Isomerism and anaesthetic drugs.

Isomers are two or more different substances with the same molecular formula (i.e., the same number of different types of atoms). There are two main types of isomerism: 1) structural isomerism, and 2) steroisomerism. Structural isomers (e.g., enflurane and isoflurane) have different molecular structures, and usually behave like different drugs. Occasionally, structural isomers are interconvertible (i.e., they are tautomers or dynamic isomers); this occurs with the barbiturates and midazolam. Steroisomers have identical structures, but a different configuration or spatial arrangement. Stereiosomerism in drugs is often due to chirality or "handedness"; i.e., the presence of right-handed (R)- and left-handed (S)- forms of drugs which are nonsuperimposable mirror images ("enantiomers"). Approximately 60% of anaesthetic agents are chiral drugs; some of these are administered as single enantiomers. However, many synthetic chiral drugs are equal mixtures of (R)- and (S)-isomers, and there are often important differences in their activity and pharmacokinetics. Halothane, enflurane, and isoflurane are chiral drugs with different anaesthetic potencies. Similar differences occur with intravenous anaesthetics; thus, (S) (+)-ketamine causes fewer psychotic emergence reactions, less agitated behaviour, and better intraoperative amnesia and analgesia than its enantiomer. Some local anaesthetics are administered as chiral mixtures; the (S)-isomers have a longer action because of enhanced vasoconstriction. (S)-prilocaine is more slowly metabolized than its enantiomer, while (S)-bupivacaine may produce less cardiotoxicity than (R)-bupivacaine. These differences suggest that some anaesthetic drugs (particularly ketamine and chiral local anaesthetics) should be administered as single enantiomers. In recent years, their synthesis has been greatly simplified, and almost all new drugs may soon be introduced in this form.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of neuromuscular blocking agents on suxamethonium-induced fasciculations and myalgia.

The effect of pretreatment with suxamethonium, gallamine or pancuronium on suxamethonium-induced fasciculations and myalgia was studied in a controlled, randomized and double-blind clinical trial. Both fasciculations and myalgia were assessed on a four-point rating scale. There was no significant correlation between fasciculations and postoperative muscle pain at 24, 48 or 72 h, and pretreatment with suxamethonium had no significant effect on fasciculations or myalgia. Gallamine had a more marked effect on fasciculations than pancuronium, and the decrease in the fasciculation score was statistically significant. In contrast, pancuronium had a greater effect on myalgia, and decreased postoperative muscle pain significantly at 24 and 48 h. These differences may reflect the differential activity of gallamine and pancuronium at the neuromuscular junction. Pretreatment had little or no effect on plasma potassium concentrations.

Postoperative analgesia with Duromorph.

The analgesic effects and bioavailability of a slow-release preparation of morphine (Duromorph) were studied in 12 patients with acute postoperative pain. Duromorph produced significant analgesia within 1-2 h of administration i.m., and there was a progressive decrease in the mean pain score for at least 8 h. None of the patients requested or received additional analgesia within 12 h, and the incidence of side-effects was similar to that associated with i.m. morphine. During the 8-h study, plasma concentrations of morphine slowly increased for 3 h, and then gradually declined. After 3 h, concentrations were invariably greater than those produced by conventional doses of morphine sulphate i.m. The study confirmed that Duromorph was an effective analgesic with a prolonged duration of action, which was suitable for the management of postoperative pain.

Prolonged release extradural morphine.

The effects of extradural administration of a microcrystalline preparation of morphine (Duromorph) were studied in 5 patients with postoperative or malignant pain. As assessed by pain scores on a visual analogue scale, the effects of the analgesic were extremely variable; the best results were obtained in patients with postoperative pain. Two patients with chronic pain due to malignant disease developed slow respiratory rates. The plasma concentration of morphine usually followed a biphasic pattern; an initial peak between 0.5 and 1.5 hours was succeeded by a second, large peak between 6 and 12 hours. There was little or no apparent relation between the plasma concentration of morphine and the relief of pain, suggesting that Duromorph may have a local effect on the spinal cord.

Buccal morphine--a new route for analgesia?

The analgesic effects of buccal and intramuscular morphine were compared in a prospective, double-blind, double-dummy study in forty patients who experienced pain after elective orthopaedic operations. Each patient simultaneously received a buccal tablet and an intramuscular injection, only one of which contained morphine sulphate (13.3 mg); the patients were randomly allocated to two equal groups so twenty patients received each active preparation. The two preparations produced a similar degree of postoperative analgesia, assessed by the mean reduction in pain score and the pain relief score. Peak plasma morphine concentrations were slightly lower after buccal than after intramuscular administration but they declined more slowly; consequently, the drug's bioavailability was 40-50% greater after buccal than after intramuscular administration. The adverse effects of buccal morphine were generally less than those of intramuscular morphine.

Elimination of phenoperidine in liver disease.

The disposition and elimination of phenoperidine was studied in five normal subjects, and in six patients with hepatic disease. Plasma concentrations of phenoperidine were generally higher in patients with hepatic dysfunction. Secondary peaks were observed between 15 and 105 min (particularly in patients with liver disease). In the patients the terminal half-life of phenoperidine was prolonged by approximately 50%, mainly because of a decrease in the clearance of the drug. There was little or no change in the total apparent volume of distribution. However, the differences between normal subjects and patients with hepatic disease were not statistically significant. The results suggest that slight or moderate impairment of hepatic function does not significantly affect the kinetics of the drug, and that modification of its dosage may not be required.

Quantitative capillary column gas chromatographic method for the determination of glycopyrronium in human plasma.

A new sensitive and selective capillary column gas chromatographic method for the anti-cholinergic agent glycopyrronium bromide in human plasma is described. The procedure involves preliminary ion-pair extraction of the drug into dichloromethane, followed by concentration and analysis of the ion-pair complex by capillary column gas chromatography using a nitrogen-sensitive detector. The method depends on the thermal dequaternisation of the quaternary ammonium compound and can be used to detect 5 ng/ml in a 3-ml plasma sample. The assay procedure has been applied to the determination of the plasma concentration of glycopyrronium after intravenous administration to an anaesthetised patient.

Intraoperative bradycardia and hypotension associated with timolol and pilocarpine eye drops.

A 69-yr-old man, who was concurrently being treated with pilocarpine nitrate and timolol maleate eye drops, developed a bradycardia and became hypotensive during halothane anaesthesia. Both timolol and pilocarpine were subsequently identified in a 24-h collection of urine. Timolol (but not pilocarpine) was detected in a sample of plasma removed during surgery; the plasma concentration of timolol (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant bradycardia and hypotension. Pilocarpine may have had a contributory effect.

Effect of urine pH on the elimination of phenoperidine.

The effect of urine pH on the plasma concentration and elimination of phenoperidine and its main metabolites was studied in six volunteers. The clearance of unchanged phenoperidine in acid urine was significantly greater than in neutral or alkaline urine. By contrast, the elimination of its basic metabolites was enhanced in uncontrolled or alkaline urine. Other pharmacokinetic parameters were not significantly affected.

Effect of antacids on the plasma concentration of phenoperidine.

The effect of antacids on the plasma concentration of phenoperidine was studied in six volunteers. All subjects received the same dose of phenoperidine (15 micrograms kg-1) on different occasions in the presence, and absence of, an antacid preparation. In control studies, secondary peaks in the plasma concentration of phenoperidine were invariably observed; these were entirely eliminated, or modified substantially, by the concurrent administration of antacids. In the latter conditions, plasma concentrations of phenoperidine were greater during the first 20 min, and the area under the plasma concentration--time curve between 0 and 20 min was significantly greater than in control studies. In contrast, the plasma clearance of the drug was almost identical in control conditions and during treatment with antacids. After the oral administration of phenoperidine to two subjects, the systemic bioavailability of the drug was 9.9% and 13.9% respectively.

Electromyographic assessment of neuromuscular blockade induced by atracurium.

The effects of atracurium besylate 0.3 mg kg-1 or 0.6 mg kg-1 on neuromuscular function were assessed by electromyography in 11 normal subjects, using successive trains of four supramaximal stimuli. After the induction of anaesthesia, the relation between the reduction in the amplitude of the compound muscle action potential and decrement was studied during the onset and recovery of nondepolarizing blockade. During induction, the decrease in the amplitude of the initial compound muscle action potential was usually greater than decrement, and resembled the pattern observed with pancuronium. In contrast, during recovery from myoneural blockade, decrement was invariably greater than the reduction in the amplitude of the action potential. It was considered that these effects were consistent with the action of atracurium on more than one group of receptors at the neuromuscular junction. The effects of atracurium were rapidly antagonized by neostigmine, and supplementary doses of the drug showed no evidence of cumulation.

Plasma concentration of pyridostigmine during the antagonism of neuromuscular block.

The plasma concentrations of pyridostigmine were measured in eight patients during the antagonism of non-depolarizing neuromuscular blockade. After the injection i.v. of pyridostigmine bromide 14.6 mg/70 kg, the concentration of the drug rapidly decreased between 2 and 7 min, and then declined more slowly. After 2 h, significant amounts of pyridostigmine were still present in the plasma of all subjects. In the eight patients studied, the initial half-life was 1.0 +/- 0.3 min and the terminal half-life was 46.4 +/- 6.5 min (mean +/- SEM). Total body clearance of pyridostigmine was 8.7 +/- 1.5 ml min-1 kg-1, and the total apparent volume of distribution was 536 +/- 80 ml kg-1. Possible explanations for the differences between these results and previous studies are considered.