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.

Pharmacokinetic and pharmacodynamic evaluation of propafenone in patients with ventricular arrhythmia. Propafenone Research Group.

Propafenone, a class IC antiarrhythmic agent, is metabolized into two active metabolites: 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP). In a placebo-controlled, double-blind study, we examined trough plasma concentrations of propafenone and its two metabolites in 169 subjects. Patients were randomized to one of five parallel treatment groups: placebo and 337.5, 450, 675, or 900 mg/day propafenone with 24-hour ambulatory ECG monitorings, 12-lead ECGs, and plasma samples obtained at frequent intervals. Nonlinear kinetics were noted for propafenone and NDPP but not for 5-OHP. The ratio of NDPP to propafenone was about 10% at all doses, but the ratio of 5-OHP to propafenone decreased from 33% at 337.5 mg/day to 18% at 900 mg/day. Propafenone suppression of ventricular ectopy was dependent on concentration, with pairs and VT beats selectively suppressed at lower concentrations than VPBs. The PR interval and QRS duration increased significantly at propafenone concentrations above 100 ng/ml, while minimal heart rate slowing was noted at concentrations above 1,000 ng/ml.

Interaction between warfarin and propafenone in healthy volunteer subjects.

The effect of propafenone on the pharmacokinetics and pharmacologic effects of warfarin was studied in healthy normal male volunteer subjects. Each drug was administered alone for 1 week followed by a combined administration for 1 additional week. Blood samples were analyzed for propafenone and warfarin concentrations and the effect of each treatment on the prothrombin time was assessed. The concurrent administration of warfarin did not produce any changes in the absorption or disposition kinetics of propafenone. Concurrent propafenone administration did lead to a reduction in the clearance of warfarin, resulting in an average increase of 38% in the mean steady-state plasma warfarin concentration. During the combined therapy phase, the prothrombin time increased significantly (P less than 0.01) from the "warfarin alone" phase. We conclude from this study that the concomitant administration of propafenone and warfarin may lead to an enhanced anticoagulant effect that may require a reduction in the warfarin dose.

Verapamil disposition kinetics in chronic atrial fibrillation.

Verapamil disposition was studied in 12 patients with chronic and fibrillation. After an intravenous bolus of 15 mg plasma concentration was determined and the data fit in a three-compartment model. Model independent parameters were calculated and values for half-life (t 1/2), clearance, and steady-state distribution volume were 6.3 +/- 4 hr, 13.3 +/- 7.7 ml/min/kg, and 4.3 +/- 1.9 l/kg. The model was used to design a multistep infusion scheme, which was employed successfully to achieve predetermined plasma concentrations. Following single oral doses of 120 mg, plasma levels of verapamil and norverapamil were determined. The elimination t 1/2 for verapamil and norverapamil were 8.3 +/- 6.1 and 10.5 +/- 5.6 hr, respectively. The bioavailability of oral verapamil was 35 +/- 16%. During long-term oral therapy the mean verapamil plasma concentration was twice the value predicted from the single-dose studies. This suggests that verapamil may have reduced clearance during long-term oral use.

Effects of sulphydryl inhibitors on frog sartorius muscle: p-chloromercuribenzenesulphonic acid.

1. Experiments were done on frog sartorius muscles to study the effects and mechanisms of action of the -SH inhibitors, p-chloromercuribenzoic acid (PCMB) and p-chloromercuribenzenesulphonic acid (PCMBS).2. Both organomercurials produce a depolarization of the surface membrane which is associated with a period of asynchronous twitching and followed by inexcitability.3. Only PCMB produces a unique fractionation of the electrically evoked twitch into an initial rapid and later slow phase.4. PCMB and PCMBS increase the rate of (45)Ca efflux from whole muscle. Ethylenediamine tetraacetic acid (EDTA, 5 mM) causes only limited antagonism of the enhancement of (45)Ca efflux produced by PCMB whereas it completely antagonizes this same effect of PCMBS. EDTA selectively removes superficial calcium without penetrating into the intracellular space.5. The results suggest that PCMB inhibits -SH groups in the terminal cisternae causing a fractionation of the twitch. PCMBS acts primarily at surface sites with limited access to the cisternae and sarcoplasmic reticulum.

Effects of sulphydryl inhibitors on frog sartorius muscle: N-ethylmaleimide.

1. The characteristic action of the -SH inhibitor, N-ethylmaleimide (NEM), is muscle rigour. The dose-response curve indicates a biphasic effect with maximum rigour tension produced by 1.0 mM NEM; beyond 1.0 mM there was an inverse relationship between dose and response.2. NEM produces a membrane depolarization unrelated to rigour development.3. NEM causes a sustained increase in (45)Ca efflux from whole muscle. Pretreatment of a muscle with ethylenediamine tetra-acetic acid (EDTA, 5 mM) to remove membrane calcium does not alter the NEM induced (45)Ca efflux.4. It is suggested that the primary site of NEM action is inhibition of calcium uptake by the sarcoplasmic reticulum thereby producing rigour. At concentrations above 1.0 mM, NEM may affect the myofilaments.

Prenylamine-induced contracture of frog skeletal muscle.

1. Experiments were performed to determine the influence of prenylamine on excitation-contraction coupling in frog sartorius muscle. 2. Prenylamine (0.2-1.0 mM) produced a biphasic contracture in skeletal muscle characterized by an initial phasic and subsequent tonic contracture. 3. Neither dantrolene nor procaine blocked the prenylamine-induced contracture. Pretreatment with 100 mM K+ blocked the phasic but not the tonic component of the prenylamine contracture. 4. Prenylamine produced a sustained increase in 45Ca efflux at all concentrations that produce contracture. These concentrations of prenylamine also depressed the action potential, muscle twitch and resting potential. 5. Low concentrations of prenylamine (0.05 mM) which produced neither contracture, 45Ca efflux nor 45Ca influx, depressed the action potential, muscle twitch and K+ contracture. 6. The results suggest that prenylamine not only alters calcium mobility but also membrane permeability to other ions.

Alteration of medullary respiratory unit discharge by iontophoretic application of putative neurotransmitters.

1 Cats with midcollicular decerebration were vagotomized, paralyzed and artificially ventilated. Phrenic nerve activity was recorded as an index of central respiratory rhythm. Medullary respiratory neurones and non-respiratory cells located in approximation to the ventral respiratory nucleus were tested for their responsiveness to iontophoretically applied gamma-aminobutyric acid (GABA), acetylcholine (ACh) and glutamate. 2 GABA tended to inhibit, whereas ACh and glutamate excited activity both of respiratory and non-respiratory units. Some phase-spanning respiratory unit activities were converted to phasic discharge patterns linked to either inspiration or expiration concomitant with application of low GABA doses. Appropriate applications of GABA also resulted in a complete cessation of the respiratory or non-respiratory neuronal activities. 3 While application of ACh or glutamate induced continuous firing in phasic, phase-spanning respiratory neurones, the periodic discharge patterns of inspiratory or expiratory units was not altered by ACh or, in many instances, by glutamate. Only at high doses of glutamate was the phasic discharge of some inspiratory or expiratory units converted to tonic activity. 4 These observations suggest that strong inhibitory processes serve to maintain the phasic firing pattern of respiratory units. These data also support the concept that active-inhibitory phase-switching mechanisms serve to define respiratory rhythmicity.

Pharmacokinetic and pharmacodynamic interactions of propafenone and cimetidine.

The pharmacokinetics and pharmacodynamics of the extensively metabolized antiarrhythmic agent propafenone were assessed alone and during concomitant administration of cimetidine. Twelve healthy subjects were given successively the following treatments: propafenone 225 mg q8h plus cimetidine placebo; cimetidine 400 mg q8h plus propafenone placebo; and propafenone 225 mg plus cimetidine 400 mg q8h. After a minimum of 5 days on each regimen, plasma drug concentrations and electrocardiogram conduction intervals were measured during a drug washout period. The maximum concentration of propafenone in plasma was 993 +/- 532 ng/mL when propafenone was given alone compared with 1230 +/- 591 ng/mL when propafenone was given with cimetidine (P = .0622). Differences in tmax, t1/2, and Cp ss did not approach statistical significance when propafenone alone was compared with propafenone plus cimetidine. When compared with cimetidine, propafenone significantly increased the PR interval from 161 +/- 5 msec to 192 +/- 6 msec (P less than .01) and the QRS duration from 89 +/- 3 msec to 98 +/- 4 msec (P less than .01). Combination therapy caused a modest additional increase in QRS duration to 103 +/- 3 msec (P less than .01). In conclusion, cimetidine caused small changes in propafenone pharmacokinetics and pharmacodynamics; but these changes are unlikely to be clinically important.

Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects.

In a relatively small pilot study, the half-life of elimination of hydromorphone in six subjects was 2.64 +/- 0.88 hours and the drug had a high volume of distribution, 1.22 l./kg. In addition, the drug was rapidly but incompletely absorbed after oral administration. An equation to predict the plasma concentration of hydromorphone on oral administration was developed from the data of these six subjects.

Interaction between propranolol and propafenone in healthy volunteers.

The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady-state, were analyzed for propafenone and its two metabolites as well as for propranolol and 4-hydroxypropranolol. Left ventricular function, exercise performance and electrocardiographic intervals were assessed. Coadministration of propranolol did not produce any significant change in propafenone kinetics including peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination rate constant (t1/2), mean steady-state plasma concentration (Css), or area under the concentration vs time curves. However, concomitant propafenone administration significantly increased Cmax (83%), Tmax (55%), t1/2 (30%), and Css (213%) which were accompanied by significant decreases in plasma levels of 4-hydroxy-propranolol. Propafenone and propranolol significantly reduced supine systolic and diastolic blood pressure by 2.5 to 15.4%. The combination did not reduce diastolic blood pressure further (64.0 +/- 2.8 to 59.7 +/- 1.7 mmHg) nor did it produce a supplemental reduction in heart rate (12% reduction with propranolol, 10% reduction with concomitant administration). Propranolol, but not propafenone, significantly decreased end-diastolic volume index (13%), stroke volume index (15%), and velocity of circumferential fiber shortening (19%). The combination did not cause any further changes in echocardiographic measurements. Electrocardiographic intervals were not altered by either drug use alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of coadministration of propafenone on the pharmacokinetics of digoxin in healthy volunteer subjects.

Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P less than 0.05). The renal clearance and half-life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half-life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.

Characteristicas and response differences to iontophoretically applied norepinephrine, D-amphetamine and acetylcholine on neurons in the medial and lateral vestibular nuclei of the cat.

Midcollicular decerebrate cats, with their cerebellum removes, were tested with controlled acceleratory motion in order to identify neurons in the medial vestibular nucleus (MVN) and lateral vestibular nucleus (LVN) which responded to a motion stimulus. Five-barredled micropipettes were used to record single neuron activity and to apply norepinephrine (NE), d-amphetamine and acetylcholine (ACh). These agents were studied on spontaneously firing cells which responded to a motion stimulus and others which were in the MVN were inhibited by NE and d-amphetamine but were unaffected by iontophoresis of the alpha-adrenergic blocking agent phentolamine or the beta-antagonists, MJ-1999 or propranolol. In the LVN a majority of the cells tested were excited by NE and d-amphetamine. NE excitation in the LVN was antagonized by phentolamine but not by MJ-1999 or propranolo. Cats pretreated with reserpine to deplete brain catechlamines showed typical responses to NE BUT IONTOPHORESIS OF D-AMPHETAMINE WAS WITHOUT EFFECT. Unlike the differential sensitivity observed for NE, ACh excited most cells in both the MVN and LVN. NE and ACh produced similar responsed on vestibular neurons modulated by motion and those not responsive to motion. These observations suggest that NE-containing terminals are in close proximity to the vestibular neurons which were tested and further implicate both NE and ACh as neurotransmitters in afferent pathways to the vestibular nuclei.

Iontophoretic studies of histamine and histamine antagonists in the feline vestibular nuclei.

The activity of single neurons in the vestibular neuronal complex of midcollicular decerebrate, decerebellectomized cats were recorded and their responsiveness to iontophoretically applied histamine and other agents determined. The majority of the cells tested were inhibited by iontophoresis of histamine while 24% were excited by this agent. Neurons exhibiting inhibitory responses were widely distributed throughout the four vestibular nuclei and adjacent reticular formation whereas excitatory responses to histamine were obtained mainly in the region of the lateral vestibular nucleus. The H2-receptor blocking agents metiamide and cimetidine were examined as to their actions on spontaneously firing cells and cells affected by histamine. Metiamide was selective in blocking histamine-induced inhibition but not excitation while cimetidine was ineffective in blocking either response. These results suggest that histamine has both inhibitory and excitatory actions on brain stem neurons and metiamide is an effective antagonist of histamine-induced inhibition.

Plasma and saliva propafenone concentrations at steady state.

Twenty-four healthy male subjects were administered 300 mg of propafenone every 8 h for 6 d in each of two phases that were separated by 2 d. Plasma samples were collected during the approach to steady state for each phase, and plasma and saliva samples were collected frequently at steady state. Both plasma and saliva propafenone were assayed by a specific HPLC method. Two estimates of elimination half-life (t1/2), mean steady-state concentration (CPss), time to maximal concentration (tmax), and maximal concentration (CPmax) were estimated for each subject. Also mean steady-state saliva concentrations (CSss), time to maximal saliva concentration (tSmax), and maximal saliva concentrations (CSmax) were estimated. A large intersubject variance in both t1/2 and CPss were observed in the 24 subjects, with the t1/2 values ranging from 2.1 to 27.2 h and the CPss values from 0.3 to 3.03 microgram/mL. Each subject was quite consistent for the two phases, suggesting a relatively low intrasubject variance for propafenone kinetics. A histogram shows most subjects to have t1/2 values between 2 and 10 h, with diminishing numbers of subjects at greater t1/2 values rather than a bimodal distribution. Saliva concentrations ranged from 12 to 72% of the corresponding plasma concentrations, being 24.7 +/- 11.1% of the simultaneously collected plasma sample overall (mean +/- SD). a significant (p less than 0.001) positive correlation exists between CPss and CSss.