Factors affecting free (unbound) lignocaine concentration in suspected acute myocardial infarction.

1. Free plasma lignocaine concentrations were measured for up to 48 h after constant infusion of the drug in 41 subjects with suspected acute myocardial infarction. 2. The free plasma lignocaine clearance at 12 h was significantly and proportionately related to body weight and to the presence of mild (Killip Class II) heart failure, with an 18% reduction in free clearance in the latter condition. 3. The free plasma lignocaine was not related to sex, age or the presence of confirmed acute myocardial infarction, when corrected for the effects of body weight and presence of heart failure. 4. Free plasma lignocaine concentration 1 h after a fixed loading dose were also significantly related to body weight and presence of heart failure but not to sex, age or proven acute myocardial infarction. 5. The data indicate that correction of loading and maintenance infusion for body weight and presence of (even mild) heart failure should somewhat reduce variability in free (and presumably active) plasma lignocaine concentrations but that the free plasma lignocaine concentration at 12 h is most accurately predicted by measuring the free (and to a lesser extent total) plasma lignocaine concentration at 1 h.

Effect of cetamolol on epinephrine-induced hypokalemia.

The effect of cetamolol (an investigational cardioselective beta blocker with intrinsic sympathomimetic activity) on the hypokalemic response to epinephrine infusions in normal subjects was evaluated and compared with placebo and two other beta-adrenergic blocking drugs. After two daily doses of cetamolol 15 mg, atenolol (a cardioselective beta blocker) 50 mg; a long-acting propranolol preparation (a nonselective beta blocker) 80 mg; or placebo, 12 men (mean age, 26.7 years) were infused with epinephrine. The resulting average plasma epinephrine level was 1123 pg/mL, whereas average baseline serum potassium levels for the four treatment groups ranged from 3.94 to 4.07 mEq/L. Epinephrine-induced hypokalemia occurred in the placebo group (maximum potassium decrease of 1.00 mEq/L) and in the atenolol group (maximum potassium decrease of 0.59 mEq/L); potassium levels did not decrease but rose slightly in subjects receiving cetamolol or propranolol. Subjects treated with placebo or atenolol also demonstrated statistically significant prolongation of the QTc interval (0.039 seconds with placebo; 0.023 seconds with atenolol) and frequently developed T-wave flattening and U-wave appearance. After pretreatment with cetamolol or propranolol, however, the QTc interval was unaffected, T-wave abnormalities did not occur, and U waves appeared only rarely. The results of this study indicate that cetamolol blocks epinephrine-induced hypokalemia and associated electrocardiographic changes.

The effect of etodolac administration on renal function in patients with arthritis.

The effect of etodolac 50-600 mg/d on renal function was assessed in four- to 52-week trials in 1,382 patients with arthritides. No patient was withdrawn from treatment due to an abnormal renal function test related to etodolac administration. There were no significant differences in the incidence of definite renal function abnormalities between patients receiving etodolac and those receiving placebo. Both etodolac and placebo groups had a significantly lower incidence of deviant BUN results than either aspirin- or sulindac-treated patients. Fewer than 2% of patients receiving etodolac showed either a persistent or variably persistent pattern of deviant renal function tests. The results in these studies indicate that chronic etodolac therapy did not adversely affect renal function in patients with arthritis.

In support of cardiac chronotropic beta 2 adrenoceptors.

The effects of atenolol (50 mg) and propranolol (40 mg) on exercise- and isoproterenol-induced heart rate increments were studied in 9 male volunteers. Propranolol reduced maximal heart rate from 187 +/- 4 to 146 +/- 7 beats/min and atenolol reduced it to 138 +/- 6 beats/min. There was no difference between the drugs at any point during exercise. Isoproterenol sensitivity was measured as the dose of isoproterenol required to increase resting heart rate by 25 beats/min (CD-25). Propranolol increased the CD-25 from 1.8 +/- 0.3 micrograms after placebo to 39 +/- 8 micrograms and atenolol increased the CD-25 to 8 +/- 2 micrograms. The increase by propranolol was significantly greater than that of atenolol. Intravenous atropine (0.04 mg/kg) did not alter the isoproterenol CD-25 during placebo or atenolol. The CD-25 with propranolol decreased after atropine (39 +/- 8 versus 25 +/- 5 micrograms) and was due to diminished plasma propranolol concentrations as the drug sensitivity (measured by Ka) was unchanged before (12 +/- 2 ml/ng) and after (10 +/- 3 ml/ng) atropine. These data support the hypothesis that moderate exercise is primarily a beta 1-mediated response and therefore equally antagonized by cardioselective and nonselective blockers, but that isoproterenol stimulates both beta 1 and beta 2 receptors. The greater ability of the nonselective agent to antagonize isoproterenol tachycardia with no significant change after atropine suggests the presence of cardiac beta 2 chronotropic receptors. The physiologic and pathologic importance of these receptors has yet to be determined.

A free lignocaine index as a guide to unbound drug concentration.

A free lignocaine index was developed on the basis of measurements of plasma lignocaine and its principle binding protein, alpha 1-acid glycoprotein (AAG) in 80 samples from 16 patients admitted to the coronary care unit and given prophylactic lignocaine therapy. The free drug fraction, fu, of lignocaine was determined by equilibrium dialysis and its relationship to AAG and total lignocaine concentration (T) defined by multiple linear regression analysis as l/fu = 1.45 + 0.023 (AAG) -0.129 (T) (multiple r = 0.872, P less than 0.001). This relationship was used to calculate the 'free lignocaine index' as fu X T and compared with the observed value obtained by equilibrium dialysis of 178 samples from 41 separate subjects who received lignocaine after suspected myocardial infarction. There was a highly significant relationship (r = 0.933, n = 178, P less than 0.001) between the observed and predicted values. We conclude that the free drug index may be useful in rapidly assessing the unbound (free) concentration of lignocaine in plasma.

Determinants of plasma alpha 1-acid glycoprotein (AAG) concentrations in health.

The concentration of alpha 1-acid glycoprotein (AAG) was measured in plasma from 200 healthy subjects belonging to 78 family units. The AAG concentration varied markedly between individuals (mean 0.77, range 0.36-1.46 g 1(-1]. When the genetic contribution to the variability was assessed, the only significant correlation observed was that between husband and wife and this was weak. We conclude that in addition to the known effects of age and gender, environmental (rather than genetic) factors largely determine the variance of AAG concentrations.

The effects of age and smoking on the plasma protein binding of lignocaine and diazepam.

In 63 healthy ambulant subjects 18 to 88 years of age, the plasma protein binding of diazepam (principally bound to albumin) decreased with age. Diazepam binding in plasma correlated positively with plasma albumin concentration which also decreased with age. In contrast, the plasma protein binding of the basic drug, lignocaine (predominantly bound to alpha 1-acid glycoprotein [AAG]), tended to increase slightly with age. Lignocaine binding in plasma correlated positively with plasma AAG concentration which also increased slightly with age. Smoking did not affect the plasma protein binding of diazepam or lignocaine or the plasma concentrations of albumin, AAG or nonesterified fatty acids. These results suggest that age-related changes in plasma protein binding of lignocaine and diazepam are determined in part by age-related changes in the concentrations of the binding proteins in plasma. The ageing process alone causes only small changes in the plasma protein binding of these drugs compared with the effect of disease states, however.

Beta 1-selective and non-selective beta-adrenoceptor blockade, anaerobic threshold and respiratory gas exchange during exercise.

The effect of oral doses of the beta 1-selective adrenoceptor antagonist atenolol (50 mg), the non-selective antagonist propranolol (40 mg) and placebo was investigated during exercise in a crossover comparison in six healthy but untrained subjects. Descriptors of ventilation, respiratory gas exchange, and arterialized blood lactate and glucose were obtained during steady state bicycle ergometric exercise at 20% and 60% of the subjects' previously determined maximal oxygen uptake (VO2 max). At these work intensities, the previously reported increase of respiratory exchange ratio (RER) during non-selective beta-adrenoceptor blockade was found to be trivial (placebo = 0.96 +/- 0.03 s.e. mean; propranolol = 0.97 +/- 0.01; atenolol = 0.97 +/- 0.04; 60% VO2 max, 10 min exercise) and only present during the early minutes of effort. Oxygen uptake and carbon dioxide production did not differ between treatments. Both drugs produced highly significant falls in peak expiratory flow (PEF) rates and tidal volume (VT) which were compensated by an increase in respiratory rate. PEF, 60% VO2 max: placebo = 3.8 +/- 0.3 l/s; propranolol 3.6 +/- 0.3 l/s (P less than 0.03); atenolol 3.1 +/- 0.3 l/s (P less than 0.01). VT, 60% VO2 max: placebo 2.0 +/- 0.1 l; propranolol 1.8 +/- 0.21 (P less than 0.05); atenolol 1.7 +/- 0.1 1 (P less than 0.01). Arterialized lactate was significantly elevated during work at 20% and 60% VO2 max, but rose progressively at the 60% VO2 max load. Ventilation, oxygen uptake and ventilatory equivalent for carbon dioxide also rose progressively at this workload. Ventilatory equivalent for oxygen showed no significant rise.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of cimetidine on verapamil kinetics and dynamics.

The kinetics and dynamics of single doses of verapamil (10 mg iv and 120 mg by mouth) were followed in eight subjects on oral cimetidine (300 mg every 6 hr) and placebo. Cimetidine had no effect on intravenous verapamil kinetics but induced a significant rise in oral verapamil bioavailability. Other kinetic parameters of verapamil were not altered by cimetidine. Verapamil induced a significant slowing of atrioventricular conduction (39.8 msec intravenous; 24.5 msec oral). Although there was a significant increase in oral verapamil bioavailability, after cimetidine, there was no change in PR interval prolongation with either oral or intravenous verapamil. Our data demonstrate the importance of correlating measurable drug effects with kinetic studies when drug interactions are studied and their clinical significance is assessed.

Hemodynamic and metabolic responses to exercise after adrenoceptor blockade in humans.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metabolic responses to acute exercise 2 h after prolonged prior exercise to induce skeletal muscle glycogen depletion, enhancing the dependence on hepatic glucose output and circulating free fatty acids (FFA). Plasma catecholamines were higher during exercise after, as opposed to before, glycogen depletion and were elevated further by all three drugs. Propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. Atenolol reduced systolic blood pressure and did not change diastolic blood pressure. Both beta-blockers reduced FFA levels, but only propranolol lowered plasma glucose relative to placebo during exercise after glycogen depletion. In contrast, prazosin reduced systolic and diastolic blood pressures and resulted in elevated FFA and glucose levels. The results indicate important differences in the hemodynamic effects of beta 1-selective vs. nonselective beta-blockade during exercise after skeletal muscle glycogen depletion. Furthermore they confirm the importance of beta 2-mediated hepatic glucose production in maintaining plasma glucose levels during exercise. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamines, which in the absence of blockade of hepatic beta 2-receptors produces elevation of plasma glucose. The results suggest there is little role for alpha 1-mediated hepatic glucose production during exercise in humans.

Demonstration of beta adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic, radioligand binding and adenylate cyclase activation studies.

The postulated beta adrenoceptor blocking properties of the new antiarrhythmic drug propafenone were studied by in vivo comparison against placebo and propranolol in the antagonism of both exercise- and isoproterenol-induced tachycardia and by in vitro radioligand binding studies of animal and human left ventricular muscle membrane preparations. Interaction with frog erythrocyte membrane adenylate cyclase was also investigated. In the clinical studies, a double blind crossover comparison of oral propafenone (300 mg), propranolol (40 mg) and placebo indicated significant antagonism of chronotropic response to isoproterenol 2 hr postdose with dose ratios of 4.1 +/- 1.3 (mean +/- S.E.M.) for propafenone and 16.8 +/- 5.1 for propranolol. Chronotropic response to exercise was modestly reduced by propafenone. Analysis of the binding of [125I]iodocyanopindolol to human left ventricular membranes revealed specific beta adrenoceptor competition by propafenone with an EC50 of 111 +/- 13 nM. Propranolol EC50 was 2.4 +/- 0.2 nM in this system. Competitive inhibition of isoproterenol-stimulated frog erythrocyte membrane adenylate cyclase activity was also obtained with propafenone. The ratio of affinities (calculated from the apparent dissociation constant; KD) for propranolol-propafenone was 1:40 for the in vivo study and 1:50 for the in vitro system. Propafenone is a specific antagonist of the human beta adrenoceptor and this action can be demonstrated during in vivo study in human subjects. At clinical dosages it appears likely that it will achieve a modest degree of beta blockade which may contribute to its antiarrhythmic effect.

Hemodynamic and metabolic responses to exercise after alpha 1-, beta 1-, and nonselective beta-adrenoceptor blockade in man.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study. The study involved measurement of the hemodynamic and metabolic responses to exercise after heavy exercise in order to induce skeletal muscle glycogen depletion and thus enhance the dependence on hepatic glucose output and circulating free fatty acids. Catecholamine responses to exercise were enhanced by glycogen depletion and by both beta-blocking drugs. Catecholamine levels were highest with propranolol; as a consequence, at high work loads, propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. At high work loads, atenolol reduced systolic blood pressure but did not change diastolic blood pressure. Both beta blockers reduced free fatty acid levels, but only propranolol accelerated the fall of plasma glucose levels during "glycogen-depleted" exercise. In contrast, during exercise prazosin reduced systolic and diastolic blood pressures, and elevated heart rate and plasma catecholamines, particularly noradrenaline. Concomitantly, prazosin raised free fatty acid and lactate levels, and increased the plasma glucose level at a time when placebo therapy resulted in a steady fall in glucose levels. The results indicate important differences in the hemodynamic effects of cardioselective versus nonselective beta-blockade during long-term (or glycogen-depleted) exercise. The importance of beta 2-mediated hepatic glycogenolysis in man is confirmed. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamine levels. There is no indication of an important role for an alpha 1-mediated mechanism in hepatic glucose production in man.

alpha 1-Acid glycoprotein and plasma lidocaine binding.

The relationship between the degree of plasma binding of lidocaine (lignocaine) and the concentration of the acute phase reactant, alpha 1-acid glycoprotein (AAG), is reviewed. Studies in normal subjects and patients with myocardial infarction, renal disease, hepatic failure and receiving antiepileptic drug therapy have all shown a remarkably good relationship between AAG concentration and the binding ratio for lidocaine. In situations where AAG is altered, particularly myocardial infarction, the usual therapeutic range for total plasma lidocaine concentrations may not apply and must be interpreted appropriately. This provides the strongest rationale for monitoring free rather than total drug concentration as an aid in lidocaine therapy.

Life-table methods for evaluating antiarrhythmic drug efficacy in patients with paroxysmal atrial tachycardia.

Spontaneous variability in the occurrence of paroxysmal arrhythmias has made it difficult to apply objective and quantitative methods to describe their clinical course. In this study of paroxysmal atrial tachycardia, the "tachycardia-free interval" was used as a quantitative measure of drug efficacy during treatment with oral verapamil. The tachycardia-free interval is the time a patient remains free from an episode of tachycardia after drug treatment is begun. We documented recurrent tachycardia by telephone transmission of the electrocardiogram. Improvement caused by increasing the drug dose (360 versus 480 mg/day) or by comparing verapamil with placebo treatment was demonstrated by upward shifts in the cumulative tachycardia-free interval curves. The tachycardia-free interval is an easily measured clinical variable that has substantial promise in the study of paroxysmal arrhythmias.

Effect of verapamil on left ventricular function at rest and during exercise in normal men.

Verapamil is a calcium channel blocking agent used primarily for treatment of arrhythmias and coronary artery disease. It may also depress myocardial contractility. The purpose of this study was to assess the effect of verapamil on left ventricular function. Twelve normal men, 22-29 years of age, were studied at rest and during exercise, with and without verapamil, using first-pass radionuclide angiocardiography. Verapamil was administered by continuous intravenous infusion to produce steady-state blood levels of 106-123 ng/ml. The heart rate, ejection fraction, stroke volume index, and end-diastolic volume index were measured with and without the drug. Verapamil increased the mean resting heart rate from 74 to 78 beats/min (p = 0.001), decreased the mean stroke volume index from 48 to 42 ml/m2 (p = 0.01), and decreased the mean end-diastolic volume index from 77 to 71 ml/m2 (p less than 0.05). No changes in cardiac index, ejection fraction, end-systolic volume index, or peak systolic pressure/end-systolic volume ratio were observed at rest. No differences occurred in exercise hemodynamics. Thus verapamil at therapeutic dose levels did not significantly depress contractility or have other clinically important hemodynamic effects at rest or during exercise in normal subjects.

Comparison of high-dose and medium-dose propranolol in the relief of exercise-induced myocardial ischemia.

The effects of medium-dose (160 mg/day) and high-dose (480 mg/day) oral propranolol were compared in 22 patients who had typical angina pectoris and objective evidence of myocardial ischemia during exercise. Left ventricular (LV) ejection fraction (EF) and wall motion score (WMS) (an index of regional LV dysfunction) were assessed by radionuclide angiography both at rest and during exercise to the pretreatment maximum work load. Functional class improved in 11 of the 22 patients during medium-dose propranolol therapy. Medium-dose propranolol reduced mean resting heart rate from 71 to 55 beats/min, exercise heart rate from 122 to 93 beats/min, and exercise systolic blood pressure from 183 to 162 mm Hg (p less than 0.001 for each). The incidences of exercise-induced chest pain and S-T segment depression were reduced from 19 to 9 patients (p less than 0.001), and from 20 to 10 patients (p = 0.002), respectively. Medium-dose propranolol had no effect on mean EF or WMS at rest, but improved function in ischemic regions during exercise; WMS decreased (p = 0.001), and mean exercise EF increased from 0.51 to 0.56 (p = 0.025). Compared with the medium dose, high-dose propranolol improved functional class in 3 additional patients, and further reduced mean resting heart rate (from 55 to 52 beats/min, p = 0.001) and mean exercise heart rate (from 93 to 86 beats/min, p = 0.001). Exercise-induced chest pain and S-T segment depression were abolished in a further 7 and 6 patients, respectively. Exercise EF and WMS improved further in several patients, but the changes were not statistically significant for the group (p = 0.095 and 0.082, respectively). Thus, in patients with coronary artery disease and exercise-induced ischemia, propranolol reduced heart rate and blood pressure and the incidence of exercise-induced chest pain, electrocardiographic changes, and ischemic LV dysfunction. Although most of these effects were seen with medium-dose propranolol, higher doses provided additional relief of chest pain and S-T segment depression, and further improved global and regional LV function in several patients.

Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol.

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

Clinical pharmacology of the beta-blocking drugs: implications for the postinfarction patient.

All available beta-adrenergic blocking agents share the property of blocking beta 1 adrenoceptors, including those in the heart. They differ, however, in their ability to block beta 2 receptors (cardioselectivity), their membrane stabilizing action, intrinsic sympathomimetic activity and their pharmacokinetic properties. The strongest evidence for efficacy in secondary prevention has been obtained with timolol, metoprolol and propranolol. Timolol and propranolol block all beta-receptor-mediated responses and are therefore nonselective, whereas metoprolol is relatively cardioselective. Propranolol and metoprolol have membrane stabilizing action, but timolol does not; none of these agents show intrinsic sympathomimetic activity. Thus, no ancillary property is a requirement for efficacy. All of these agents may precipitate heart failure, but this problem has been exaggerated, and transient failure during the early course of myocardial infarction is no longer a contraindication to therapy. Cardioselective agents cause less bronchospasm, but this can still occur, especially with higher dosages. In addition, these agents probably cause somewhat less fatigue and result in less hypertension during hypoglycemia than nonselective agents. The availability of at least three effective agents allows for a choice of therapy to offer individual patients.

Pharmacokinetic and pharmacodynamic effects of diltiazem.

The pharmacokinetic and pharmacodynamic effects of diltiazem were studied in 8 patients after a short intravenous infusion (20 mg over 10 minutes), a single oral dose (60 or 90 mg), and repeated oral administration (60 or 90 mg every 6 hours for 16 doses). Diltiazem levels decreased in a triexponential manner after intravenous infusion. Terminal half-lives after intravenous, single oral, and repeated oral administration were not significantly different (4.5 +/- 1.3, 3.7 +/- 0.6, and 4.9 +/- 0.4 hours, respectively). The kinetic effects of oral diltiazem were nonlinear. With repeated oral administration, there was accumulation of both diltiazem and its metabolite, deacetyldiltiazem. The diltiazem area under the time versus concentration curve increased by a factor of 2.39 +/- 0.42 (p = 0.00002). Most patients showed a double peaked time versus concentration curve after oral administration, indicating possible enterohepatic recirculation. After intravenous administration, there was a substantial increase in the P-R interval (14.3 +/- 5.4%). Although only small changes in P-R interval were seen with a single oral dose, with chronic administration there was persistent P-R interval prolongation, peaking at 17.3 +/- 5.6% over control. Counterclockwise hysteresis was present in the P-R interval versus plasma diltiazem concentration curve after intravenous administration. Only small changes were seen in heart rate and blood pressure.