CSF penetration and pharmacokinetics of midazolam.
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Administration, Oral↗
Biomedical subjects
J Kanto
Publications and source records attributed to J Kanto.
Placental transfer and maternal midazolam kinetics.
Midazolam was given in a single 15-mg oral dose as a sedative the evening before elective cesarean section. Twelve hours later, levels of this new benzodiazepine were measureable in the fetomaternal entity in only one of 13 cases. After 15 mg midazolam orally or 0.05 mg/kg midazolam intramuscularly 15 to 60 min before elective cesarean section, there was evident transfer of drug into the placenta, but transfer took place more slowly than with diazepam. On the basis of kinetics derived from maternal serum concentrations after oral, intramuscular, or intravenous dosing, midazolam appears to have a rapid onset and short duration of action, which was also evident from subjective assessments by the patients. There was wide interindividual variation in the gastrointestinal absorption of midazolam in full-term pregnant women. Clinically, midazolam nevertheless seemed to be very useful for nocturnal sedation before elective cesarean section; it ensures a mean duration of sleep of about 6 hr and there are virtually no detectable levels of drug in the fetomaternal entity the next morning.
Adolescent↗
Antidiuretic hormone concentrations following midazolam premedication.
Midazolam given orally the night before and on the morning of operation had a distinct subjective pre-operative sedative effect as compared with placebo. Patients receiving midazolam also experienced less apprehension and excitement before surgery, but in relation to quality of sleep, the difference between the two groups was not statistically significant. Antidiuretic hormone (ADH) concentrations were determined just before induction of anaesthesia and were significantly lower in the midazolam group (2.14 pg/ml, SD 0.96) than in the placebo group (3.07 pg/ml, SD 1.73). Our results show that midazolam is a useful sedative anxiolytic oral premedicant, which appears to prevent initiation of a stress reaction before induction of anaesthesia.
Anti-Anxiety Agents↗
Saliva concentrations of lignocaine in patients with acute myocardial ischaemia.
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Acute Disease↗
Benzodiazepine receptors in the human fetus.
The existence of benzodiazepine receptors in the human fetal brain, liver and placenta has been studied. At 12-15 weeks of gestation specific binding to fetal brain occurs. The dissociation constant of [3H]-flunitrazepam-specific binding was 1.5-2 nM and the maximum number of binding sites was 2.3-3.8 fmol/mg of total brain tissue. In the fetal liver and placenta some specific binding exists, yet the nonspecific binding is more extensive.
Adult↗
Clinical pharmacokinetics of ergotamine, dihydroergotamine, ergotoxine, bromocriptine, methysergide, and lergotrile.
The clinical pharmacokinetics of ergotamine, dihydroergotamine, ergotoxine, bromocriptine, methysergide, and lergotrile are reviewed. Generally the new radioimmunoassay methods have partially resolved the problems involved in determining some of these ergot derivatives in biologic fluids after the low doses used clinically. However, our present knowledge of their pharmacokinetics is limited and much work remains to be done in this area. Many cases show a great difference between results produced with a radioactive drug and with radioimmunoassay. The longer half-lives measured by using a radioactive derivative are apparently due to the many metabolites of ergot alkaloids. However, we still do not know the clinical importance of these metabolites. For instance, the amount of dihydroergotamine reaching the systemic circulation remains below 1% (radioimmunoassay), but according to studies performed with a radioactive derivative the absorption quotient is about 30%. Further studies are needed to resolve the problem of an apparently high "first-pas" metabolism of this and other ergot alkaloids in the liver or gastrointestinal mucosa.
Absorption↗
Pharmacokinetics and the sedative effect of midazolam.
The pharmacokinetics and their relation to the pharmacodynamic properties of midazolam, the first water-soluble benzodiazepine derivative, are reviewed. Pharmacokinetically, midazolam is a unique derivative among the benzodiazepines. After both oral and parenteral routes of administration, it has a fast absorption rate, and differing from older derivatives it is very rapidly excreted with a half-life of only about 2 h. A reasonably good correlation has been found with the plasma levels and clinical effects, indicating a fast but short clinical response. Midazolam appears to be a useful short-acting hypnotic having almost no residual effects the following morning. In anesthesiology both oral and parenteral drug forms can be used for premedication. In addition, it is a new alternative for inducing anesthesia when a slow induction time is chosen or its advantageous properties: good cardiovascular stability, transient and mild respiratory depression, low frequency of venous irritation, production of anterograde amnesia, and short duration of action (last-mentioned property in comparison with other benzodiazepines).
Animals↗
Hormone response in gynecologic surgery.
We measured plasma arginine vasopressin (AVP), plasma renin activity (PRA), human growth hormone (HGH), immunoreactive insulin (IRI), and blood glucose in 25 gynecologic inpatients. Six were undergoing dilatation and curettage (Group 1), nine were undergoing hysterectomy (Myomata uteri) and receiving acetated Ringer's lactate without glucose (Group 2), and ten were undergoing hysterectomy and receiving acetated Ringer's lactate in 5% glucose (Group 3). The measurements were made the night before the operation, during the operation, and postoperatively. Plasma AVP did not change significantly in Group 1, but it increased in both Groups 2 and 3. PRA showed no significant changes in any group studied. HGH decreased slightly at the end of the operation in Groups 1 and 2, but it increased significantly in Group 3 in the recovery room 1 h after surgery. Blood glucose and insulin remained at normal levels in Groups 1 and 2, but they increased significantly in Group 3. We believe that stress was caused more by greater surgical trauma than by the depth of anesthesia and anesthetic agents in Groups 2 and 3, when compared to Group 1; this is a possible mechanism of the increased AVP secretion. Acetated Ringer's lactate without glucose appeared to cause a more physiologic response during gynecologic surgery than did acetated Ringer's lactate in 5% glucose.
Adult↗
Segmental epidural analgesia - a modern method for safe and effective management of labor pains.
The effect and safety of segmental epidural analgesia (SEA) were investigated in three groups of parturients totaling 250. Three comparative groups were also created. In 50 primigravidae, the analgesic effect was good in 90%, moderate in 8%, and poor in only 2%. The opinion of midwives on analgesic effect was also similar. Investigation of the duration of labor showed that the duration of both first and second stages was longer in SEA groups than in nonepidural groups. However, with more liberal use of oxytocin in the SEA group this difference disappeared. The SEA did not lead to more malpositions than were present in the nonepidural groups. Nevertheless, the rate of instrumental deliveries was approximately three times higher in the SEA groups than in nonepidural groups (15.2% vs 4.7%, respectively). No difference between the groups occurred when Apgar scores at 1 and 5 min were investigated.
Adult↗
New aspects in the use of atropine.
Several new factors have recently been shown to influence the pharmacokinetics of atropine. Age appears to have a clear effect on the elimination of atropine: for example, prolonged elimination has been found in children under 2 years of age and in the elderly. The higher sensitivity of these patients to the effects of atropine can be explained, at least partly, by this phenomenon. Due to the fast placental transfer of atropine, i.v. administration before cesarean section can have strong effects on the newborn. Most important, however, it decreases the barrier pressure of the lower cardioesophageal sphincter (pulmonary aspiration). Thus, routine atropine premedication is contraindicated before cesarean section. On the other hand, children appear to need a routine anticholinergic premedicant. Without it profuse salivary secretion may interfere with anesthesia. The use of atropine in premedication of healthy adult patients is controversial. Because peroral premedication (benzodiazepines) is nowadays increasing in the adult patient, especially in the elderly, routine use of atropine should be avoided.
Aging↗
Severe abuse of psychotropic drugs during pregnancy with good perinatal outcome.
A case of severe abuse of phenothiazines, benzodiazepines and barbiturates and smoking 40 cigarettes a day throughout pregnancy is described. Intoxication requiring hospitalization occurred 3 times during pregnancy. The mother was hospitalized for the last 10 days of pregnancy and only lorazepam and oxazepam were given in order to improve the co-operation of the mother and to alleviate fetal withdrawal symptoms. At 39 weeks a healthy baby boy of 3150 g was delivered. Obvious withdrawal symptoms in the neonate appeared at the age of 20 hours. Due to repeated drug intoxications of the mother after discharge, the baby was located in a custody home. At his postnatal examination at the age of 3 months the baby appeared somatically and neurologically unaffected. A slight muscular hypotonia of lower limbs was suspected, though. At check-ups at the age of 6 and 12 months the baby was normal in all respects.
Apgar Score↗
Effect of different kinds of premedication on the induction properties of midazolam.
The effects of different premedication (i.m. and i.v.) on the usefulness of midazolam or thiopentone as induction agents for minor surgery was studied in 194 women undergoing either dilatation and curettage or explorative fractionate curettage. Midazolam appeared to produce light sedation which required powerful premedication (i.m. atropine + pethidine and i.v. fentanyl or fentanyl + dehydrobenzperidol) when used as an induction agent for minor surgery. The clinically useful dose of midazolam is about 0.30 mg kg-1 i.v. There was greater variability in onset and duration of action among patients receiving midazolam than among those receiving thiopentone. Midazolam caused less respiratory depression, but there were no clinically significant differences between midazolam and thiopentone with respect to cardiovascular variables. Muscular movements were found more often, and postoperative sedation lasted longer in patients receiving midazolam. Midazolam as an induction agent appears more suited for major than for minor surgery.
Adult↗
Comparison of midazolam and flunitrazepam for night sedation. A randomised double-blind study.
In a double-blind randomized study midazolam 15 mg and flunitrazepam 2 mg caused a significantly better night's sleep than placebo. Midazolam had a moderate sedative effect the following morning but, in other respects studied, no residual effects were found. In contrast, flunitrazepam decreased both the degree of apprehension and excitement the following morning. Flunitrazepam also inhibited salivary secretion and caused less cardiovascular changes than placebo or midazolam. The dose of thiopentone needed for induction of anaesthesia was significantly lower in those given flunitrazepam. The results show that midazolam is a potent sedative agent with a short duration of action.
Adult↗
Saliva concentrations of lignocaine in healthy volunteers.
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Adult↗
Midazolam compared with thiopentone as an induction agent.
In patients premedicated with scopolamine + morphine (+5 mg nitrazepam the evening before surgery), the sleep-inducing effect of midazolam 0.15 mg/kg i.v. was clearly slower in onset than that of thiopentone 4.67 mg/kg i.v. Somewhat fewer cardiovascular and local sequelae were found in the midazolam group, but, although apnoea occurred less often in the midazolam group it lasted longer. On the whole, the differences between midazolam and thiopentone had no apparent clinical consequences. Midazolam is a new alternative agent for induction in combination anaesthesia.
Adolescent↗
Pharmacokinetic studies on atropine with special reference to age.
Pharmacokinetic studies on atropine were performed in 52 patients under general or spinal anaesthesia. Age had a clinically significant effect on the kinetics of this alkaloid: in children under 2 years of age and in the elderly a prolonged elimination was found. This might explain, partly at least, the higher sensitivity of these age groups to the effects of atropine. Age had no effect on the serum protein binding of this alkaloid. Atropine was found in human CSF after a single i.m. administration, but not after a single i.v. administration. During anaesthesia after i.v. atropine administration, a diminished cardiovascular response was found in the elderly in comparison with healthy adult patients. This indicates changes also at the cholinergic receptor sites in the elderly.
Adolescent↗
Flunitrazepam as an induction agent in elderly, poor-risk patients.
Great interindividual variation was found in response to flunitrazepam when the latter was used as an induction agent for general anaesthesia in elderly, poor-risk patients. However, no significant changes in the pharmacokinetics of this nitrobenzodiazepine derivative were found, which suggests that there are pharmacodynamic alterations in response to the drug with advancing age. A sudden but transient drop in blood pressure was found in three out of 12 patients, even although flunitrazepam was given, i.v., in low 0.3-0.5 mg incremental doses. A marked amnesic effect was found. No analgesics were needed in the recovery room (2 h), supporting the evidence that flunitrazepam has an analgesic-sparing effect. Flunitrazepam resulted, in general, in smooth induction of anaesthesia, but a long time was needed for induction.
Age Factors↗
Intravenous benzodiazepines as anaesthetic agents: pharmacokinetics and clinical consequences.
Despite extensive and numerous pharmacokinetic studies on benzodiazepines, the published pharmacokinetic data do not adequately explain the clinical differences found between different benzodiazepine derivatives after intravenous administration. Especially, correlations between initial drug responses and distributional changes of the benzodiazepines are limited. However, during the elimination phase some relationships exist between the kinetic and dynamic phenomena. Age, sex, diseases and concomitantly given drugs cause clinically important alterations in the pharmacokinetics of benzodiazepines. Generally these anxiolytics and sedatives should be considered as adjuvants to general anaesthesia, but not primarily as routine induction agents. The major reasons for this limitation are a high variability in drug response, a relatively slow onset of action and long-lasting residual effects. However, benzodiazepines have many important advantages (see Table 5) when used as intravenous inducing agents of general anaesthesia.
Adult↗