P. S. Collier

Cimetidine and ranitidine increase midazolam bioavailability.

Cimetidine has been shown to inhibit the oxidative metabolism of a variety of low‐ and high‐extraction drugs. Despite the findings of initial investigators, there is evidence that ranitidine may exert similar effects. Eight healthy volunteer subjects took part in a within‐subject crossover study. They received midazolam, 15 mg, by mouth after pretreatment with cimetidine, ranitidine, or nothing and midazolam, 10 mg, intravenously on separate occasions. Mean absolute bioavailability of midazolam was increased by more than 30% after cimetidine (P < 0.01) and 26% after ranitidine (P < 0.05). The data, which agree with a concurrent clinical study indicating greater hypnotic action of midazolam after ranitidine, indicate that this is not a result of enhanced midazolam absorption and that reduced hepatic clearance is the most likely explanation.

Propofol sedation after open heart surgery A clinical and pharmacokinetic study

One hundred adult patients who required mechanical ventilation after open heart surgery for coronary revascularisation were studied. All received a standard premedication and a high dose opioid anaesthetic. On arrival in the intensive care unit they were allocated randomly to receive either propofol or midazolam to maintain sedation within a predetermined range. Patients who received propofol underwent extubation of the trachea, using standard criteria, after a mean time (log‐transformed) of 7.6 minutes after sedation for approximately 17 hours. The corresponding time was 125 minutes in those given midazolam. There were significantly higher morphine requirements during sedation, and higher arterial carbon dioxide tensions 30 minutes after extubation of the trachea, in patients who received midazolam. Pharmacokinetic analysis in 20 patients showed that the elimination half‐life of propofol was prolonged (470 minutes) and clearance was reduced (1.14 litres/minute) compared with subjects who had not undergone cardiopulmonary bypass. The rapid clinical recovery was reflected in a rapid redistribution half‐life (13.4 minutes), but this was also longer than the redistribution time of 2–4 minutes in other patients.

A comparison of the early pharmacokinetics of midazolam in pregnant and nonpregnant women

The early pharmacokinetics of midazolam were compared in pregnant (active labour, awaiting and during elective Caesarean section) and matched gynaecological patients scheduled to undergo elective hysterectomy, half of whom were given an oxytocin infusion. A standard dose of 5 mg was given intravenously. For the first 15 minutes patients in labour had significantly higher plasma midazolam levels compared to all other groups. This was associated with the largest area under the curve (2 hours), the smallest volume of distribution and lowest clearance. Midazolam when given immediately before Caesarean section, can result in depression of the infant.

Effect of intravenous cimetidine on lignocaine disposition during extradural Caesarean section

We studied whether an intravenous bolus of cimetidine altered the disposition of extradurally administered lignocaine in the parturient. Mothers who requested extradural analgesia for elective Caesarean section were randomly pretreated with either cimetidine 200 mg intravenously (n = 5) or no H2‐receptor antagonist (n = 5). No difference was found between peak plasma lignocaine levels or area under the plasma concentration/time curve between the two groups after administration of 6 mg/kg lignocaine 2% with adrenaline 1:200 000. There was no evidence for an effect of a single intravenous dose of cimetidine on lignocaine disposition in the obstetric patient. In addition, the extradural administration of 6 mg/kg lignocaine produces plasma levels well below toxic levels.

Single dose oral H2-antagonists do not affect plasma lidocaine levels in the parturient

We studied whether a single oral dose of either cimetidine or ranitidine affects the disposition of epidurally administered lidocaine in the parturient. Patients given epidural analgesia for elective caesarean section were randomly pretreated with either cimetidine 400 mg (n=5), ranitidine 150 mg (n=7) or no H2 receptor antagonist (n=5). Following the administration of 400 mg of lidocaine 2% with adrenaline 1:200 000 no difference was found in peak plasma lidocaine levels or area under the plasma concentration/time curve (AUC) between the three groups. A single oral dose of cimetidine or ranitidine does not affect lidocaine disposition in the obstetric patient.

Bioavailability of three formulations of intravenous diazepam

It has been generally assumed that the bioavailability of different formulations of intravenous diazepam is identical. In a within‐subject crossover study using eight healthy volunteers, we have found that both thr initial and the overall plasma diazepam levels are significantly lower after both emulsion (Diazemuls®) and micelle preparations than after an organic formulation (Valium®). These findings are relevant to the interpretation of the results of past, present and future clinical studies involving intravenous diazepam. The studies with Valium and Diazemuls confirm the clinical impression of the lesser potency of the latter formulation.