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Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

The reversibility of verapamil-induced hemodynamic and electrophysiologic changes by intravenously administered CaCI2 and NaCI was tested in 34 anesthetized open-chest dogs during verapamil infusions which produced plasma verapamil concentrations of 70-2042 ng/ml. An increase of serum calcium concentration (Ca). to an average 6.5 mEq/l abolished the depressive effects of verapamil on cardiac output and left ventricular dp/dt and diminished drug-related hypotension by an average of 52%, but did not affect verapamil-induced prolongation of AH interval and slowing of sinus rate. Further increase of (Ca). to an average of 8.2 mEq/l decreased AH prolongation caused by verapamil from an average of 95% to 45% of control value, but had no effect on verapamil-induced slowing of sinus rate or second-degree atrioventricular (AV) block during atrial pacing. Rapid intravenous injection of 40 ml 2 M NaCI, transiently raised serum Na+ concentration to 162 mE/l, decreased AH prolongation caused by verapamil to an average of 22% of control value, decreased slowing of sinus rate from an average of 34% to an average of 19% of control value, and decreased the severity of second-degree AV block, but had no effect on verapamil-induced complete AV block or sinus arrest. Hypernatremia had no effect on AH interval and sinus rate without prior CaCl2 infusion. In the absence

The electrophysiological characteristics of demyelinated axons are sensitive to changes in plasma calcium concentration. This study investigated the effect of verapamil, a calcium antagonist drug, on brainstem auditory, visual, and somatosensory evoked potentials in multiple sclerosis patients. Eight clinically stable patients with abnormal visual and/or brainstem auditory evoked potentials and four normal volunteers were studied. During intravenous infusions of verapamil (mean plasma concentration = 130.0 +/- 56.4 ng/ml), the latencies of peaks III and V were shortened (p less than 0.05) in multiple sclerosis patients with abnormally prolonged BAEPs. The I-III (delta = 0.08 ms), III-V (delta = 0.46 ms), and I-V (delta = 0.53 ms) interpeak intervals, and the P100 latency (delta = 10.15 ms) of the visual evoked potential were similarly affected in these patients. In contrast, normal evoked potentials of both multiple sclerosis patients and control subjects were not altered compared to baseline recordings obtained 24 hours earlier. Intravenous verapamil, therefore, alters the BAEPs and VEPs of some multiple sclerosis patients with demyelinated auditory and visual pathways by shortening pathologically prolonged latencies toward normal. The present study suggests pharmacological manipulation of calcium-dependent processes, possibly at the level of the demyelinated axon, can acutely facilitate central conduction of electrical impulses in some patients with clinically stable multiple sclerosis.

Verapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels. Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism, with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound in in vitro studies. After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug. Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, 'standard' dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil's disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and beta-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

The response of plasma renin activity (PRA) to the stimuli of upright posture and sodium deprivation was determined in three normal adults and in ten hypertensive patients before and after chronic alpha-adrenergic receptor blockade with phenoxybenzamine and chronic beta-blockade with propranolol. Alpha-receptor blockade produced little effect on supine or upright PRA values; beta-receptor blockade, however, consistently and significantly suppressed PRA in both the supine and standing positions. Dose-response studies suggest that the maximal suppression of PRA attainable after oral propranolol administration occurs at peak plasma levels of about 30–50 ng/ml. Beta-adrenergic receptors appear to constitute that part of the sympathetic nervous system which mediates a significant portion of the renin release mechanism. Pharmacologic interference with renin secretion by beta-adrenergic receptor blockade is easily achieved in both normal and hypertensive subjects. The suppression of supine and upright PRA with b...

In this method for measuring nifedipine, a calcium-channel inhibitor now widely used in the treatment of cardiovascular disease, the drug is extracted from plasma under basic conditions into toluene, and an aliquot of the extract is injected directly into a gas chromatograph equipped with an OV-101 column and an electron-capture detector. The standard curve is linear between 1 and 100 micrograms/L; the assay measures not only nifedipine, but also a major metabolic product (found only after oral administration of the parent drug) and photodegradation products. The procedure is rapid and adequately sensitive for routine use in clinical monitoring of nifedipine in plasma.

Verapamil was administered intravenously to 30 open-chest dogs and the electrophysiologic and hemodynamic effects of the drug were correlated with the corresponding plasma concentrations. At concentrations below 152 ng/ml, verapamil prolonged the A-H interval, abolished ventriculoatrial conduction, but did not significantly change sinus rate, cardiac output, left ventricular dp/dt, of systemic vascular resistance. Concentrations above 200 ng/ml were associated with slowing of the sinus rat, high degree atrioventricular block during atrial pacing, 24% decrease in mean aortic pressure, and decreased cardiac output and left ventricular dp/dt. Sinus arrest, high degree atrioventicular block during sinus rhythm, decreased systemic vascular resistance and increased left ventricular end-diastolic pressure occurred when plasma verapamil concentrations exceeded 400 ng/ml. These results show that plasma verapamil concentrations reliably reflect the electrophysiologic and hemodynamic actions of the drug, and that "therapeutic" drug effects can be achieved at plasma concentrations at which myocardial depressant effects are unlikely.

The administration of verapamil to patients receiving beta-adrenergic blocking drugs is reported to produce adverse circulatory reactions, but a systematic investigation of this potential drug interaction has not been performed in man. We administered 40-, 80- and 120-mg doses of verapamil orally to 15 patients with angina pectoris who were receiving high doses of propranolol or metoprolol. Verapamil produced dose-dependent decreases in cardiac performance: with 120 mg, cardiac index decreased by 0.38 l/min/m2, stroke volume index decreased by 2.8 ml/beat/m2 and heart rate decreased by 6 beats/min, associated with increases in pulmonary capillary wedge (2.2 mm Hg) and mean right atrial pressures (1.7 mm Hg) (all p less than 0.01); two patients had marked, but asymptomatic, hypotensive reactions. In contrast, repeat administration of 120-mg doses of verapamil 24--30 hours after withdrawal of beta blockade produced no significant cardiodepressant effects despite significantly higher plasma levels of verapamil than during propranolol therapy (383.1 vs 205.1 ng/ml, p less than 0.01). In conclusion, verapamil produces significant negative inotropic and chronotropic effects in patients treated with beta-adrenergic antagonists; combination therapy should therefore be used with caution in patients with angina pectoris.

Propranolol was given intravenously to 6 adult patients with essential tremor, using a bolus-infusion regimen for rapid production and maintenance of predicted drug plasma levels. Tremor in the outstretched hand was quantitated by integration of the waveform signal recorded from a miniature accelerometer. Propranolol had no effect on tremor frequency (6 to 8 cps), but it suppressed tremor amplitude in all patients in direct proportion to the drug's plasma concentration and to the intensity of beta-adrenergic blockade produced. Among this group of patients the maximal tremor decrease occurred at plasma levels of about 100 ng per milliliter and varied widely between individuals (18 to 85%), implying that the efficacy of propranolol therapy in essential tremor depends on both the plasma drug level and the innate sensitivity of the disorder in the individual patient.

A model for the intravenous administration of propranolol by a bolus-infusion technique designed to rapidly produce, then maintain, predicted plasma drug concentrations was derived from elimination kinetics in single-dose studies. Prospective testing of this model in 6 adult male subjects revealed a close correlation between predicted and observed drug levels; desired plasma concentrations were achieved within 5 min and maintained over the 30-min study period. By subtracting previously given bolus doses from the dose calculated as needed to produce a desired plasma level, progressive increases in predicted propranolol levels could be effected, with apparent maintenance of equilibrium. Correlations between the bolus doses and infusion rates and the plasma drug levels were consistent and significant, and constitute nomograms from which the dose of drug required to produce a desired plasma level may be approximated. The clearance of propranolol declined slightly as the drug plasma level increased, but did not significantly affect the accuracy of the model.

Slow channel calcium antagonists inhibit in vitro both vascular smooth muscle contraction and adrenal steroidogenesis. We assessed the effects of one of these drugs, verapamil, upon pressor responses and increments in plasma steroid concentrations to adrenal trophic factors in normal volunteers. Given acutely iv, verapamil in amounts sufficient to produce plasma concentrations of approximately 200 ng/ml significantly blunted the pressor action of angiotensin II in six normal subjects but did not alter increments in plasma aldosterone or cortisol in response to either angiotensin or ACTH compared to paired control studies. When verapamil was given orally (120 mg three times daily for 5 days), the plasma concentrations were equivalent to those after iv administration of the drug in six other volunteers, and verapamil again significantly blunted pressor responses to angiotensin II and norepinephrine. Oral verapamil also blunted the increments in plasma aldosterone to angiotensin and cortisol to ACTH, but did not alter the aldosterone response to ACTH. We conclude that verapamil given either acutely or chronically impaired the action of pressor hormones by a nonspecific action on vascular smooth muscle. When given for a sustained period of time, verapamil also impaired to a moderate degree adrenal steroidogenesis to two trophic factors, suggesting that its adrenal effect is time dependent.

We studied the effects of the calcium-channel blocker, nifedipine, on solid and liquid phases of gastric emptying in 10 healthy male volunteers. Each subject underwent a dual-isotope radionuclide gastric emptying determination with and without the preadministration of nifedipine, 30 mg orally, given 20 min prior to ingestion of the test meal over 10 min, following which the subject lay supine under the gamma-counter for 2 hr. Blood samples for measurement of plasma nifedipine concentration were obtained at the time of drug administration and every 30 min throughout the gastric emptying determination. There was a threefold variation in the areas under the plasma nifedipine concentration vs time curve (AUC) obtained in these 10 subjects. Percent gastric retention of either the liquid (water) or the solid (chicken liver) marker was not significantly different after 30 mg oral nifedipine, as compared to the nontreatment day. We concluded that plasma nifedipine concentrations previously reported to be associated with significant esophageal motility effects in humans were not associated with effects on gastric emptying of either liquids or solids.

As further clinical indications for verapamil become apparent, the need to define drug plasma concentrations at which specific pharmacologic effects predictably occur grows increasingly important. The activity of verapamil as an antagonist of calcium-dependent processes provides the basis for a wide range of therapeutic effects, and at the same time allows prediction of the toxicity which must result when the drug is present in excess. High plasma verapamil levels can interfere sufficiently with excitation-contraction coupling [1] to produce profound depression of myocardial pump function [2]. In the same fashion, antagonism of calcium-dependent impulse conduction across the atrioventricular (AV) node can be intense enough to produce complete heart block [2]. Since these manifestations of drug toxicity are potentially lethal, the establishment of plasma concentration ranges at which therapeutic, but not toxic, effects can reasonably be anticipated will allow more consistently effective use of verapamil in patient management.

Fever, tachycardia, and hypertension developed concurrently with the administration of thiothixene during an acute episode of agitation in a case of catatonic schizophrenia. No cause for the fever or hyperkinetic state was found, and the syndrome resolved spontaneously one week after antipsychotic drug therapy was halted. This case appears to be an example of "acute lethal catatonia" or the neuroleptic "malignant" syndrome, both of which may be due to disturbances of dopamine function within the CNS. Such cases are rare, but may be dramatic in their presentation; however, antipsychotic drugs must be withheld during the duration of the disorder. (Arch Intern Med138:1154-1156, 1978)

We evaluated efficacy and mechanisms of the antiarrhythmic action of verapamil in 20 patients with sustained supraventricular tachycardia. Two patients had sinus nodal re-entrant tachycardia, nine atrioventricular (AV) nodal re-entrant tachycardia, and nine AV reciprocating tachycardia associated with the Wolff-Parkinson-White syndrome. The study design comprised a double-blind, randomized, cross-over phase using a 0.075 mg/kg dose of verapamil versus placebo and an open-label phase using a 0.15 mg/kg dose of verapamil. The overall results of both phases showed that 15 of 19 patients converted to sinus rhythm with verapamil while only one of 16 converted to sinus rhythm with placebo. The effective plasma verapamil concentration measured 123 +/- 40 ng/mL (mean +/- SD). Verapamil suppressed sinus nodal and AV nodal re-entry but exerted no selective depression between fast and slow AV nodal pathways. It had no significant effect on accessory AV bypass tract but was effective in terminating AV reciprocating tachycardia by its depressive action on the AV node.