Intensive Care Med (1991) 17:S1-S 10

Intensive Care Medicine 9 Springer-Verlag1991

Pharmacology of drugs frequently used in ICUs: midazolam and flumazenil R. Amrein and W. Hetzel F. Hoffmann-La Roche Ltd, Grenzacherstrasse124, Basel, Switzerland In a multicenter study of ICU drug utilization [i] it was pointed out that among the drugs acting on the central nervous system benzodiazepines (BZDs) are most frequently prescribed. BZDs have anxiolytic, anticonvulsive, sedative-hypnotic, muscle relaxant, and anterograde amnesic properties in common. However, according to the type of BZD and the administered dose, one of these properties may predominate. BZDs have no narcotic potential and patients remain arousable within a wide dose range. These are advantages over other sedative and anxiolytic drugs. BZDs are suitable drugs for use in the intensive care of critically ill patients. They have a wide safety margin, a low potential of interference with existing organ impairment, and limited drug interactions. Interactions with other central acting drugs are known but the degree of the synergistic effect is not always well defined. In the intensive care unit BZDs are used for the sedation of patients who have to be ventilated mechanically or who have to undergo stressful intensive care procedures. Diazepam and flunitrazepam two often used BZDs have now been joined by the newer and shorter acting midazolam. In contrast to the older BZDs, midazolam has no long-lasting metabolites. The duration of action becomes more predictable and the degree of sedation is better adjustable to the patients current condition. Accumulation, especially during long-term use may be found in patients with reduced hepatic blood flow, but is unlikely in liver healthy patients. Hangover effects after longterm infusion of midazolam are of a shorter duration than with diazepam. They can be limited if the dose is adapted to the age and physical condition of the patient. In the intensive care of patients it becomes necessary to interrupt sedation transiently or definitely. Neurological examinations, weaning from mechanical ventilation, or drug overdose are examples. Until recently attempts were sometimes made to reverse BZD sedation by use of non-specific antagonists like physostigmine or aminophylline, or the patient had to be left until he/she awoke spontaneously. With the specific BZD antagonist flumazenil it is possible to abolish central nervous effects caus-

ed by a BZD much more reliably and immediately after administration. In a previous paper [2] we pointed out the general pharmacological properties of midazolam and flumazenil as BZD agonist and antagonist. In this paper we would like to give an additional overview on the experience with both drugs in ICU and the properties which make them suitable for use in intensive care.

Ideal profile of a drug used in intensive care

The ideal drug used in intensive care should facilitate patient management and make treatment safer. The drug effect is expected to be immediate and restricted to the target organ. Degree and duration of effect must be controllable by dosage, or by the mode of administration, and the onset of effect should be immediate. Vital parameters should remain stable. Interaction with other drugs is not desired and the therapeutic margin has to be wide. Finally the use of the drug should not cause adverse events. Of course, neither midazolam nor flumazenil are able to fulfil these criteria completely. However, each of them as well as their combined use, may come closer to some of the required ideals than other CNS drugs used in ICU. Table 1 lists the desired pharmacological properties and how midazolam and flumazenil correspond to them. Mode of action

Midazolam and flumazenil belong to the newer class of imidazobenzodiazepines. Like all BZDs they act through the specific BZD receptor in the central nervous system. The BZD receptor is a modulator subunit of the GABA (gamma-aminobutyric acid)-A receptor. GABA is the most important inhibitory neurotransmitter which regulates the influx of chloride ions into the postsynaptic neuronal membrane. A BZD occupying the BZD receptor can alter the GABA-mediated channel-gating process by enhancing the effects of suboptimal amounts of GABA at a synapse. For a functional effect of a BZD a minimum

R. Amrein and W. Hetzel: Pharmacologyof midazolam and flumazenil

$2 Table 1. Drug profiles of midazolam and flumazenil Desired property

Propertyof midazolam and flumazenil

Distribution into deeper compartments within 5 - 15 min after administration. Access to the CNS within 1- 2 arm-brain circuits Rapid onset of action Onset of action within 1- 5 rain after i.v. administration Controllable action This is enabled by the titrated administration, by the short elimination half-lives, and the short acting or inactive metabolites No interaction with Possible relevant interaction limited to other CNS drugs like opioids or barbiturates other drugs Reduced metabolism, prolonged elimination in No influence of case of liver failure, reduced liver blood flow, organ impairment reduced cardiac output, renal failure Excellent local tolerability due to waterNo side effects solubility, systemic adverse events minimized by dose titration and careful observation of the patient Metabolites of midazolam are shorter acting No active or toxic than midazolam, metabolites of flumazenil are metabolites inactive. Activesubstances have a verylow toxicity and a high therapeutic index. Hydroxymetabotites are non-toxic The pharmaeokinefic properties of the two No accumulation substances make accumulation very unlikely Even after long-term administration of midaLow potential of zolam development of tolerance is rare. After tolerance flumazenil tolerance is not observed Rapid absorption

amount of GABA has to be present. A maximal response to GABA cannot be intensified further by increasing the BZD dose [3]. Flumazenil molecules compete with the BZD agonist molecules to occupy the BZD receptor once the agonist has left it. If the antagonist has occupied the receptor the effect of the agonist is abolished. This competition signifies that a BZD receptor may again be occupied by an agonist after the antagonist is dissociated from it. In practical terms this means that sedation induced by midazolam and reversed by flumazenil can again be induced (and the effect of flumazenil be surmounted) by an additional dose of midazolam. For the degree of effect of a BZD the number of receptors occupied by the BZD is decisive. The receptor occupancy by the agonist in presence of the antagonist obeys the mass-action law. The potency of a BZD depends on the affinity of a BZD to the receptor. The receptor affinity also influences the total number of receptors which can be occupied by the BZD. The higher the affinity, the greater the number of receptors to be occupied. Midazolam and flumazenil are BZDs with a high receptor affinity and therefore considered as a potent agonist and antagonist. A low number of receptors occupied by midazolam results in an anxiolytic effect and a large number of occupied receptors end in a hypnotic condition. In the latter case a low dose of the antagonist only reduces the hypnotic to a slight sedative condition. Drowsiness, anxiolysis, and anticonvulsant effect of the agonist may persist. These effects can be antagonised by a higher dose of the antagonist.

0

Fig. 1. Schematicrepresentation of the postsynaptiemembrane of an effector neuron with a GABA receptor (GABA-R) complex. The benzodiazepinereceptor (BZD-R) is an integrative part of the GABAreceptor complex. BZD agonists (AG) as well as antagonists (ANT) bind specifically to the BZD-R. Only BZDs with agonistic properties (AP) are able to enhance the GABAeffect on the chloride channel allowing influx of negatively charged chloride ions (C1-) into the effector neuron. The antagonist occupies the BZD-R without triggering an effect

The receptor occupancy can be calculated if the affinity of the BZD to the receptor and the free BZD concentration near the receptor is known. Reversal of the agonistic activity by the antagonist additionally takes into consideration the free concentration and the affinity of the antagonist. In a previous paper [41 we calculated the receptor occupancy after 15 mg midazolam to be 91~ which stands for deep sedation. When this condition is reversed by 0.3 mg flumazenil there remains a midazolam receptor occupancy of 18~ which is sufficient for a resting anxiolytic effect of midazolam. In positron emission tomography studies it could be demonstrated that unlabelled flumazenil dose dependently reduces binding of HC-flumazenil in the cerebral cortex. Flumazenil 0.5 m g / k g reduced binding by about 90070, injection of 0.01 m g / k g led to a reduction of about 70070 of labelled flumazenil binding within 10 rain of administration [5]. These results are confirmed by numerous clinical results when midazolam-sedated patients became fully awake after the use of flumazenil but remained peaceful without signs of anxiety.

Physicochemical properties (Table 2) The chemical structure of midazolam is characterised by an imidazole ring. The methyl group added to the imidazole ring is responsible for the short duration of action since it is rapidly oxidised by liver enzymes [6]. The nitrogen in position two of this ring renders midazolam a high basicity, which allows the formation of water-soluble salts. From the hydrochloric salt of midazolam the ready to use aqueous ampoule solution is prepared. The diazepine ring of midazolam shows a pH dependent ring-opening phenomenon. At pH ~ 300 ~ 475 [8]

303 200 ~ 14 [91

27 mg/ml (at p H 3.3) 6.0

0.4 mg/ml (pH 7.4) 1.7

the acidic solution of midazolam is buffered to pH 7.4 at 37 ~ the diazepine ring closes with a half-life of about 10 min. The ring closed form has a high lipophilicity and therefore has an easy access to the brain. Midazolam is very stable in aqueous solution since it contains no lactam function which makes it sensitive to hydrolysis. Midazolam can be stored at room temperature, no degradation products were found after heating to 80~ for 1 month [8]. Flumazenil, an imidazobenzodiazepine as well, lacks the phenyl group of other BZDs which is replaced by a carbonyl group (see Fig. 3). Flumazenil is a much weaker base than midazolam and less water-soluble. The solubility in water is, however, still sufficient to prepare an aqueous, injectable ampoule formulation [9] with a concentration of 0.1 mg/ml. At room temperature only about 0.2% flnmazenil is degraded to the corresponding acid within one year of storage.

Midazotam

o{-Hydroxymidozolem

H3C %,,..,N

H0 CH2,,,,T~N

~ / N ~ 0 C[/

~

~ N

El f ~

H

~ N

U l,-Hydroxymiduzolam

a, L-DihydroxymidazotQm

Glucuronide

Glucuronide

Fig. 2. Midazolam undergoes hepatic metabolism into several metabolites. The main metabolite is ct-hydroxymidazolam with a shorter duration of action than midazolam. All metabolites are bound to glucuronide and rapidly eliminated from the body

Pharmaeokinetics (Table 3) Pharmacokinetic parameters of midazolam are consistent over a wide dose range in healthy volunteers. They are characterised by a distinct distribution [7, 1 0 - 1 2 ] into deeper compartments followed by an elimination with a short half-life tl/2 [3. The elimination half-life of the metabolites even is shorter and hence does not contribute to the duration of effect of midazolam after i.v. injection. In elderly subjects the volume of distribution may be increased from 1 1/kg to 2.5 1/kg [13] and the elimination Table 3. Average pharmacokinetic data for midazolam and flumazenil

Initial distribution phase Distribution half-life t 1/211 Elimination half-life ti/2~ (Major metabolite c~-OH midazolam tl/z[3 ) Volume of distribution V~s Total clearance Clpl Blood/plasma concentration coefficient Hepatic extraction ratio Protein binding IM bioavailability

Midazolam

Flumazenil

5 - 15 min 25 - 30 min 1.5 - 3 h (0.8 h)

< 5 min 0.7 - 1.3 h

0.7 - 1 1 kg - 1 0.6 - 1. l 1 k g - 1 0.35 - 0,51 m i n - ~ 0.5 - 1.3 1 m i n - 1 0.53 0,88

half-life may be prolonged in elderly or obese subjects. Blood clearance is estimated to be one third [14] to one half of liver blood flow [10] which is high for a BZD and values up to 823 ml/min are dealt with for volunteers [15]. Since blood clearance of midazolam is sensitive to changes in hepatic perfusion and liver cell function midazolam may accumulate in ICU patients with hepatic failure or reduced liver blood flow. Erythrocyte binding of midazolam is low [12, 14] but seems to depend on the plasma concentration in a non-linear fashion [16]. Following single intravenous doses of 5 mg midazolam maximal mean plasma levels of 112+_16 ~tg/mI were measured [161 and levels of 200#g/ml were attained after 0.075 mg/kg [14].

co0c2H5 F~N~

Flumazenil ~-F O

0.3 - 0.5 96~ 90%

0.6 50%

f>-cooH

CH3

lucur~ P-0

CH3

Free carboxyfic acid Fig. 3. Flumazenil is rapidly metabolised into its free carboxylic acid and the corresponding glucuronide. The metabolites are inactive

$4 The distribution of flumazenil is very rapid and as extensive as midazolam, indicated by a comparable distribution volume although flumazenil is less lipophilic. Peak plasma levels of flumazenil are attained in less than five minutes [17] following i.v. administration as shown by immediate decline of the plasma concentration time profile [18, 19]. The mean terminal elimination half-life of flumazenil is slightly shorter compared to midazolam [17, 18]. Total plasma and blood clearance exceed those of midazolam after high intravenous doses of 20 and 40mg flumazenil [17-20]. Flumazenil achieves a relatively higher plasma water concentration than midazolam with the unbound fraction being approximately 50070. The blood: plasma ratio is 0.8-1.3 [20]. Plasma levels attained after a single i.v. injection of 2.5 mg are near 70 gg/ml [181.

Metabolism Both substances undergo rapid hepatic enzyme degradation. Mida'zolam is oxidised to its major metabolite a-hydroxymidazolam. Two further metabolites, 4-hydroxymidazolam and a,4-dihydroxymidazolam have been identified in smaller amounts [7]. All metabolites are subsequently conjugated with glucuronic acid from which up to 80~ are excreted renally within 24 h. Less than 0.507o of unchanged midazolam is recovered in the urine. After 5 - 6 h a single 0.15 mg/kg dose of midazolam the drug is no longer measurable in the circulation [71. The observation that liver healthy patients may show prolonged elimination halflives of midazolam provoked the still open question whether the metabolism of midazolam is influenced by genetic metabolism [21] or is in consequence of large volumes of distribution and low clearance. Flumazenil is completely metabolized to the free carboxylic acid (Ro 15-3890) and the corresponding glucuronide which are both inactive and excreted renally. Less than 0.2% of unchanged drug was recovered in the urine.

Pharmacodynamies Midazolam The pharmacodynamic effects of midazolam have been verified in numerous test settings using different observer rating scales, self-ratings, visual analogue scales and psychomotor tests in healthy subjects as well as in hospitalised patients. Anxiolytic, anticonvulsant, and sedative properties of midazolam are present in i.v. doses below 5 rag. However, for a deep hypnotic effect under stressful conditions i.v. doses higher than 10 mg may be necessary. Compared to diazepam, midazolam is considered to be more potent. In rats midazolam has twice the sedative potency of diazepam. In tests for muscle tone and coordination in mice midazolam has been shown to be 4 times as potent as diazepam. In EEG investigations in volunteers [22] the total voltage was measured after midazolam 7.5, 15, and 25 mg i.v.

R. Amreinand W. Hetzel: Pharmacologyof midazolamand flumazenil and compared to the measurement after 15, 30, and 50 mg diazepam i.v. Midazolam was found to be 5 times more potent than diazepam. The muscle relaxant property of midazolam can reduce the activity of the upper airway muscular system and increase inspiratory resistance. Intravenous midazolam also acts on higher respiratory centers and can lead to respiratory depression and apnoea. Patients with chronic obstructive airway disease are more susceptible than normal subjects. Respiratory depression by midazolam is potentiated by the co-administration of opioids. Supervision of respiratory parameters is mandatory with i.v. midazolam.

Bolus administration In a study on the influence on respiratory and cardiovascular effects in 8 volunteers 0.05 mg midazolam/kg were found to be equipotent to 0.15 mg/kg diazepam [23]. In comparative clinical studies with i.v. administered diazepam (0.15 - 0.4 mg/kg) or midazolam (0.07- 0.2 mg/kg) it was observed that midazolam given as half of the dose of diazepam has a still more potent amnesic and sedative hypnotic effect than diazepam [24-26]. First effects of midazolam were reached with plasma levels above 40 ~tg/ml. 80 gg/ml showed muscle relaxation with ataxia and levels above 100 gg/ml were followed by slurred speech and sleep including anterograde amnesia [14, 18]. Midazolam 5 mg i.v. led to mean plasma levels of 112.6+_ 16 ~g/ml in 6 healthy subjects [16]. Subjects fell asleep within 1 - 2 min and slept for an average of 1.3 h. A transient sedative effect of midazolam can already be reached with 0.025 mg/kg [27]. 7.5 mg midazolam caused unresponsiveness to verbal stimuli [28] and 10 mg i.v. can lead to the loss of the palpebral reflex. With 15 mg midazolam EEG variations are found as early as 50 s after i.v. administration with a patient sedated for induction of anesthesia. In elderly patients midazolam showed a greater reliability of effect and a shorter induction time than in the young [29]. After 15 mg midazolam given during a 20-min infusion subjects were sleeping for another 30 rain. They were fully awake after 3h [11]. After a single i.v. dose of 0.15 mg/kg midazolam, individual plasma peak levels ranged between 291 and 425 gg/ml in 6 healthy volunteers [12]. These levels caused maximal impairment of psychomotor tests [30]. Plasma levels decreased to 35-73 gg/ml after 3 h, volunteers being awake [121. Subjective feelings and objective testing of drug influence lasted up to 4 h with a good correlation with the plasma concentration of midazolam [30].

Continuous infusion Under ICU conditions midazolam is given as an initial bolus injection (0.03- 0.3 mg/kg) to ascertain immediate sedation. It is followed by a continuous infusion of 4 - 1 4 m g / h [31] to allow mechanical ventilation and maintain an adequate sedation level over days or weeks. Doses higher than 10 mg/h are often needed only for agitated or excited patients.

R. Amreinand W. Hetzel: Pharmacologyof midazolamand flumazenil Under conditions of aortocoronary bypass surgery low postanesthetic infusion doses of 1 - 2 mg/h midazolam together with low doses of morphine produce adequate sedation at plasma levels of between 80 and 90 gg/ml [32]. After induction of anaesthesia with 0.25 mg/kg midazolam postoperative sedation in the ICU was maintained with midazolam 5 mg/h as a continuous infusion. Patients were asleep but arousable with mean midazolam plasma levels near 150 gg/ml during a 24-h period. Recovery was fast and allowed extubation at 2.2h_+0.7 (SD) after cessation of midazolam [33]. To produce a deep hypnotic effect for total intravenous anesthesia 0.3 mg/kg midazolam was given as a bolus for induction followed by an infusion of 0.25 mg/kg/h. Mean plasma levels were near 400 ~tg/ml. These high levels were associated with postoperative drowsiness [34]. On the other hand with long-term infusion in critically ill patients adequate sedative effects were observed at high plasma levels of 500-1000 gg/ml [31] only. However, sedation did not appear to be abnormally prolonged after cessation of the infusion. The observed interindividual variability is high. Despite the differences in doses or plasma levels of midazolam changes in the infusion regimen are quickly reflected in the patient's sedative condition due to the rapid elimination of the drug [35]. In ICU patients with normal liver function tests recovery from sedation was observed to be rapid despite eventually prolonged elimination half-lives [31] leading to the conclusion that the pharmacokinetic and dynamic response of critically ill patients is not different from that observed in healthy subjects [36].

Flumazenil Flumazenil was shown in a series of animal tests to be a highly specific benzodiazepine antagonist. It showed its highest antagonistic potency against motor incoordination and muscle relaxation induced by diazepam. It showed its weakest potency in antagonising the anxiolytic effects of diazepam [37]. No loss of activity could be found with long term treatment and no effect on peripheral benzodiazepine receptors could be demonstrated in various tests [5]. An interaction with diazepam at the rats hemidiaphragm peripheral BZD receptors is suggested [38]. Initial studies in animals have failed to reveal intrinsic effects of flumazenil. Subsequent studies demonstrated weak partial agonist activity.

Antagonistic effects In human pharmacological studies flumazenil reversed all the central nervous effects known from benzodiazepines including neurochemical effects such as decrease of cGMP and decrease of dopamine turnover [2]. Flumazenil exerts its antagonistic effects independently of whether the agonist is given before, simultaneously with, or after the antagonist. The potent antagonistic efficacy of flumazenil was demonstrated when the expected sedative effect of 8 - 2 0 m g of the benzodiazepine meclonazepam were completely blocked for 2.5 h by the simultaneous oral administration of 200 mg flumazenil. This was evaluated by

$5 cognitive and psychomotor tests. Comparable results were received in different studies when flumazenil was given during a running midazolam infusion of 0.025 to 0.04 mg/kg/h preceded by a bolus of 0.07 mg/kg midazolam. In this case 2.5 mg i.v. flumazenil almost completely reversed the significant psychomotor impairment caused by midazolam [2]. It could also be shown that the BZD receptor blocking effect of 5 mg i.v. flumazenil can be overcome by a subsequent dose of 6 - 1 0 mg midazolam, whereas the effect of a lower dose of midazolam was inhibited by the previously administered flumazenil [21. The antagonistic effect of flumazenil after the administration of a benzodiazepine is of great practical interest. It not only offers the possibility to terminate benzodiazepine sedation after anesthesia but also allows the awakening within minutes, of deeply unconscious patients after iatrogenic or accidental benzodiazepine overdose. Since flumazenil specifically reverses the effects of benzodiazepines the effects of other centrally acting drugs are not touched. Continuous unconsciousness after the use of flumazenil strongly indicates that the condition of the patient is caused either by other drugs or by brain damage. In healthy volunteers 0.i mg/kg i.v. flumazenil given 5 rain after 0.15 mg/kg midazolam antagonised the abolition of the ciliary reflex, reversed apnoea and sleep state within 60 s after administration [39]. No effects of flumazenil on the cerebral blood flow (CBF) of healthy volunteers could be found when 0.1 mg/kg flumazenil was given alone or simultaneously with 0.15 mg/kg midazolam. When midazolam was given alone a 30~ decrease in CBF was measured [40]. EEG effects of flumazenil are not different from placebo in healthy subjects. In patients with severe head injury and treated with a continuous infusion of 0.1 - 0.2 mg/kg/h midazolam the administration of a maximum dose of 1 mg flumazenil led to a decrease in cerebral perfusion pressure and an increase in intracranial pressure in those head injured patients with episodes of intracranial hypertension before flumazenil administration [41].

Agonistic effects Human findings on agonistic effects of flumazenil are somewhat controversial. In early human studies single oral doses of 200 and 600 mg did not exhibit significant effects in psychometric tests. Shifts in mood however were seen following 400 and 600 mg of oral flumazenil [2,5]. These exceptionally high oral doses as well as intravenous doses of 2.5-100 mg flumazenil were excellently tolerated by healthy volunteers. Especially, no cardiovascular or respiratory intolerance was reported. Subjective mood changes were also observed in another study after 30 mg oral flumazenil. Benzodiazepine like effects followed 100 mg flumazenil and alerting or stimulating effects were stated already after 5 mg i.v. [5]. Some anticonvulsant activity of flumazenil is ascertained by reduced or abolished epileptic potential in patients after 2.5 mg i.v. or 50 mg p.o. flumazenil [42]. Ongoing studies will clarify the practical value of this observation.

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Influence of pathological variables

Hepatic disease Midazolam and flumazenil undergo an extensive hepatic metabolism. Therefore any disease state that interferes with the normal function of this organ may influence drug metabolism and pharmacokinetic parameters like hepatic clearance or elimination half-life and lead to accumulation of the active drug in the plasma. An experimental animal model [43] revealed that midazolam does not undergo a gastrointestinal presystemic extraction after oral administration. On the contrary it was observed in liver transplant patients that midazolam given after removal of the liver was metab01ised when there were no functional hepatocytes in the body [441. The authors conclude that the liver may not be the only site of midazolam metabolism in patients with severe liver disease. These results need further confirmation. In general impaired liver function does not influence the metabolism of single i.v. bolus doses of midazolam and does not alter pharmacokinetic parameters of midazolam to a clinically important extent. On the other hand, patients who showed a prolonged recovery after therapeutic doses of midazolam were found to have an impaired liver function or a reduced hepatic blood flow. Results on the effects of midazolam in patients with chronic liver disease are conflicting [45]. Reduced liver perfusion delays midazolam metabolism and reduces midazolam clearance in patients with septic shock [46]. After liver failure in ICU patients prolongation of the elimination half-life of more than 10 h was found [47]. Normal metabolic rates of midazolam and prolongation of the elimination half-life to 4 h with a prolonged effect was seen after a single oral dose of 15rag midazolam in patients with compensated liver cirrhosis [48]. Alterations of pharmacokinetic parameters of midazolam in patients with severe liver impairment are individually very different and even normal values are found. Therefore dosing of midazolam, especially in long-term administration, has to be adapted to the individual patient reactions. In general, a reduction of the dose o f midazolam in patients with severe liver disease is to be recommended. FlumazeniI undergoes the same metabolic pathway and prolongation of terminal half-life can also be expected in cases of liver failure. Since flumazenil is administered in low doses as a single injection and has no active metabolites, alterations of pharmacokinetic parameters with a prolongation of the elimination half-life to 2.5 h [49] in patients with severe liver disease may be less important. It may even be desired if the activity of the previously given BZD is also prolonged.

Renal disease In renal failure patients the emergence of anesthesia induced with 0.2 mg/kg i.v. midazolam was 53 rain and found to be prolonged. The free drug clearance of midazolam was decreased and the elimination half-life

R. Amrein and W. Hetzel: Pharmacology of midazolam and flumazenil

increased to a mean of 4.7 h. After long term infusion of 5 - 15 mg/h midazolam there is a higher AUC ratio between the c~-hydroxy midazolam glucuronide and midazolam. Clearance of both substances is decreased and elimination half-life may be prolonged to 13 h for midazolam and 25 h for the glucuronised metabolite [5t1 in ICU patients.

Cardiovascular disease Known cardiovascular effects of midazolam consist of a blood pressure decrease in the range of 15% which does not seem to be very dose dependent [23]. The mechanism of the blood pressure decrease is not completely clear. It involves a decrease in systemic vascular resistance, a vasodilation, and a decrease in myocardial contractility [10]. An activation of baroreflex control to compensate for blood pressure decrease is also stated. On the contrary, another study found a transient decline of the baroreflex slope by 43% after 0.3 mg/kg midazolam and a sustained decrease of sympathetic tone. This is suggested to prevent a full compensation for haemodynamic alterations related to hypovolaemia [52]. Intravenous midazolam 0.2 or 0.3 mg/kg were safely given to patients with coronary artery disease [53, 54]. The deviations of the controlled cardiac parameters (coronary sinus blood flow, myocardial oxygen consumption, aortic pressure, cardiac index, systemic vascular resistance) after midazolam were not important enough to necessitate any intervention. The administration of 0.2 mg i.v. flumazenil in cardiac patients, sedated with 10mg oral diazepam, reversed diazepam-induced sleep without any significant changes in cardiovascular parameters [55].

Interaction with other drugs Due to the hepatic metabolism midazolam and flumazenil are prone to interference with hepatic microsomal enzyme inhibiting drugs. Derived from the mode of action it becomes clear that midazolam like other benzodiazepines may potentiate the effects of other substances acting on the central nervous system. This includes drugs relevant for ICU like barbiturates, opioids, and other psychotropic agents, but also alcohol.

Opioids Benzodiazepines were found to inhibit morphine glucuronidation in rat liver microsomes [56]. In a further animal experiment [57] the intrathecal coadministration of 10 ~tg of midazolam and morphine increased analgesia by 146~ but not with 20 ~tg of both drugs. The authors suggest that only low doses of midazolam potentiate morphine analgesia. The potentiating effect of low doses of opioids on midazolam induced sedation is well known from practice and results in lower dose requirements of the opioid or of midazolam. A small dose of 3 ~g/kg alfentanil already shifted the dose response curve of midazolam to the left [58]. In another study a reduced infusion rate of allen-

$7

R. Amrein and W. Hetzel: Pharmacologyof midazolam and flumazeni! tanil 1 gg/kg/min together with 0.15mg midazolam/ kg/h was sufficient to maintain total intravenous anesthesia [59]. An additional analgesic effect of midazolam in combination with morphine was observed in animals [601 and in patients [611 after intrathecal administration. The potentiating effect of opioids on midazolaminduced respiratory depression has already been mentioned.

Ca-antagonists In an interaction study [62] a constant infusion of 0.035 mg/kg/h midazolam was given for 6 h to healthy volunteers. After 2 h the subjects received 20 mg of the potent Ca-antagonist nitrendipine. No pharmacokinetic nor pharmacodynamic interaction as measured by means of an EEG and by psychomotor testing was seen between both drugs. The hypnotic effects of midazolam were not attenuated by the concomitant administration of nitrendipine.

H2-receptor blockers H2-receptor blocking agents cimetidine and ranitidine do not seem to influence to a relevant extent the pharmacokinetics of parenterally administered midazolam, Bioavailability of 15 mg p. o. midazolam was found to be increased by about 30% after pretreatment with cimetidine or ranitidine [63] with a more marked soporic effect of midazolam as compared to placebo pretreated volunteers, Increased plasma concentration of infused midazolam was found after cimetidine but not after ranitidine without increase of the sedative activity of midazolam [64]. No significant differences in midazolam plasma concentrations were measured after co-administration of cimetidine~ ranitidine, or 5 mg i.v. midazolam alone [65].

the high dose of 0.1 mg/kg flumazenil antagonised the decrease in plasma noradrenaline induced by both benzodiazepines [691.

Flumazenil Flumazenil which has no relevant agonistic effect at low doses, may only interact in the sense of abolishing effects of substances acting through the benzodiazepine receptor. In interaction studies with either midazolam, lormetazepam, flunitrazepam, or ethanol pharmacokinetic interactions between these substances and flumazenil could be ruled out [20]. There are a few reports that flumazenil antagonises cerebral effects of the volatile anesthetics isoflurane [70] or halothane [71]. The mode of this action is not very clear and may be non-specific. The antagonistic effects of flumazenil on alcoholic patients are inconsistent and most probably unspecific as well. When flumazenil is used in the situation of an intoxication with multiple drugs, including benzodiazepines and proconvulsant drugs such as tricyclic antidepressants, the protective effect of the BZD can be removed and convulsions may result. This reaction was observed in 7 out of 714 patients [72] when flumazenil was administered in a rapid injection and high dose. Careful incremental titration of small doses of flumazenil may prevent such reactions from occurring [73]. In the administration of flumazenil to such patients the benefit has to outweigh the risk for the patient [74]. In patients suffering from respiratory depression due to the combined effect of a BZD and an opioid, flumazenil safely antagonises the BZD component. This does not necessarily mean that respiration is fully and definitely restored. The effect of the opioid may still be present and a BZD effect may reappear if the dose of flumazenil was very low and the dose of the previously given BZD was high [75].

Neuromuscular blocking drugs In an in vivo animal experiment looking for the interaction of vecuronium and tubocurarine with midazolam it was found that the neuromuscular blockage induced by vecuronium was potentiated by i7~ with 0.5mg/kg midazolam and by 34070 with 5 mg/kg midazolam at 15min after injection. The dose response curve for vecuronium shifted to the left with 5 mg/kg midazolam [56]. With tubocurarine a 33~ potentiation of the muscular blocking effect was reached only at 45 min after administration of 5 mg/kg midazolam.

Endocrinological changes Etomidate is known to inhibit adrenocorticoid synthesis. Midazolam has no negative influence on adrenocortical function but reduces stress related hormone increase [35, 67] possibly via hypothalamic GABA receptors and reduced nociceptive input [67]. Flumazenil antagonises midazolam sedation without evidence of a stress response [681. In a placebo controlled double blind study with 0.06 mg/kg lormetazepam or 0.03 mg/kg flunitrazepam,

Discussion and conclusion Midazolam shows the qualities of a full benzodiazepine agonist at the benzodiazepine receptor. It is characterised by a short onset and a short duration of effect in healthy volunteers. This imidazobenzodiazepine has a marked hypnotic component and is of a higher potency than diazepam. Like other benzodiazepines, midazolam exerts its different pharmacological effects with increasing doses, which correlates with an increased number of occupied central BZD receptors. This feature can be utilized by the titrated administration of small doses until the desired effect is reached. In low doses of approximately 2 - 5 mg the anxiolytic and tranquillizing effects of midazolam are predominant. They are followed by more obvious muscle relaxant, anticonvulsive and sedating effects in doses of 5 - 1 0 mg. The anterograde amnesic effect, even with low dose, prevents the recall of unpleasant measures or events such as endoscopies or in surgical surroundings. Doses as high as 15 mg lead to the loss of the palpebral reflex and are often sufficient for induction of

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anesthesia. There is a great interindividual variability also necessitating lower doses in elderly patients. Due to the large therapeutic range and the safety of midazolam, the dose can further be increased when it seems necessary in agitated patients, in tetanic patients, or in patients not tolerating intensive care measures. Midazolam is very well tolerated. However due to its lowering effect on peripheral vascular resistance, it should be given with care to hypotensive or hypovolaemic patients. With the exception of the potentiating effect on opioids, interactions with other drugs are not known to be important. Liver or renal impairment are not contraindications for midazolam, since no untoward or toxic reaction with midazolam results. From the metabolic pathway and the mode of excretion it becomes clear that in both cases an accumulation of active drug may occur. This can be counteracted by reducing the dose, frequent observation of the patient, and in case of a too long lasting effect by administration of the antagonist flumazenil which increases the patient's vigilance immediately and dose dependently. Administration of midazolam in continuous infusion rapidly achieves steady state plasma levels with doses depending on the patient's condition ( 1 - 2 mg/h for postoperative cardiac patients, doses up to 15 m g / h for agitated patients). Mechanical ventilation is possible in a patient remaining responsive. Whether the newer anaesthetic drug propofol offers advantages over midazolam when used for prolonged sedation in critically ill patients is uncertain and clinical experience is still limited. Interaction o f propofol with fentanyl was reported to increase blood propofol concentration [761 and alfentanil plasma concentration increases in the presence of propofol [77]. In a multicenter study in 100 ICU patients [78] the rate of recovery after 20 h of sedation was found to be less variable after propofol than after midazolam. If propofol, however, was used for prolonged sedation of 72 h in 9 ICU patients [79] with normal renal and hepatic function considerable interpatient variability in term of delayed awakening was observed and the mean elimination half-life of propofol was prolonged to more than 30 h. There exists no antagonist to reverse propofol sedation. Flumazenil was originally recognised as a pure and highly specific BZD antagonist at the BZD receptor. Today some weak partial agonistic effects are known which may be used therapeutically (anticonvulsant effect), or which do not appear at therapeutic doses. The BZD specifity allows flumazenil to be used in all cases where a BZD induced sedation is too deep or no longer desired [74]. The quality of the antagonistic effect is independent of the time of administration. It allows interruption of continuous sedation transiently for diagnostic purposes or to terminate BZD sedation definitely. The duration o f the effect of flumazenil is influenced by the type of the BZD agonist to be reversed (long or short acting) by the time elapsed between the administration of the agonist and antagonist and by the administered doses of both types of drugs.

R. Amrein and W. Hetzel: Pharmacology of midazolam and flumazenil

From their pharmacokinetic characteristics midazolam and flumazenil are to some extent related which results in pharmacological properties which fit both drugs very well together. The short onset of action of both drugs allows an immediate assessment of the patient's situation and of an adaptation o f the patient's awareness according to his present condition and situation [80]. The short duration o f midazolam in general does not allow reappearance of sedation after the use of flumazenil. If a prolonged effect of flumazenil is needed, it can be administered by a continuous infusion [80]. The short duration of flumazenil allows to awaken a patient only transiently during a running infusion of midazolam. Under observation of the principle rule of a slow and titrated administration and the observation of cardiorespiratory parameters, both drugs are very safe and easy to handle.

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