Jouni Ahonen

The effect of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0- infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for shorttime sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided. (Anesth Analg 1996;82:511-6)

Recombinant factor VIIa for life-threatening post-partum haemorrhage

The treatment of life-threatening post-partum haemorrhage (PPH) still remains challenging, and hysterectomy may be required to control the bleeding. We present 12 cases of severe PPH treated with recombinant factor VIIa (rFVIIa). We briefly describe the causes of the haemorrhage and the medical and surgical interventions before rVIIa administration. In 11 women there was a partial or good response to rFVIIa administration, while in one there was no response. In the four women undergoing a subsequent selective arterial embolization, the bleeding was significantly reduced although not completely stopped. From our experience with these 12 cases, and from previously reported cases, the use of rFVIIa may be of benefit in life-threatening PPH. However, treatment with rFVIIa, in addition to standard surgical and medical interventions, may not be definitive in every patient and a selective arterial embolization may be needed.

A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy

&NA; Pregabalin has anticonvulsant, antihyperalgesic, and anxiolytic properties. In this study we evaluated the control of pain after perioperative administration of pregabalin 300 or 600 mg, compared with diazepam 10 mg. Altogether 91 women scheduled for laparoscopic hysterectomy were randomized to receive diazepam 10 mg (D10), pregabalin 150 mg (P300) or 300 mg (P600) for premedication, and the dose was repeated after 12 h, except for the D10 group, in which the patients received placebo. Up until the 1st postoperative morning, analgesia was provided by oxycodone using patient controlled analgesia. The visual analogue scale scores for pain and side effects, and the amounts of the analgesics were recorded for three days after surgery. The doses of oxycodone during hours 0–12 after surgery were similar in the three groups, whereas the dose of oxycodone during hours 12–24 after surgery was smaller in the P600 group than in the P300 group (0.09 vs. 0.16 mg kg−1; P = 0.025). The total dose of oxycodone (0–24 h after surgery) was smaller in the P600 group than in the D10 group (0.34 vs. 0.45 mg kg−1; P = 0.046). The incidence of dizziness (70% vs. 35%; P = 0.012), blurred vision (63% vs. 14%; P = 0.002) and headache (31% vs. 7%; P = 0.041) were higher in the P600 group than in the D10 group. In conclusion, perioperative administration of pregabalin 600 mg decreases oxycodone consumption compared with diazepam 10 mg, but is associated with an increased incidence of adverse effects.

Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery

BACKGROUND Multimodal pain management has been suggested to improve postoperative analgesia. In this study, we evaluated the quality of analgesia in women undergoing day-case gynaecological laparoscopic surgery, after premedication with pregabalin 75 mg (P75) or 150 mg (P150), compared with diazepam 5 mg (D5). All patients were given ibuprofen 800 mg orally. METHODS Altogether 90 consenting women were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day with fentanyl i.v. on request in the recovery room (RR), and combination tablets with acetaminophen and codeine after the RR. The visual analogue scale (VAS) scores for pain and side-effects and the amounts of postoperative analgesics were recorded for 24 h after surgery. The areas under the curves (AUC) were calculated for the VAS scores for pain at rest, pain in motion, and pain at cough 1-8 and 1-24 h after surgery. RESULTS The median AUC values for VAS scores for pain at rest (P=0.048) and in motion (P=0.046) 1-8 h after surgery were lower in the P150 group than that in the D5 group. The amounts of rescue analgesics or the degree of drowsiness did not differ in the three study groups. CONCLUSIONS Analgesia was better after premedication with pregabalin 150 mg than after diazepam 5 mg, both with ibuprofen 800 mg, during the early recovery after day-case gynaecological laparoscopic surgery. Pregabalin 150 mg did not reduce the amount of postoperative analgesics required.

Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam

To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting.

Background Midazolam and alfentanil are desirable anesthetic adjuncts for cardiac anesthesia. They are metabolized by cytochrome P450 3A (CYP3A) enzymes. These isozymes are inhibited by concurrent medications, including the calcium channel antagonist diltiazem, which may have an effect on recovery from anesthesia. Methods Thirty patients having coronary artery bypass grafting were randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an infusion of 0.1 mg [centered dot] kg sup -1 [centered dot] h sup -1 started at induction and continued for 23 h) or placebo in a double-blind study. Anesthesia was induced with 0.1 mg/kg midazolam, 50 micro gram/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 of both midazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration-time curves were determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t50) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation were performed according to the study protocol. Results Diltiazem increased the mean concentration-time curves (from end of anesthesia until 23 h) of midazolam by 24% (P < 0.05) and that of alfentanil by 40% (P < 0.05). The mean half-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t50 of alfentanil was 40% longer (P <0.05) in patients receiving diltiazem, but the change in the mean t50 of midazolam (25%) was not statistically significant. In patients receiving diltiazem, tracheal extubation was performed on average 2.5 h later (P = 0.054) than in those receiving placebo. Conclusions Diltiazem slows elimination of midazolam and alfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be considered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABAAR) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABAARs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABAARs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABAARs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABAAR agonist remimazolam, have recently been published.

The Effective Analgesic Dose of Dexamethasone After Laparoscopic Hysterectomy

BACKGROUND: Apart from being antiemetic, glucocorticoids have an analgesic property. The optimal dose of dexamethasone in the management of pain after surgery has not been established. In this placebo-controlled, dose-finding study, we evaluated the analgesic effect of three doses of dexamethasone after laparoscopic hysterectomy. METHODS: We randomized 129 women scheduled for laparoscopic hysterectomy to receive placebo, dexamethasone 5 mg (D5), 10 mg (D10), or 15 mg (D15) IV before the induction of anesthesia. The patients were anesthetized with propofol and remifentanil in a standardized manner. Until the first postoperative morning, postoperative pain was managed with IV oxycodone using patient-controlled analgesia. The visual analog scale scores for pain and side effects, and the amounts of the analgesics were recorded for 3 days after surgery. RESULTS: The total dose of oxycodone (0–24 h after surgery) was smaller in the D15 (0.34 mg/kg [0.11–0.87]) group than in the placebo group (0.55 mg/kg [0.19–1.13]) (P = 0.003). The doses of oxycodone during Hours 0–2 after surgery were smaller in the D10 (0.17 mg/kg [0.03–0.36]) and D15 (0.17 mg/kg [0.03–0.35]) groups than in the placebo (0.26 mg/kg [0.10–0.48]) (P = 0.001, D10 versus placebo; P < 0.001, D15 versus placebo) group. During Hours 2–24 after surgery, however, the doses of oxycodone were equal in the placebo, D5, D10, and D15 groups (0.31 mg/kg [0.03–0.78], 0.22 mg/kg [0.03–0.92], 0.24 mg/kg [0.05–0.87], and 0.20 mg/kg [0–0.65], respectively). The visual analog scale scores for pain at rest, in motion, or at cough did not differ in the study groups. The incidence of dizziness was lower in the D15 group than in the placebo group (P = 0.001), the D5 group (P = 0.006), and the D10 group (P = 0.030) during the first 24 h after surgery. During the later course of recovery, the incidence of dizziness did not differ among the four study groups. CONCLUSIONS: IV dexamethasone 15 mg before induction of anesthesia decreases the oxycodone consumption during the first 24 h after laparoscopic hysterectomy. During first 2 h after surgery, dexamethasone 10 mg reduces the oxycodone consumption as effectively as the 15 mg dose.

An open non-randomized study of recombinant activated factor VII in major postpartum haemorrhage

Background:  Empirical off‐label use of recombinant activated factor VII (rFVIIa) has been reported to be effective in some cases of severe postpartum haemorrhage (PPH). Successful management of these patients has lead to more wide‐spread use of rFVIIa in less severe cases without any evidence for the advantages of its administration.

The Influence of Ondansetron on the Analgesic Effect of Acetaminophen After Laparoscopic Hysterectomy

The 5‐HT3 antagonists tropisetron and granisetron have been shown to block the analgesic effect of acetaminophen in healthy volunteers. To study the interaction between ondansetron and acetaminophen in women undergoing laparoscopic hysterectomy, we randomized 134 patients into three groups to receive acetaminophen–placebo (AP), acetaminophen–ondansetron (AO), or placebo–placebo (PP). One gram of intravenous acetaminophen or placebo was administered at the induction of anesthesia and every 6 h thereafter for 24 h, and 4 mg of ondansetron or placebo was administered at the end of surgery. Pain control was provided by patient‐controlled analgesia (PCA)‐oxycodone. Acetaminophen (as compared to placebo) in periodic doses starting at induction of anesthesia reduced the total dosage of oxycodone required over 0–24 h (P = 0.031), but ondansetron given at the end of the surgery had no impact on the analgesic effect of acetaminophen (P = 0.723). The Numeric Rating Scale (NRS) scores for pain were similar whether ondansetron or placebo was administered at the end of the surgery. Therefore, it may be concluded that in women undergoing laparoscopic hysterectomy, the administration of periodic doses of intravenous acetaminophen (as compared to placebo) starting at induction of anesthesia reduces the total dose requirement of oxycodone, and a concomitant dose of a 5‐HT3 antagonist such as ondansetron at the end of the surgery does not block the analgesic effect of acetaminophen.