Vincent P. Gotz

Seizures following Oral Lidocaine for Esophageal Anesthesia

Lidocaine is absorbed from mucous membranes of the oropharynx, gastrointestinal tract, and tracheobronchial tree. First-pass hepatic metabolism of the drug greatly reduces the amount reaching the general systemic circulation in the normal individual. In patients whose hepatic metabolism is reduced by disease or drugs, or in whom liver blood flow is reduced, this first-pass effect is decreased and lidocaine concentrations may be higher than those produced by the same dose in normal patients. We report an elderly man taking cimetidine with congestive heart failure in whom the accidental ingestion of lidocaine solution for esophageal anesthesia was followed by seizures and elevated serum lidocaine concentrations.

Dose-dependent kinetics of theophylline in adults with pulmonary diseases.

Summary: The incidence of dose-dependent pharmacokinetics of theophylline was retrospectively investigated in adults with pulmonary disease receiving continuous aminophylline infusions. Twenty-one of 180 successive admissions to medical intensive care units with a diagnosis of chronic obstructive pulmonary disease, asthma, or respiratory failure met the criteria of two steady-state serum theophylline concentrations on two different doses. Of these, 14 patients continued to smoke, whereas 7 had never smoked or had stopped<1 year prior to admission. No statistical difference existed between the mean systemic clearances of theophylline at the two different doses, using either total body weight or ideal body weight. Only 1 of the 21 patients met the criteria for dose dependency of a ± 50% reduction in clearance with dosage increase. Six of eight subjects with decreased clearance on the higher dose were nonsmokers. In contrast, all nine with augmented clearance following dosage increase were smokers. Four were considered to have proportional changes. In general, nonsmoking patients tended to have greater changes in serum theophylline concentration than in dosage. Conversely, smoking patients demonstrated smaller changes in concentration. The relationship of smoking status and dose-dependent theophylline elimination is discussed.

Bronchodilatory effect of subcutaneous epinephrine in acute asthma

Thirty-two adult patients presenting to the emergency department for treatment of acute asthmatic attacks refractory to home medications were studied. Each patient was randomly given a subcutaneous injections of 0.1 mg, 0.3 mg, or 0.5 mg epinephrine in a double-blind fashion. Bronchondilatation, as measured by peak expiratory flow rate (PEFR), was measured before and at 10, 20, and 40 minutes after injection. Bronchondilatation occurred with all dosages of epinephrine. No significant difference in PEFR was demonstrated among the three doses of epinephrine. Mean PEFR at each time differed significantly from the means of the other three values, with a steady increase over time (0.01 less than p less than 0.05). Repeating subcutaneous doses of epinephrine before maximal bronchondilatation is obtained may be irrational and potentially dangerous.

Computer-Simulated Conversion from Intravenous to Sustained-Release Oral Theophylline

A computer equipped with a pharmacokinetic program was used to theoretically determine the proper time to administer the first dose of a commonly prescribed, sustained-release oral theophylline product (Theo-Dur) in patients maintained on a continuous intravenous aminophylline infusion. Four conversion methods were tested. They included giving the first oral dose (1) immediately upon discontinuation of the iv infusion, (2) two hours after discontinuing the iv infusion, (3) four hours after discontinuing the iv infusion, and (4) two hours before discontinuing the iv infusion. Each of the four methods was simulated in three groups of patients: Smokers, nonsmokers, and patients with cirrhosis. Results showed that, in most situations, giving the first oral dose immediately upon discontinuation of the intravenous infusion provided minimal deviation from eventual steady-state levels. In addition, this computer simulation suggests that the initial 12-hour maintenance dose recommended by the FDA may result in toxicity in certain patient groups.

Effect of Dose and Ointment Application Technique on Nitroglycerin Plasma Concentrations

Each of ten non‐smoking, healthy male volunteers between the ages of 20 and 30 and within 10% of their ideal body weight received four nitroglycerin ointment (NTG‐O) treatments: ½″ NTG‐O over 3.94 in2 and 7.88 in2, and 1″ NTG‐0 over 3.94 in2 and 7.88 in2 in a randomized order. Eleven blood samples and 22 determinations of heart rate and blood pressure were obtained over each 6‐hour study period. Nitroglycerin plasma concentrations were determined by gas‐liquid chromatography with electron capture detection. Area under the nitroglycerin plasma concentration‐time curve (AUC), peak plasma concentration (Cmax), and time to peak concentration (Tmax) were determined for each study. Cmax and AUC values were corrected for the actual dose applied. Differences between AUC, Cmax and Tmax were tested using repeated measures analysis of variance. Change in surface area had no statistically significant effect on AUC, Cmax and Tmax. Mean AUC for the ½″ and 1″ doses differed (648 vs 2003 ng.ml−1 min, p = 0.016), as did Cmax (4.6 vs 12.4 ng.ml−1, p = 0.022); however, there was no correlation between individual doses and AUCs. Generally, NTG plasma concentrations within the proposed therapeutic range of 1.2–11.1 ng.ml−1 were detectable throughout each study interval. These data suggest that continuous absorption occurred throughout the 6‐hour dosing interval, that a trend toward increased AUC and Cmax occurred with the larger surface area, and that, in general, doubling the dose of NTG‐O doubles the AUC.

Clinical Pharmacy Case Reports: Recurrence of Intravenous-Diazepam-Induced Phlebitis from Oral Diazepam

A patient who developed phlebitis from the intravenous administration of diazepam is described. This episode resolved in two days after treatment with moist heat packs. Three days after complete resolution, the phlebitis recurred approximately eight hours after a single oral dose of diazepam. This recurrence of phlebitis resolved slowly over seven days, with warm soaks and aspirin therapy. Oral diazepam may have exacerbated the initial phlebitis by interfering with a subclinical healing process.

Clinical Utilization of Serum Theophylline Concentrations in a University-Affiliated Hospital:

Figure I. Nomogram for determination of endogenous creatinine clearance: (I) draw a perpendicular line at the patients weight (kg or Ib) until it crosses the line corresponding to the patients age; (2) draw a horizontal line at the crossing until it intercepts the line corresponding to the patients serum creatinine concentration; (3) draw a perpendicular line at the last crossing until it intersects the creatinine clearance axes; and (4) read the value at the intersection with the axis appropriate for the patients sex.

Influence of medroxyprogesterone on theophylline disposition

T HEOPHYLLINE is an effective bronchodilator widely used in the treatment of obstructive lung diseases. Serum theophylline concentrations correlate well with the ability of the drug to relax bronchial smooth muscle as well as with various mamfestations of toxicity. Theophylline has a narrow therapeutic index with optimal bronchodilator response and minimal toxicity occurring in the range of 10 to 20 ig/ml.’ The drug is metabolized in the liver, with only about 10 per cent excreted unchanged in the urine.2 In the rat, theophylline is metabolized via the cytochrome P,-450 (also known as P-448) hepatic microsomal oxidase system.3 Evidence suggests that theophylline is also primarily degraded by cytochrome P448 in humans since cigarette smoking markedly increases theophylline elimination,4’5 whereas phenobarbital exerts a lesser effect.67 Chronic hypoxia resulting from alveolar hypoventilation is frequently seen in patients with obstructive lung disease and thus the role of respiratory stimulants in the treatment of these diseases is of current interest. Progesterone is recognized as a potent respiratory stimulant that causes hyperventilation resulting in lowered PaCO2 and elevated Pa02.8 Recent investigations have found progesterone to be of some benefit in patients who hypoventilate, particularly obese patients and those with chronic obstructive lung disease.”#{176}

Serum lidocaine concentrations following application to the oropharynx: effects of cimetidine

Solutions of lidocaine hydrochloride are widely used for anesthesia of the oropharynx and respiratory tract prior to endoscopic procedures. It is commonly believed that this route of administration is not associated with clinically significant systemic absorption of the drug, and large doses of topical lidocaine are routinely used in this setting. Serious adverse effects, including seizures, occasionally occur. The extent of absorption of lidocaine from the oropharynx was studied in eight healthy volunteers. Wide variation in serum lidocaine concentrations was observed. A 14-fold range of peak lidocaine concentrations occurred following identical, accurately metered doses of a lidocaine aerosol spray preparation. The effects of cimetidine on lidocaine pharmacokinetics were also studied. Therapeutic doses of oral cimetidine significantly increased the area under the lidocaine time-concentration curve (p = 0.019), but no effect on the terminal-phase elimination rate constant was observed. Serum concentrations of α1-acid glycoprotein, a major binding protein of lidocaine, were significantly elevated following cimetidine (p = 0.030). Maximum lidocaine concentration, time to reach maximum concentration, and mean residence time of lidocaine were unchanged following cimetidine. These observations suggest an effect of cimetidine on the volume of distribution of lidocaine. Because of the wide variability in lidocaine pharmacokinetics and the potentially serious nature of adverse reactions, caution is advised in the use of topical lidocaine solutions in “standard” doses.

Effect of Filtering Amphotericin B Infusions on the Incidence and Severity of Phlebitis and Selected Adverse Reactions

This study evaluated the effectiveness of filtering amphotericin B (ampho B) on the incidence and severity of drug-related complications. Fifteen males receiving ampho B via peripheral vein infusion participated in this randomized, double-blind study. Each patient had his dose of ampho B diluted in 500 ml of dextrose 5% in water, to which hydrocortisone 25 mg was admixed and infused over four to six hours. Eight patients had their ampho B infusions filtered through a 1 μm filter after preparation, while seven patients did not have their ampho B infusions filtered. Patients were evaluated daily for phlebitis and selected adverse effects. The two groups were comparable with regard to diagnosis, concomitant drugs, cannula type and size, vein selection, and frequency of iv site change. Four patients in each group developed phlebitis. Statistical testing using the Mann-Whitney U test revealed no difference between groups with regard to patient age, dose of ampho B, frequency and severity of phlebitis, time to onset of initial phlebitis, and frequency of adverse effects (fever, chills, headache, nausea, vomiting, and anorexia). Filtration of ampho B infusions using a 1 μm filter does not appear to decrease the incidence or severity of phlebitis and associated adverse effects.