Stuart M. MacLeod

Intravenous paraldehyde for seizure control in newborn infants

We studied 14 newborn infants with seizures after birth asphyxia or other causes. Paraldehyde was given as a 200 mg/kg IV bolus followed by an infusion of 16 mg/kg/h (10 cases), or as a 400 mg/kg bolus (4 cases). Serum concentrations of paraldehyde were higher in periods of adequate seizure control than in periods of little or no response. Paraldehyde serum concentrations above 10 mg/dl were associated with anticonvulsant effects and were achieved in most neonates with a 2-hour infusion of 200 mg/kg/h. If there is no effect, serum concentrations are probably below 10 mg/dl and an additional 200 mg/kg can be given safely over 1 hour.

Clinical pharmacokinetics of chlordiazepoxide.

SummaryChlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biolransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (t1/2β) chlordiazepoxide following single doses in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5 %. Elimination of the parent compound is mirrored by formation of the first active metabolite.Clearance of chlordiazepoxide is reduced and (t1/2β) is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals.A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.

Propranolol Effect on Tremor in Alcoholic Withdrawal

Excerpt Alcoholic withdrawal tremor frequently appears in chronic alcoholics 6 to 48 hours after the cessation of longterm heavy alcohol consumption (1). The tremor is often sufficiently large to c...

Chlordiazepoxide and oxazepam disposition in cirrhosis

When disease impairs clearance of drugs, multiple‐dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy‐proven cirrhosis. In the normal subjects, mean (±SE) kinetic parameters were: t½β, 10.0 (±0.9) hr; Vd, 0.38 (±0.04) 1/kg; clearance, 0.54 (±0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = −0.63). Values in cirrhotic patients were: t½β, 34.9 (±8.7) hr; Vd, 0.34 (±0.024) 1/kg; and clearance, 0.185 (±0.034) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean tVifîfor oxazepam (7.1 ± 1.0 hr) was 27% longer than in control subjects (5.6 ± 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.

Unexpected alterations in fentanyl pharmacokinetics in children undergoing cardiac surgery: age related or disease related?

We assessed the pharmacokinetics of fentanyl in 19 infants and children undergoing cardiac surgery for correction of tetralogy of Fallot, A-V-canal and transposition of the great arteries. Distribution T1/2 (10.2 +/- 2.4 min) and total body clearance (13.3 +/- 6.5 ml/kg/min) were similar to adult values. An elimination t1/2 (102 +/- 85 min) shorter than in adults is readily explained by the significantly smaller distribution volume of the drug (1,203 +/- 777 ml/kg). Good correlation was found between distribution volume (Vss) and elimination t1/2 (r = 0.86, p less than 0.01) and between Vss and age of patients with tetralogy of Fallot (r = 0.85, p less than 0.01). However, older children with Fallots had higher values of PO2 due to a milder condition (r = 0.89, p less than 0.01); consequently PO2 correlated positively with Vss (r = 0.76, p = 0.05). Fentanyl total body clearance (TBC) tends to decrease with age in these patients (r = 0.66, p = 0.05) similar to noncardiac children. Our studies suggest that the alterations in the distribution volume of fentanyl in these children may largely depend upon the severity of the hemodynamic disturbance whereas TBC of the drug may depend on their age.

Diazepam and N-desmethyldiazepam in saliva of hospital inpatients.

Saliva samples were obtained from 25 hospital inpatients (14 males, 11 females, aged 19 to 79 years) taking diazepam (6 to 45 mg) daily. Despite interindividual variations in pharmacokinetics, a correlation was found between both dose and salivary diazepam concentration (r = 0.54, P less than 0.01) and dose and salivary N-desmethyldiazepam concentration (r = 0.78, P = 0.01). The correlation between the salivary concentration of diazepam and that of its metabolite is good (r = 0.76, P less than 0.01). The slope of this linear regression, 1.58, reflects the relative clearances of the metabolite and parent drug and agrees with the theoretical value, 1.60, obtained by calculation using known plasma pharmacokinetic and protein-binding parameters. There is a weak linear correlation of steady-state salivary benzodiazepine (drug and metabolite) concentration per milligram dose and age (r = 0.37, P less than 0.01).

Fentanyl-oxygen versus fentanyl-N2O/ oxygen anaesthesia in children undergoing cardiac surgery

Fentanyl-oxygen (fentanyl-02) anaesthesia was compared to fentanyl-nitrous oxide/oxygen (fentanylN20I02) anaesthesia in 14 children undergoing cardiac surgery. Children were randomly assigned to one of the two techniques studied, with seven patients in each group. The mean age (mean ± SE) was 3.9 ±0.75 years (0.5–8.25 years) and mean weight 14.7 ± 2 kg (3.5– 29.5 kg). Patients were premedicated with IM atropine 0.02 mg’kg’-1 and morphine 0.2 mg·kg’-11 hour preoper-atively. They received a fentany I bolus of 30 μg·kg’-1 with a concomitant continuous infusion of 0.3μg·kg-1·min-1. Pancuronium 0.l mg·kg-1 was administered immediately following the fentanyl bolus. Fifty per cent nitrous oxide was given with oxygen in one group and 100 per cent oxygen was administered to the other group. Fentanyl plasma concentrations were similar in the two groups at the various stages of surgery. There were no significant differences between the two treatment groups in systolic and diastolic blood pressure or in heart rate in response to induction, intubation, and incision. There was a significantly greater increase in systolic blood pressure after sternotomy in thefentanyl-O2 group, in addition, in six of seven patients recieving fentanyl-O2 there were events of sudden increase in blood pressure during various stages of surgery before the bypass, necessitating an additional fentanyI bolus or the addition ofdroperidol in four cases. Similar phenomena were not documented in the fentanyl-N2OIO2 group. Our studies suggest that fentanyl-O2 anaesthesia in the schedule described, in children undergoing elective cardiac surgery for Tetralogy of F allot, A-V canal, and transposition of the great arteries, is not sufficient to prevent elevation in systolic blood pressure despite fentany I plasma concentrations in excess of 20 mg·ml-1. The addition of nitrous oxide prevents this phenomenon.RésuméL’anesthésie au fentanyl-oxygène (fentanyl-O2) a été comparée au fentanyl-protoxide d’azote/oxygène (fentanyl-N2O/O2) chez 14 enfants devant subir une chirurgie cardiaque. Les enfants ont été choisis au hasard par rapport à l’agent utilisé et divisés en deux groupes de sept. L’âge moyen (moyenne ± SE) était de 2.9 ± 0.75 ans (0.5–8.25 ans) et le poids moyen 14.7 ± 2 kg (3.5–29.5 kg). Les patients étaient prémédiqués avec l’atropine 0.02 mg·kg-1 et la morphine 0.2 mg·kg-1 deux heures avant l’opération. Ils ont reçu dufentanyl en bolus de 30 μg·kg-1 suivi d’une perfusion continue de 0.3 μg·kg-1·min-1. Le pancuronium 0.1 mg·kg-1 a été administré immédiatement après l’injection du bolus de fentanyl. Cinquante pour cent de protoxyde d’azote a été administré avec l’oxygène pour un groupe et 100 pour cent d’oxygène pour l’autre. Les concentrations plasmatiques de fentanyl ont été similaires dans les deux groupes aux différentes étapes de la chirurgie. Il n’y avait aucune différence significative entre les deux groupes tant qu’à la pression artérielle systolique et diastolique ni dans la fréquence cardiaque en réponse à l’induction, l’intubation ou l’incision. Il y avait cependant une augmentation signification de la pression artérielle systolique après sternotomiepour le groupe fentanyl-O2. En plus chez six des sept patients recevant dufentanyl-O2 on observa des épisodes d’augmentation de la pression artérielle durant les différentes étapes de la chirurgie avant la CEC, nécessitant une administration additionnelle de bolus de fentanyl ou l’administration de dropéridol chez quatre patients. Des phénomènes identiques n’ont pas été documentés chez les groupes recevant le fentanyl-N2O/O2. Nos études suggèrent que l’anesthésie au fentanyl-O2 tel que décrite chez les enfants subissant une chirurgie cardiaque pour une Tétralogie de Fallot, un canal A-V, ou une transposition des gros vaisseaux n’est pas suffisante afin de prévenir ;’élévation dans la pression artérielle systolique malgré les concentrations plasmatiques de fentanyl en excès de 20 ng·ml-1. L’addition de protoxyde d’azote prévient ce phénomène.

Sex differences in the pharmacokinetics and bioequivalence of the delayed‐release combination of doxylamine succinate‐pyridoxine hydrochloride; implications for pharmacotherapy in pregnancy

Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single‐center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine–pyridoxine 10 mg–10 mg delayed‐release tablets. Healthy males (n = 12) and non‐pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre‐dose until 72 hours post‐dose. After 21 days, dose administration and blood sampling were re‐conducted. All analytes were measured using liquid chromatography‐tandem mass‐spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non‐compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0−t for each analyte. Females had significantly larger AUC0−t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine–pyridoxine.

Once-daily versus twice-daily dosing of digoxin in the pediatric age group

The recommended maintenance dosage interval for digoxin in infants and children is 12 hours] ,2 whereas in adults the drug is administered once daily. Because target trough and peak values in children do not differ from those in adults, and because elimination half-life.is not shorter, it is not clear why digoxin should be administered twice daily. On the basis of available studies, the elimination half-life of digoxin averages between 20 hours in infants and up to 40 hours in children. 3-5 In our study, we compared serum concentrations and clinical observations in infants and children during once-daily and twice-daily administration of the cardiac glycoside.

385 INTERPRETATION OF PUTATIVELY TOXIC DIGOXIN SERUM CONCENTRATIONS IN CHILDREN

Between January 1981 and April 1984 serum concentrations of digoxin in excess of 5 ng/ml were recorded in 47 children (age range 2 days to 16 years). In 10 of them high concentrations were measured 9-48 hours after death and were significantly higher than antemortem levels in all cases (8.3 ± 2.4 vs 3.3 ± 1.5, P < 0.0001). In 15 cases (40.5% of the living patients) serum concentrations of ≥ 5 ng/ml reflected sampling errors in that drug concentrations were monitored too soon after administration. On subsequent drug discontinuation later serum determinations were not in the toxic range. None of these children exhibited clinical digoxin toxicity. In 9 cases the excessive concentrations could be associated with renal failure and prolonged T½ of digoxin. In only two of these children were there signs of digoxin toxicity. Six cases were caused by digoxin overdose (accidental ingestions, dispensing error, suicide attempt, and excessive dose for age). In 6 additional cases the presence of an endogenous digoxin like substance (EDLS) could be shown as a component of elevated drug concentration. One case could be attributed to digoxin-amiodarone interaction. Overall, in 10/37 living patients digoxin toxicity was diagnosed. These observations suggest that serum concentrations of digoxin in excess of 5 ng/ml do not uniformly predict toxicity. Sampling errors, postmortem determinations and circulating EDLS should be considered as possible alternative explanations.