Fever, tachycardia, and hypertension with acute catatonic schizophrenia.

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.

Tricuspid regurgitation following inferior myocardial infarction.

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.

Peripheral beta-receptor responsiveness in patients with essential hypertension.

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.

Clinical implications of patient-provider agreements in opioid prescribing.

In June, 2012 the United States Food and Drug Administration (FDA) developed a "blueprint" for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

Effects of intravenous and oral verapamil upon pressor and adrenal steroidogenic responses in normal man.

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.

Hypertension and neurofibromatosis. Case report.

A 14-year-old girl with neurofibromatosis presented with severe hypertension. She was subsequently found to have a cerebellar glioblastoma multiforme and vascular lesions producing coarctation of the abdominal aorta and 50% and 95% stenosis of the left and right renal arteries respectively. No evidence of pheochromocytoma was found. After removal of the cerebellar tumor, marked amelioration of the hypertension suggested that the tumor had a major role in the pronounced elevation of her blood pressure. Patients who have both neurofibromatosis and hypertension should be carefully evaluated for these several potential lesions.

Intravenous propranolol administration: a method for rapidly achieving and sustaining desired plasma levels.

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.

The pharmacology of verapamil. IV. Kinetic and dynamic effects after single intravenous and oral doses.

Kinetics and plasma level-effect correlates for verapamil were studied in 20 normal young men (mean age, 25.2 +/- 3.6 yr). In a randomized four-way crossover design, each subject received 10 mg verapamil intravenously and 80, 120, and 160 mg in single oral doses. Changes in heart rate, blood pressure, and PR interval were evaluated serially after each dose; plasma concentrations of verapamil were measured by high-performance liquid chromatography. Levels of the active metabolite norverapamil were determined in five subjects. Verapamil kinetics were the same after intravenous and oral doses: elimination half-life (t 1/2 beta) ranged from 3.7 to 4.8 hr, apparent volume of distribution varied between 4.2 and 5.5 l/kg, and total clearance was 0.71 to 0.86 l/hr/kg. Verapamil bioavailability was not dose dependent and averaged 19.4%. Norverapamil, found only after oral doses, had a t 2/2 beta and maximum concentration much the same as the parent drug. There were only minor effects on heart rate and blood pressure after single doses. Hysteresis analysis showed that plasma verapamil concentrations after intravenous doses correlated with PR interval prolongation only after a 30-min lag time; there was no lag after oral doses. There was considerable interindividual variation in sensitivity to verapamil's effect on atrioventricular conduction; subjects with longer control PR interval values tended to have greater prolongation of effect than those with shorter intervals. Verapamil was well tolerated in both dosage forms by all subjects.

Verapamil plasma levels and ventricular rate response in patients with atrial fibrillation and flutter.

The acute effect of verapamil on the ventricular rate in atrial fibrillation and flutter was studied in 15 patients, 13 of whom had heart rate inadequately controlled with digitalis. Plasma concentrations were measured 5 and 10 min after intravenous doses of 0.075 mg/kg and 0.15 mg/kg verapamil. In 9 patients who were clinically compensated, the 0.075-mg dose alone decreased the ventricular rate to under 100/min (responders); in the remaining 6, who had acute congestive heart failure manifested by orthopnea, rales, and pulmonary congestion, ventricular rates were above 100/min after the 0.075-mg dose (nonresponders). The 6 nonresponders received the 0.15-mg dose 30 min later. In all, the response was greater when plasma drug concentration rose after the high dose, although the rate decrease was smaller than in the 9 compensated patients who received the low dose. These results can be explained by assuming an antagonism of the verapamil effect by sympathetic stimulation in nonresponders.

Effects of hypothermia on propranolol kinetics.

Propranolol may be uniquely useful in cardiac surgical procedures, since beta adrenergic blockade can prevent the hypokalemia and associated arrhythmias which result from systemic hypothermia. To determine the effects of hypothermic cardiopulmonary bypass (HCPB) on the in vivo handling of propranolol, serial drug plasma concentrations (Cp) were measured during HCPB in 12 patients who had been treated chronically with propranolol prior to surgery. Although no further propranolol was given during the procedure, Cp values (corrected for plasma volume dilution) were higher during hypothermia than in the preoperative period, falling to or below control levels after rewarming. Due to the variables inherent in patient surgery, meaningful kinetic analysis could not be carried out. Therefore, intravenous propranolol (1 mg/kg) was given twice to each of 5 dogs, first after anesthesia only, then after anesthesia and systemic cooling to 26 degrees in a water bath Cp values measured serially over 2 hr after drug administration were consistently higher during hypothermia. Compared with the paired normothermic control studies, hypothermia markedly reduced the apparent volume of distribution (6.78 +/- 1.65 vs 2.08 +/- 0.58 L/kg; p less than 0.001) and the total body clearance of propranolol (64.4 +/- 11.0 vs 32.3 +/- 7.2 ml/kg/min; p less than 0.005). These data show that hypothermia substantially alters the pharmacokinetics of propranolol, resulting in plasma drug levels higher than those predicted from kinetic patterns derived under normothermic conditions.

Kinetics and dynamics of nifedipine after oral and sublingual doses.

Nifedipine is frequently administered by the sublingual route to provide rapid onset of intense effect, especially in patients in whom urgent reduction of elevated blood pressure is indicated. Previously available data, however, suggest that peak levels of nifedipine are higher and occur earlier when the drug is administered orally. Results of pharmacodynamic studies show that maximal hypotensive effects occur between 30 and 60 minutes after administration by either route, but that such effects are often achieved earlier when the drug is given orally. Recent work implies that the absorption of nifedipine through the buccal mucosa is poor, if it occurs at all, and that the appearance of nifedipine in plasma requires delivery of the drug to the stomach for active absorption. The small time lag in absorption that may be attributed to the dissolution of the nifedipine capsule may be obviated by biting through the capsule and swallowing the contents; this bite-and-swallow approach to dosing provides the most rapid rise in plasma nifedipine concentrations, and produces peak levels well above those achieved with sublingual administration.

Clinical pharmacokinetics of verapamil.

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.

Age-related changes in drug handling in man.

Persons older than 65 years constitute 10% of the U.S. population but require approximately one-third of its health care service. A significant proportion of their disease states is related to adverse reactions to prescribed drugs. The origins of this disturbingly high incidence of untoward consequences from drug therapy are multiple and complex. They include: (1) alterations in expected patterns of drug handling associated with physiologic changes of the aging process itself, (2) alterations in responsiveness to specific types of drugs and (3) frequent occurrence of chronic and acute diseases. The data documenting pharmacokinetic changes in aging subjects are rudimentary, and the physician is commonly aware only of pharmacokinetic profiles derived from studies in healthy, young subjects. Without a firm basis on which to rest pharmacologic therapy, the clinical approach to drug treatment in the elderly patient must be cautious and conservative.

Effect of verapamil on retrograde conduction in atrioventricular nodal reentrant tachycardia.

Using His bundle electrograms, incremental ventricular pacing and the ventricular extrastimulus (V2) technique, the effects of intravenous verapamil, 0.2 mg/kg, on retrograde atrioventricular (AV) nodal conduction during ventricular pacing, premature ventricular stimulation (H2A2 interval) and paroxysmal supraventricular tachycardia (SVT) (H-Ae interval) were evaluated in 11 patients with AV nodal reentrant tachycardia. During the control study, SVT could be induced in all 11 patients. After verapamil administration, SVT or atrial echo beats could be induced in 5 patients. Verapamil produced ventriculoatrial (VA) block at a longer cycle length than that during the control study in 10 of 11 patients (295 +/- 27 vs 352 +/- 40 ms, p less than 0.01), but prolonged H2A2 interval in only 5 of 11 patients (37 +/- 6 vs 60 +/- 31 ms, p less than 0.05). In all 5 patients with persistence of inducible SVT or atrial echo beats after verapamil treatment, the H-Ae interval remained unchanged even though in 4 of these 5 patients VA conduction time or H2A2 interval was prolonged. Correlation between the paced cycle length which induced VA block, the shortest V1H2 interval achieved during premature ventricular stimulation and the cycle length of SVT revealed that in all instances in which verapamil induced VA block at a longer cycle length than in controls but did not prolong H2A2 or H-Ae interval, the shortest V1H2 interval and the cycle length of SVT (H-H interval) were significantly longer than the ventricular paced cycle length which produced VA block.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics and dynamics of calcium entry antagonists in systemic hypertension.

The calcium-entry antagonists verapamil, diltiazem and nifedipine (and their analogs) are all eliminated by hepatic metabolism and the rate of disposition is dependent on the rate of liver blood flow. During long-term administration, the profound hemodynamic effects of these agents result in changes in hepatic blood flow in association with decreases in arterial pressure, and either increases or decreases in measured cardiac output. This alters the drug's rate of delivery to the site of elimination, with concomitant changes in systemic clearance and a prolongation in elimination half-life. The pharmacokinetic data determined after initial single doses, therefore, only suggest the kinetic characteristics during long-term administration, because this profile depends on the drugs' sustained effects on liver blood flow. The elimination half-life of all 3 prototypical calcium antagonists is probably significantly prolonged during long-term dosing with clinically effective regimens. Patients with hepatic disorders in which liver blood flow is altered, such as cirrhosis, have profound changes in pharmacokinetics with both short- and long-term administration of verapamil and are likely to have similar changes with other calcium antagonists. During short-term administration, the plasma concentrations of verapamil and other calcium antagonists relate closely to the observed hemodynamic (and electrophysiologic) effects. With long-term administration, however, these correlations are much less impressive. When given in tablet form, nifedipine lowers blood pressure roughly in proportion to plasma levels between 20 and 200 ng/ml; verapamil plasma levels between 80 and 800 ng/ml are associated with antihypertensive efficacy. Plasma level measurements, therefore, are not of clinical importance as guides to antihypertensive therapy, except to identify noncompliance or abnormal patterns of drug handling.

Pharmacokinetics of calcium-entry blockers.

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.

Cardiovascular and pharmacokinetic consequences of combined administration of verapamil and propranolol in dogs.

Verapamil and propranolol, alone and in combination, were given intravenously to anesthetized dogs to analyze the interaction between drug-induced cardiovascular effects and the resulting changes in pharmacokinetics. Dosing regimens were used that produced steady state plasma levels of both drugs, and the observed effects were clearly related to the plasma concentrations of the agents. When given alone, at stable "therapeutic" levels in plasma, verapamil or propranolol decreased spontaneous heart rate, increased atrioventricular conduction time, and had opposite effects on cardiac output. At the same doses, the combined infusion of the 2 drugs rapidly resulted in profound depression in cardiac function; in addition, plasma concentrations of both agents increased into ranges associated with cardiovascular toxicity. When verapamil doses were reduced, combined infusion with propranolol decreased atrioventricular conduction and cardiac output, but drug plasma concentrations (and associated effects) remained stable. When reduced doses of propranolol were added to infusion of verapamil, similar effects on cardiovascular function occurred, but plasma drug levels increased progressively throughout the remainder of the study period. In all combinations studied, beta blockade with propranolol decreased liver plasma flow and, therefore, the systemic clearance of verapamil. The in vitro effects of propranolol on verapamil metabolism were small, although significant, and not clinically relevant. These acute studies suggest that the hemodynamic effects resulting from verapamil and propranolol in combination may significantly diminish clearance of 1 or both drugs, thereby resulting in accumulation during continued administration, increased drug effects with increasing plasma concentrations, and potentially lethal drug toxicity.

Efficacy of verapamil in exercise-induced ventricular tachycardia.

The antiarrhythmic efficacy of verapamil was determined by serial treadmill testing in 16 patients with reproducible exercise-induced ventricular tachycardia (VT). Twelve of the 16 patients responded to verapamil, 0.2 mg/kg intravenously; in 8 of these 12 responders, an oral verapamil regimen of 160 to 320 mg given every 8 hours also prevented exercise-induced VT. Plasma verapamil concentration was significantly higher in the responders than in the nonresponders to intravenous verapamil, but levels were similar in responders and nonresponders to oral therapy. The 8 responders to the oral drug were followed up while receiving verapamil therapy for 6 to 22 months (mean 15), and exercise-induced VT did not recur in any patient. Five of the 8 responders also had concomitant spontaneous VT unrelated to exercise which verapamil suppressed initially as well: 4 remained free of spontaneous VT, while 1 patient had recurrence of spontaneous VT. Thus, in patients with exercise-induced VT, verapamil is a promising alternative therapy to beta-adrenergic blocking agents. The effectiveness of verapamil is consistent with a mechanism of arrhythmogenesis involving calcium channels.

Guanethidine in antihypertensive therapy: experience with an oral loading regimen.

Guanethidine sulfate, a potent antihypertensive agent with a prolonged duration of action, was given in large oral doses to eight hypertensive patients in a loading technique. Blood pressure control resulted within one to three days without side effects, with total loading doses varying from 125 to 650 mg. Based on the drug's pharmacokinetic properties, a maintenance dose required to sustain the desired antihypertensive effects was calculated from the loading dose for each individual. Blood pressure was satisfactorily controlled in the seven patients followed for at least 12 months, and no modification of the calculated guanethidine dose was required. Side effects were minimal and well tolerated. The ease of initial blood pressure regulation with this regimen and the precision with which a maintenance dose can be determined suggest that guanethidine deserves a more prominent role in the therapy of established hypertension.

Correlation of plasma levels of nifedipine and cardiovascular effects after sublingual dosing in normal subjects.

Only limited work has been reported about the relationships of cardiovascular effects and plasma concentrations of the calcium-channel blocker nifedipine. In this study, placebo and nifedipine in 10-, 20-, 30-, and 40-mg doses were administered sublingually to ten normal subjects with at least three days between dosing periods. Blood pressure and heart rate were monitored every 30 minutes for two hours, and blood samples were taken after each measurement for determination of plasma nifedipine concentration by a sensitive and specific gas chromatographic method. Systolic blood pressure fell significantly (P less than 0.05) although briefly after 10 mg, but the effect persisted with larger doses. Diastolic blood pressure fell significantly only after 30- or 40-mg dosing. Heart rate increased significantly after all doses of nifedipine with the effect lasting longer with higher doses. Systolic blood pressure measurements were significantly related to the log of the concurrently measured plasma nifedipine concentrations (r = -.82, P less than 0.001). Diastolic blood pressure was also related to log nifedipine concentration (r = -.69, P less than 0.01). Heart rate, too, was linearly related to the log of nifedipine plasma levels (r = .75, P less than 0.001). These data indicate that the hemodynamic effects observed after acute nifedipine administration may be used to estimate whether or not significant quantities of the drug are being absorbed and that the intensity of the hemodynamic effects may, therefore, serve as a bioassay to evaluate the appearance of drug in plasma in therapeutic quantities.