Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Safety and efficacy of procainamide infusions.

Thirty-four patients who were resistant to conventional doses of lidocaine received procainamide intravenously according to a pharmacokinetically designed two infusion technique. A mean peak serum concentration of 7.1 mg/liter was achieved with an average loading dose of 989 mg administered over 1 hour. A mean steady state serum concentration of procainamide of 6.5 mg/liter was achieved with a mean dose of 64.4 mg/kg body weight for the first 24 hours of treatment. Dose, renal impairment, the degree of congestive heart failure and acetylator status influenced the steady state serum concentration of procainamide. Dangerous ventricular arrhythmias were abolished in 74% of the patients at a steady state level of 6.9 +/- 3.7 mg/liter (mean +/- standard deviation). Nonresponders to procainamide had a mean steady state serum concentration of procainamide of 4.2 +/- 2.1 mg/liter (P less than 0.05). Systolic and diastolic blood pressures decreased moderately (10 and 8%, respectively), and heart rate decreased 11%. The infusion was interrupted in one patient because of hypotension. The duration of electrocardiographic conduction intervals was increased slightly in some patients. It is concluded that procainamide administered by this two infusion method is effective and well tolerated by most patients.

Hyperventilation-induced T-wave changes in the limb lead electrocardiogram.

Seventy-two healthy young individuals were subjected to controlled, moderate hyperventilation with room air and with 4.9 percent CO2 in air, and monitored electrocardiographically. Significant summed frontal T-wave changes with hyperventilation (sigmaT1,2,3 larger than or equal to 1.5 mm) were observed in 12 patients. Six subjects (8.3 percent) showed T-wave depression. It was reversed in five patients by hyperventilation with 4.9 percent CO2 in air. T-wave elevation, observed in six subjects, was reversed in four patients by hyperventilation with 4.9 percent CO2. A short period of hyperventilation with an air mixture containing 4-5 percent CO2 is suggested as a means of screening patients under suspicion of ischemic heart disease exclusively on the basis of ECG changes.

Nitroglycerin pharmacokinetics after intravenous infusion in normal subjects.

The purpose of this investigation was to examine the pharmacokinetics of nitroglycerin in normal volunteers after intravenous drug administration. Eight subjects (including one subject on two occasions) received a dose of approximately 0.6 mg iv of nitroglycerin at a rate of 18 micrograms/min. Plasma concentrations of intact drug during and after the infusion were determined using a GLC method. Intra- and intersubject variability in nitroglycerin plasma kinetics was substantial. Generally, however, plasma nitroglycerin disposition was characterized by: (a) a large apparent plasma clearance (0.3-1 liter/min/kg), (b) a large volume of distribution (approximately 3 liters/kg), and (c) a rapid plasma half-life (approximately 3 min). From the apparent volume of distribution obtained, plasma drug can be estimated to account for only approximately 1.3% of total drug in the body. Minor fluctuations in tissue distribution, which can be produced by a myriad of external and internal stimuli, could cause dramatic fluctuation in plasma nitroglycerin concentrations and, hence, in the calculated pharmacokinetic parameters. For example, in two subjects studied, plasma nitroglycerin concentrations oscillated to such an extent that pharmacokinetic analysis could not be performed. In some subjects, steady-state concentrations were not observed in spite of the apparent short plasma half-life, and rebound in plasma concentrations during the postinfusion phase were evident. These phenomena were also observed in other kinetic studies involving organic nitrates.

Low intensity physical conditioning: effects on patients with coronary heart disease.

The effects of 12 weeks of low intensity physical conditioning on serum lipid levels, body composition, and cardiorespiratory function were studied among patients with coronary heart disease. Twenty-three men, 45 to 59 years old, volunteered to participate. Three were excluded for medical reasons, and one voluntarily discontinued exercise. The conditioning program included a 10-minute warmup, 15 to 30 minutes of walking-jogging at an individually prescribed intensity corresponding to 70% to 75% of maximum heart rate (HRmax), and a 5-minute recovery period. The conditioning resulted in a decrease (p less than 0.05) in heart rate and blood pressure during standard submaximal work (200 kg/m/min). Maximal heart rate increased (p less than 0.05) by five beats per minute. Symptom-limited maximal oxygen uptake increased 12.8% (p less than 0.001) when expressed per unit body weight. Body weight remained essentially unchanged (-0.34 kg), while fat-free weight and fat weight increased (+0.68 kg, p less than 0.05) and decreased (-1.02 kg, p less than 0.05), respectively. Serum lipid levels remained unaffected by the conditioning regimen. Low intensity exercise is effective in cardiac reconditioning and should be favored at least during the initial stages of a training regimen in view of the decreased orthopedic problems, added safety, high adherence level and tolerable working rate.

Digoxin concentrations in serum and saliva.

Serum and mixed saliva concentrations of digoxin were measured in 34 hospitalized patients. The mean saliva:serum concentration ratio of digoxin was 1.14 (plus or minus 0.48). Of 20 patients with saliva digoxin concentrations in the range of 0.7 to 1.5 ng/ml, 18 patients had serum concentrations which were within the same range. Saliva offers a convenient and noninvasive means of monitoring the digoxin status of patients.

Clinical pharmacokinetics of procainamide infusions in relation to acetylator phenotype.

The pharmacokinetics of procainamide was determined in 21 lidocaine-resistant patients who received the drug according to a pharmacokinetically designed double-infusion technique. Thirteen patients were phenotyped as slow acetylators, seven as fast, and one as intermediate. The total body clearances (ClT) of PA in slow and fast acetylators were 22.6 and 34.8 liters/hr, respectively. The fraction of PA cleared by the formation of NAPA in the corresponding acetylator group was 0.2 and 0.4. Renal impairment affected the pharmacokinetics of PA more profoundly as the ClT's of PA in patients with and without renal impairment were 17.9 and 31.2 liters/hr, respectively. None of the calculated volumes of distribution was affected by acetylator phenotype or renal impairment. These data identify the contribution of at least two of the major factors accounting for variability in PA disposition in patients undergoing therapy.

Pharmacokinetic approach to intravenous procainamide therapy.

A pharmacokinetic approach was employed to design a dosing regimen for the i.v. use of procainamide (PA) which consisted of a loading infusion given over one hour followed by a maintenance infusion. Therapeutic serum concentrations of PA were achieved in less than 15 min, and toxic serum concentrations were avoided in 12 patients. A mean maximum serum concentration of PA of 5.78 mg/l was obtained with a loading infusion of 16.6 mg/min PA HCl. An average steady-state serum concentration of PA of 5.05 mg/l was obtained with a mean maintenance infusion of 222 mg/hour PA HCl. The total body clearance of PA in slow and fast acetylators averaged 31 and 43 l/h respectively. Use of PA in cardiac patients by i. v. infusion can be safe and effective therapy.

Normalization of hypertensive responses during ambulatory surgical stress by perioperative music.

OBJECTIVE: The purpose of this study was to determine whether cognitive appraisals of stress level and hypertensive responses to ambulatory ophthalmic surgery can be ameliorated by patient-selected music. METHODS: We studied 40 elderly individuals requiring ophthalmic surgery, 20 in an experimental group (mean age, 74 years) and 20 in a control group (mean age, 77 years). All patients had an established resting blood pressure <140/90 mm Hg. In the experimental group self-selected music was provided by headphones throughout the preoperative, surgical, and postoperative periods. In the control group patients had neither headphones nor music. All patients received similar (weight-determined) doses of alfentanil and midazolam during surgery. Heart rate, blood pressure, and patient-reported stress and coping levels were the dependent variables. RESULTS: In both groups, blood pressure values were normal (approximately 129/82 mm Hg) during screening examinations 1 week before surgery. On the day of surgery both groups displayed increased preoperative blood pressures (approximately 159/92 mm Hg) associated with increases in heart rate (by approximately 17 beats/min). Intraoperative blood pressures in the experimental group returned quickly to screening baseline values, whereas the control group experienced persistent elevations in intraoperative blood pressure similar to preoperative levels. Over the course of the surgical experience, patients with music reported significant reductions in perceived stress and increases in coping abilities (p < .001), whereas those without music did not. CONCLUSIONS: The perceived stress of ambulatory surgery in geriatric patients is associated with a clinical hypertensive response that is ameliorated by self-selected perioperative music, which also decreases perceived stress and increases patients' sense of personal control and well-being.