Search

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

Cardiac beriberi is considered a rare disease in western society. A patient with fulminant Shoshin-type beriberi was studied in the acute phase and found to have severe metabolic acidosis, high output biventricular failure, and markedly low systemic vascular resistance. Red blood cell transketolase activity was abnormally low. Following treatment with thiamine, diuretics, digitalis and oxygen, all abnormalities disappeared. The historical background of the disease is reviewed along with a discussion of pathophysiologic mechanisms responsible for the hemodynamic profile and lactic acidosis. Angiographic and hemodynamic data on the patient presented suggest relative depression of left ventricular function in the acute phase of beriberi. Since beriberi is uncommonly encountered, emphasis is placed on diagnostic and therapeutic implications of the disease which may not be widely appreciated.

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.

✓ Two distinct and sequential patterns of hemodynamic alteration were observed after acute cervical spinal cord transection in anesthetized dogs. Interruption of the cord initially caused a 45% increase in mean arterial pressure (p < 0.01), a 34% increase in systemic vascular resistance (p < 0.05), and a 92% increase in left ventricular dp/dt (p < 0.01), reflecting a generalized sympathetic response to trauma. Concomitant bradycardia and escape arrhythmias suggested relative parasympathetic hyperactivity. Resolution of the brief pressor response was followed by a second, more prolonged, period characterized by a fall in arterial pressure to 71% of control levels (p < 0.05), a 16% decrease in systemic vascular resistance, and a 58.5% decrease in left ventricular dp/dt (p < 0.01). These latter hemodynamic changes are consistent with sympathetic denervation and failure of regulatory mechanisms mediated by both alpha- and beta-adrenergic peripheral vascular and myocardial receptors.

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...

The effect of β-adrenergic blockade by intravenous dl-propranolol on pulse rate, tremor and Achilles reflex time has been compared with the effect of inactive d-propranolol and saline alone in anxious and thyrotoxic subjects. β-blockade significantly reduced pulse rate, decreased the amplitude of tremor, and prolonged reflex time in both groups.

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.

The effects of intravenous verapamil (0.15 mg/kg) and procainamide (12-14 mg/kg) on intraventricular conduction and reentry within the His-Purkinje system were studied in eighteen patients using His bundle electrograms and ventricular extrastimulus method. Verapamil's effects were studied in eight patients and procainamide's effects in ten patients. Plasma verapamil concentrations ranged from 56 to 192 ng/ml (mean +/- SD: 139.0 +/- 46.0); plasma procainamide concentrations ranged from 11.3 to 19.0 mg/liter (mean +/- SD: 14.9 +/- 2.5). Verapamil caused no change in latency, intramyocardial conduction (duration of QRS complex), and His-Purkinje (V2H2 interval) conduction of even the earliest premature impulses introduced before the completion of repolarization of the His-Purkinje system and the ventricular myocardium, i.e. when some fibers were presumably at the level of membrane potential at which conduction becomes, wholly or in part, dependent on slow inward calcium current. Verapamil did not abolish or modify the zone of reentry, and did not significantly change the determinants of reentry in any of the eight patients. In contrast, procainamide significantly prolonged the latency, the duration of QRS complex and the V2H2 interval in each of the ten patients, abolished reentry in seven patients, and decreased the width of reentry zone in three patients. The contrasting effects of verapamil and procainamide on intraventricular conduction and reentry within the His-Purkinje system suggest that slow conduction of early premature impulses is due to an incompletely reactivated rapid inward sodium current and not to a fully activated slow inward calcium current. Further, our observations suggest that the system responsible for slow conduction cannot be recognized from the magnitude of conduction delay.

Peripheral beta-adrenergic receptor sensitivity was characterized in 24 patients with essential hypertension and in 13 age-matched normotensive subjects using an isoproterenol hydrochloride bolus dose-response technique. Decreased beta-receptor responsiveness to this exogenously administered beta-agonist was observed in hypertensive patients; for an equivalent chronotropic effect, higher doses of isoproterenol were required in hypertensive subjects than in normal subjects. Among "normal-renin" hypertensive patients, beta-receptor responsiveness was directly related to furosemide-stimulated plasma renin activity (PRA), suggesting that independently stimulated PRA may provide an indirect estimate of endogenous beta-receptor sensitivity. Hypertensive patients whose mean arterial pressure fell at least 10 mm Hg after four weeks of treatment with hydrochlorothiazide had even further depression in beta-receptor responsiveness, whereas receptor sensitivity was unchanged in patients whose blood pressure was unaffected. Thus, it is unlikely that this decreased receptor responsiveness in patients with untreated essential hypertension is a direct consequence of elevated arterial pressure.

This study used a steady-state approach to evaluate the relationships between the pharmacodynamic and pharmacokinetic characteristics of nifedipine and verapamil. In anesthetized and instrumented dogs, i.v. bolus/infusion dosing regimens were used for each drug to achieve and maintain stable drug concentrations in four different ranges rapidly. For both compounds, increases in doses were associated with disproportionate higher plasma drug concentrations, greater hemodynamic effects and significant reductions in systemic drug clearance. Progressive increases in the dose of nifedipine produced reductions in arterial pressure and reflex augmentation in cardiac output, together with decreases in calculated hepatic plasma flow which closely paralleled the decline in mean aortic pressure. Increasing doses of verapamil also resulted in decreased hepatic plasma flow, which was associated with both systemic hypotension and drug-induced decreases in cardiac output. These data imply that the hemodynamic effects of both nifedipine and verapamil result in changes in hepatic plasma flow which, in turn, result in significant alterations in systemic drug clearance. In this experimental model, the calculated hepatic plasma flow and observed systemic clearance values for nifedipine and verapamil were closely related to concentrations of the respective drugs 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 relative distribution of verapamil and its demethylated metabolite, norverapamil, was studied in rats at intervals after intraperitoneal injection of the parent drug (30 mg/kg). This route of drug administration simulated oral drug dosing, and the highest concentrations of both unchanged drug and metabolite were found in the liver, with lung and kidney containing most of the remainder. The rates of disappearance of verapamil from various organs followed first-order kinetics, and the most rapid elimination occurred from brain and liver. In contrast, verapamil was given intravenously to 3 dogs by a bolus-infusion method to produce sustained steady state plasma concentrations (80, 140, 250 ng/ml) for 1, 2, and 3 h. After systemic administration, the lungs contained almost half the tissue verapamil and, 20% was found in kidney, with the liver accounting for only 17%. Norverapamil was not found in plasma or brain. These studies contrast the pattern of tissue distribution of verapamil after different routes of drug administration. The variable rates of drug elimination from specific tissues may explain the differing durations of the drug's observed effects.

Rhythmic automatic depolarizations (RAD) were produced in guinea-pig papillary muscles depolarized to membrane potentials at which depolarizations depend on membrane currents passing through the slow channel. Verapamil depressed the RAD and decreased their overshoot. These verapamil effects were dependent on its concentration either in the bath (in vitro) or in plasma and myocardium (in vivo). Increase in [Ca++] counteracted the effects of verapamil on RAD. Lidocaine concentrations ranging from 4 to 16 mg/l had no effect on overshoot and only a slight effect on the rate of RAD. We conclude that RAD are more sensitive to nonlethal and presumably therapeutic concentrations of verapamil than to high, presumably toxic, concentrations of lidocaine.

Tricuspid regurgitation developed in two patients after inferior wall myocardial infarction. Neither patient had preexisting valvular heart disease or evidence of endocarditis, and neither had suffered chest trauma. Because abnormalities in right ventricular function may occur after inferior infarction, and because other known causes of tricuspid incompetence were not present, we postulate that these patients developed valvular regurgitation from dysfunction of the papillary muscle complex controlling tricuspid valve function, a mechanism similar to that proposed to explain mitral regurgitation seen with inferior wall ischemia.

The stability of nifedipine in cardioplegic solution was studied. Cardioplegic solutions containing nifedipine at 275 and 500 micrograms/liter were stored in plastic bags covered in brown plastic wrappers (1) under normal room light at 25 degrees C and (2) in a dark refrigerator at 4 degrees C. Samples were removed periodically for 48 hours. Infusions of cardioplegic solution containing 275 micrograms/liter were simulated using tubing and flow rates of 100, 200, and 300 ml/min; bags were covered with aluminum foil, while tubing was exposed to normal room lighting or yellow lighting, which does not degrade nifedipine. Gas chromatography was used for nifedipine assays. Nifedipine degraded more rapidly at 25 degrees C than at 4 degrees C. However, even when protected from light and refrigerated, nifedipine concentrations declined to less than 90% of original potency by approximately six hours after preparation. There was no significant degradation during the simulated infusion regardless of light exposure or flow rate. Cardioplegic solutions containing nifedipine should be prepared immediately before the surgical procedure, refrigerated until use, and protected from light until administration.

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.

The effect of verapamil on glucose tolerance and insulin release in conscious, healthy dogs was studied at plasma drug concentrations which produce therapeutic cardiovascular effects. Plasma glucose and immunoreactive insulin were measured serially in each animal for 90 min after an intravenous glucose challenge (400 mg/kg), both during a control study and again during administration of verapamil. The drug was given by infusion protocols to produce plasma concentrations at low (84 +/- 9 ng/ml), intermediate (161 +/- 30 ng/ml), and high (367 +/- 51 ng/ml) ranges. Insulin release was impaired and glucose levels elevated at both the intermediate and the high verapamil concentrations, and to a similar degree. The reduction in insulin release and subsequent increase in plasma glucose is a pharmacologic effect of verapamil which occurs at drug concentrations likely to be achieved during clinical use.

Dynamic exercise stress testing had become a widely accepted technique in the diagnosis of cardiac patients. The results of standardized exercise testing may be used to evaluate a patient's functional capacity and to derive an exercise prescription to assist him in improving his state of cardiovascular fitness. Because the physical therapist has special training and skill in exercise-related techniques, a stress testing laboratory and an exercise-based cardiac rehabilitation program may be appropriately established in a hospital's physical therapy department. Results are presented of a diagnostic exercise testing and an exercise-based cardiac rehabilitation program organized and supervised by physical therapists in a 300-bed private hospital.

The elimination kinetics of verapamil, an experimental antiarrhythmic agent which inhibits slow-channel activity, have been studied in mongrel dogs after i.v. drug administration. The disposition of verapamil follows first-order kinetics and may be adequately described by a one-compartment model. After single i.v. doses of the drug, the overall elimination rate constant (mean +/-S.E.M.) was 0.0146 +/- 0.0021 min-1; the apparent volume of distribution was 4.47 +/- 0.40 liters/kg; and the total body drug clearance was 1244 +/- 113.4 ml/min. After longer i.v. infusions, the disposition kinetics were similar to those found with bolus dosing. A linear relationship was found between verapamil plasma concentrations and changes in atrioventricular conduction time, as estimated from the P-R interval of the surface electrocardiogram (r = 0.95, P less than .001). No changes were seen in the QRS duration of Q-T interval. These data show that the effect of verapamil of verapamil on slow-channel-dependent conduction in the heart is directly related to the concentration of the drug in plasma.

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.

This study was carried out to compare gas chromatography (GC) and high-pressure liquid chromatography (HPLC) procedures in the measurement of plasma levels of verapamil. Other analytic methods previously reported are not widely available (mass fragmentography) or are subject to interference from drug metabolites (spectrophotofluorometry). A single extraction and derivatization procedure was developed to prepare samples for either GC or HPLC analysis. The GC procedure used a nitrogen-specific detector; the HPLC, a fluorescence detector. In a 1--500 ng/ml range of verapamil concentrations, both methods resulted in good separation of verapamil from a major metabolite, norverapamil, and from compound D517, used as an internal standard. Intraassay variation was similar for both procedures, with only slightly higher interassay variability found for the GC technique. Excellent correlation was found during analysis of the same unknown samples by both methods (r = 0.97; p less than 0.001). Either assay procedure appears satisfactory for use in measurement of verapamil levels in plasma.

Propranolol and verapamil are cardioactive drugs which may be useful during surgical procedures involving hypothermic cardiopulmonary bypass. Previous in vivo studies have shown that the pharmacokinetics of propranolol are altered by hypothermia, and that clearance of the drug is significantly reduced by lowered body temperature. Since both propranolol and verapamil are eliminated largely by hepatic metabolic activity, the effect of hypothermia on the ability of the liver to metabolize both drugs was studied in vitro with rat hepatic microsome preparations. Known quantities of the drugs were added after preincubation of microsomes at 37 degrees C (normothermia) or 26 degrees C (hypothermia), and the amount of drug substrate remaining after an additional incubation period was measured. Hypothermic microsomes metabolized significantly less of each drug at all substrate concentrations studies (p less than 0.001). Double-reciprocal plots showed similar results for experiments with both propranolol and verapamil: the extrapolated Vmax was the same for both temperature conditions, but the Km values were significantly increased by hypothermia (p less than 0.001), indicating reduced affinity for drug substrate by the microsomal enzymes. These in vitro studies show that hepatic metabolic elimination of both propranolol and verapamil is decreased by hypothermia.

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.

Pharmacokinetic data are important in the development of rational regimens for drug administration, particularly for agents with the potential for serious toxicity. Pharmacodynamic studies correlate drug dose and plasma concentration with observed effects (whether therapeutic or toxic) and aid in the establishment of appropriate dose ranges for desired drug activity. Verapamil is the only calcium channel antagonist for which detailed pharmacokinetic and pharmacodynamic data are available, and relatively few studies have been carried out in patients, in whom kinetic parameters are likely to differ from those found in normal subjects. Studies thus far indicate that verapamil is eliminated by hepatic metabolism, is subject to extensive first-pass extraction, and is characterized by cumulation during chronic oral administration. Plasma levels of verapamil appear to correlate well with both electrophysiologic and hemodynamic effects. Nifedipine pharmacokinetics are not well established and erratic absorption may be seen with the capsule presently available. Toxicity from overdosage appears to be less threatening than with verapamil. Diltiazem has been studied in a limited group of normal subjects, with considerable interindividual variation in plasma levels after fixed oral doses. This suggests that the drug is subject to first-pass elimination. The half-life appears to be approximately 5 h, but may increase as dose size is increased. For drugs with such broad therapeutic application as the calcium channel antagonists, the paucity of pharmacokinetic data is surprising. Further studies, particularly in patient subjects, are clearly needed.

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

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.

We studied the effects of the calcium-channel blocker nifedipine on esophageal smooth muscle function in 10 normal volunteers. Lower esophageal sphincter pressure and relaxation and esophageal contraction amplitude, peristalsis, velocity, and duration after wet swallows were determined before and for 120 min after the sublingual/buccal administration of placebo and of nifedipine in doses of 10, 20, 30, and 40 mg. Blood samples for measurement of plasma nifedipine concentration were obtained at baseline and every 30 min during this 120-min period. Nifedipine led to decreases in sphincter pressure of 13.3%, 29.9%, 34.3%, and 35.1% as the dose was increased from 10 mg to 40 mg. These changes were significantly (p less than 0.05) different from baseline and placebo for the 20-, 30-, and 40-mg doses and were more sustained with the higher doses, lasting as long as 90 min. Contraction amplitude fell 5.3%, 5.9%, 13.5%, and 19.6% at the corresponding doses. These changes were significantly (p less than 0.05) different from baseline and placebo only for the 30- and 40-mg doses, with the effect lasting up to 60 min. Peak plasma nifedipine concentration ranged from 28.7 +/- 3.7 ng/ml (mean +/- SEM) after 10 mg to 138.7 +/- 43.7 ng/ml after 40 mg of the drug, and occurred at either the 30- or 60-min measurement. The mean percent of decrease in sphincter pressure and contraction amplitude in the esophageal body correlated (p less than 0.001) with plasma nifedipine levels. There were no changes in sphincter relaxation or in peristalsis, velocity, or duration of contraction with any dose of nifedipine. It is concluded that (a) nifedipine significantly decreases lower esophageal sphincter pressure and contraction amplitude in the body of the esophagus, (b) the effect on sphincter pressure requires a lower dose of nifedipine and is more marked than that on contraction amplitude, and (c) the effects on both sphincter pressure and contraction amplitude correlate with plasma nifedipine levels. Calcium-channel blockers such as nifedipine may have a role in the treatment of motility disorders of the lower esophageal sphincter or esophageal body, and further controlled clinical studies are indicated.

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.

The need for standardization in such aspects of radiation protections dosimetry and monitoring methods, reporting of surveys, keeping of records, and waste disposal is stressed. Problems encountered when industry started to examine its potential liabilities in connection with construction and operation of nuclear