]i) decreased after a 48-h exposure to verapamil, suggesting that the mechanisms of verapamil-induced degeneration may be associated with the disruption of intracellular calcium homeostasis and the inhibition of normal axonal elongation.     

Effects of a home-based intervention among patients with congestive heart failure discharged from acute hospital care

Day 9 rat embryos were exposed to 1,4-dihydropyridine calcium channel blockers; nifedipine (NIF), nicardipine (NIC) or nitrendipine (NIT), for 48 hr in the whole embryo culture system. There were dose-dependent growth retardation and abnormalities, predominantly in cardiovascular system. The three compounds exhibited very similar pattern of dysmorphogenic effects, but the potency of these compounds were quantitatively different. The incidences of embryos with the abnormalities were 100%, 100% and 85% following either exposure of NIF, NIC or NIT at concentration of 300, 8 and 15 microM, respectively. This study was to investigate whether these blocker-induced embryotoxicity was due to calcium channel blocking properties themselves in the embryos. Day 9 rat embryos were co-exposed to 1,4-dihydropyridine calcium channel agonist, Bay k 8644 (BAY) and each calcium channel blocker under the same culture condition. The retarded embryonic growth induced by 200 or 300 microM of NIF, 8 microM of NIC and 15 microM of NIT nearly of completely ameliorated when embryos were co-exposed with BAY at one-third or half concentration of each calcium channel blocker. Supplementation of BAY reduced the incidence of abnormalities by NIF-, NIC- and NIT-alone. These results suggested that one of mechanisms for embryotoxicity induced by calcium channel blocker was directly related to channel blocking property of the chemicals.     

Antihypertensive therapy and diabetic microvascular disease

Hypertension is commonly associated with diabetes and may represent either a manifestation or a cause of diabetic vascular injury. The following series of studies have explored the role of hypertension in accelerating diabetic microvascular injury. In addition, the role of various classes of antihypertensive agents in preventing or reversing diabetic vascular abnormalities in the presence and absence of systemic hypertension was assessed in both the experimental and clinical context. The induction of streptozotocin diabetes in SHR leads to accelerated development of nephropathy as assessed by both functional and structural parameters. ACE inhibitors but not dihydropyridine calcium channel blockers favourably influence the progression of experimental diabetic nephropathy even in the setting of a normal blood pressure. More recent studies have shown that the trophic changes in the mesenteric arteries from diabetic rats are also attenuated by ACE inhibition. Preliminary results from the Melbourne Diabetic Nephropathy Study Group suggest that the ACE inhibitor, perindopril, is more effective than the dihydropyridine calcium channel blocker, nifedipine, in retarding the rise in urinary albumin excretion in normotensive insulin and noninsulin dependent diabetic patients with microalbuminuria. In conclusion, ACE inhibitors appear to be the drugs of choice in prevention and treatment of diabetic renal disease and may also act as protective agents at other sites of vascular injury.     

Overview: biliary reconstruction after liver transplantation

Changes of intracellular calcium homeostasis in epithelial cell damage of renal tubules caused by cadmium and its relationship with the damage were studied in isolated tubular cells of rabbits. Results showed levels of free calcium (Ca++) in tubular cytoplasm increased significantly with the treatment of cadmium, and a series of cellular ultrastructure were damaged. A calcium channel blocker, phenothiazine, showed blocking and protecting effects on it. This suggested calcium overload played a very important role in kidney damage caused by cadmium.     

New developments in the use of anticonvulsants as mood stabilizers

There is increasing recognition that lithium is inadequate in the treatment of up to 50% of bipolar patients. In addition to subgroups that are nonresponsive from the outset, loss of efficacy (tolerance) and discontinuation-induced refractoriness have recently been observed. The anticonvulsants carbamazepine and valproate are effective alternative or adjunctive treatments, but tolerance can also occur during their long-term prophylactic use. New treatment algorithms for this loss of efficacy, including combination therapies, require further systematic study. Preliminary data suggesting that some patients with extremely rapid and chaotic mood fluctuations may respond to the L-type calcium channel blocker nimodipine are presented, and the theoretical implications discussed.     

PROTECT (Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial): a randomized, double-blind clinical trial of diltiazem versus atenolol in secondary prophylaxis post non-Q wave myocardial infarction

OBJECTIVE: To describe the rationale and design of the Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial (PROTECT). DESIGN: A multicentre, randomized, double-blind, parallel-group comparison of once daily beta-therapy versus heart rate lowering calcium channel blocker therapy, in the reduction of one-year nonfatal reinfarction and cardiovascular death (combined primary end-point) initiated 24 to 96 h post non-Q wave myocardial infarction. SETTING: One hundred and twenty hospitals across Canada. PATIENTS: Over 7500 women and men aged 21 years or older with enzyme-confirmed non-Q wave infarction and without significant left ventricular systolic dysfunction will be recruited over two years. INTERVENTIONS: Once daily beta-blocker therapy (oral atenolol, 50 to 200 mg) versus once daily calcium channel blocker therapy (oral diltiazem 120 to 360 mg) with follow-up for up to three years. CONCLUSIONS: The PROTECT will be the largest all-Canadian cardiovascular trial to date and will compare two commonly prescribed agents for secondary prophylaxis following non-Q wave infarction. The scientific question addressed by the PROTECT is of major public health importance and the results of the study will directly affect current clinical practice.     

Heart rate variability in patients with atrial fibrillation is related to vagal tone

A "reduced retina" preparation, consisting of the photoreceptor layer attached to the pigment epithelium in the eyecup, was used to study the pharmacology of the calcium channels controlling glutamate release by photoreceptors in Xenopus. Glutamate release was evoked either by dark adaptation or by superfusion with elevated (20 mM) potassium medium. Both darkness- and potassium-induced release were blocked by cadmium (200 microM). The N-type calcium channel blocker, omega-conotoxin GVIA (500 nM), the P-type calcium channel blocker, omega-agatoxin IVA (20 nM), and the P- and Q-type channel blocker omega-conotoxin MVIIC (1 microM) had no effect on glutamate release. In contrast, the dihydropyridines, nifedipine (10 microM) and nitrendipine (10 microM), which affect L-type calcium channels, blocked both darkness- and potassium-induced release. Bay K 8644 (10 microM), which promotes the open state of L-type calcium channels, enhanced glutamate release. These results indicate that photoreceptor glutamate release is controlled mainly by dihydropyridine-sensitive calcium channels. A dependence of glutamate release on L-type calcium channels also has been reported for depolarizing bipolar cells of a fish retina. Thus, it appears that non-inactivating L-type calcium channels are appropriate to mediate transmitter release in neurons whose physiological responses are sustained, graded potentials.     

Investigation of the intracellular stability and formation of a triple helix formed with a short purine oligonucleotide targeted to the murine c-pim-1 proto-oncogene promotor

Glucose was found to induce large amplitude oscillations of cytoplasmic Sr2+ and Ca2+ in individual pancreatic beta-cells exposed to the respective cation. Subsequent addition of 20 nM glucagon or other agents raising cAMP triggered pronounced transients superimposed upon the large amplitude oscillations. Hyperpolarization with diazoxide prevented both the large amplitude oscillations and the superimposed transients. After short exposure to carbachol or ATP there was a temporary, and after addition of the Ca2+-ATPase inhibitor thapsigargin a permanent, disappearance of the transients with persistence of the glucose-induced large amplitude oscillations. The Ca2+ channel blocker methoxyverapamil exhibited opposite specificity in preventing the large amplitude oscillations under conditions when the transients often remained. In the presence of methoxyverapamil the transients disappeared during diazoxide hyperpolarization and were restored by subsequent K+ depolarization, which also elevated the content of inositol 1,4,5-trisphosphate (IP3) by 45%. The glucagon-induced transients were obliterated by 12-O-tetradecanoylphorbol 13-acetate, insensitive to ryanodine and paradoxically inhibited by high concentrations of caffeine. The IP3-mediated intracellular ion mobilization induced by carbachol was amplified by glucagon. The results indicate that depolarization-dependent formation of IP3 causes intracellular Ca2+ mobilization in individual beta-cells when the IP3 receptors are sensitized by cAMP. This mechanism may be an important determinant for the electrophysiological burst activity in intact pancreatic islets due to the presence of endogenous glucagon.     

The protective effects of CP-060S on ischaemia- and reperfusion- induced arrhythmias in anaesthetized rats

1. CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against ischaemia- and reperfusion-induced arrhythmia was evaluated in anesthetized rats. 2. Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion. 3. In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30-300 microg kg(-1)) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 microg kg(-1) in VF (incidence: 42%) and mortality (8%), and at 300 microg kg(-1) in VT (50%), VF (33%) and mortality (8%). This protective effect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30-1000 microg kg(-1)) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be sufficient to explain its potency. 4. In the same model, co-administration of ineffective doses of diltiazem (300 microg kg(-1)) and a sodium and calcium overload inhibitor, R56865 (100 microg kg(-1)), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of R56865 at the same dose with CP-060S (300 microg kg(-1)) did not add to the effect of a single treatment of CP-060S. 5. In the ischaemia-induced arrhythmia model, CP-060S (300 microg kg(-1)) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg(-1)) was ineffective. 6. These results suggest that CP-060S inhibits both ischaemia- and reperfusion-induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.