Midazolam, opportunities and prospects of using in emergency treatment
The challenge of protecting patients from aggressive impact of surgery and anaesthesia is one of the major issues of anesthesiologists and surgeons. Excessive stress reaction leads to the high level of neuroendocrinal tension, haemodynamic changes, metabolism intensification and other negative deviances. Modern general anaesthesia concept refers primarily to such notions as adequate and component-based anaesthesia. In order to support adequate anaesthesia and fulfil complexity principle, various pharmacological aids have currently been used that correspond to one or another anaesthesia components: hypnotics, analgesics, muscle relaxants [2].
Sedation is one of the general anesthesia components, which is achieved by administration of the products of different pharmacological classes; these are barbiturates, benzodiazepines and other.
Benzodiazepines include pharmaceutical products with 5-aril?1,4 benzodiazepine structure, which formed as a result of combination of benzene ring in a seven-membered diazepine ring[1]. The first diazepine (chlordiazepoxide) was synthesised in 1956, diazepam - the first product in the group for intravenous administration - in the 1960s.
Benzodiazepines reveal all their pharmacological effects by alleviation of the effect of gamma-aminobutyric acid (GABA) – the major inhibitory neutrotransmitter in the central nervous system (CNS), equalizing the effect of activating neutrotransmitters that leads to the inhibition of functional activity of CNS cells and suppression of neuronal transmission in CNS structures.
These days, thousands of various benzodiazepines have been synthesised, about 30 of which are used in clinical practice.
Depending on the elimination half-life, all benzodiazepines fall into three groups. Long-lasting action products with the elimination period of more than 24 hours include diazepam, mazepam and nitrazepam. Nozepan and flunitrazepam have medium elimination duration (5-24 hours). Midazolam, the product of last generation in this class, has short half-life period (less than 5 hours). Midazolam has increasingly been used in anaesthesiology due to significantly better controllability than diazepam [2].
Midazolam (8-chlor?6-(2-fluorophenyl)-1-methyl ?4H-imidazo[1,5-a][1,4]benzodiazepine in a form of hydrochloride (C 18H13ClFN 3) was synthesised in 1976.
The product “Midazolam” (FSUE Moscow Endocrine Plant, Russia) is a generic drug with midazolam being the active component (in a form of hydrochloride).
Midazolam contains imidazole ring, which marks if out from classical benzodiazepines. Midazolam imidazole ring increases product’s stability in solution, provides fast metabolism, the highest lipophilicity and solubility in water in low pH value. Midazolam basicity allows for obtaining salts (for example, hydrochloride, maleate, lactate) with high solubility in water. Midazolam is specially prepared in acid buffer with pH 3.5, as imidazole ring opening depends on pH: when pH < 4, the ring is opened and the medicinal product is soluble, when pH > 4 (physiological value), the ring closes and the medicinal product becomes liposoluble - one of the most lipophilic benzodiazepines[3].
Various hydrophility and lipophilicity of Midazolam depending on pH is of high importance. High lipophilicity of the “closed” form of midazolam ensures its fast absorption in the gastrointestinal tract and penetration through the blood-brain barrier into the brain tissue. The official midazolam solution is compatible with 5% glucose water solution, physiological solution and Ringer's solution - lactate, at the same time, the product does not penetrate though the infusion vessel walls, mixtures are stable at room temperature during 24 hours. The product can be mixed in one syringe with other salt solutions, such as, morphine, skopolamine and atropine[3].
Intravenous and intramuscule administration of midazolam solutions is virtually painless and not associated with local reactions.
Methyl group at the first position of imidazole ring provides short duration of midazolam effect. This group is quickly oxidized by liver oxidases, much faster that the methylene group at the fourth position of diazepine ring, which is a target for liver ferments in classic benzodiazepines.
Pharmacokinetics
In intramuscular administration, the level of midazolam absorption is 80–100 %. High lipophilicity of midazolam determines relatively large volume of its distribution which is larger in women than in men. The age does not influence on midazolam distribution volume much. In overweight, the distribution volume increases, also benzodiazepine half-elimination prolongs in stable clearance[4]. 1-hydroxymidazolam half-elimination period is about 70 minutes[4].
Midazolam binds actively to plasma proteins, only 4% remain in unbounded condition. Due to high lipophilicity and predominant bond to albumin, midazolam penetrates through histohematic barriers: blood-brain and placental, and in breast milk. In the experiment, the balance between midazolam plasma concentration and its content in spinal fluid is achieved in several minutes [4]. Midazolam penetrates through placenta worse than diazepam[6].
Midazolam elimination half-life does not depend on the rout of its administration and is 1.5–3.5 hours at average. Major operations contribute to the increase in midazolam distribution volume and prolong the half-life period[4].
Basic pharmacokinetic parameters of midazolam are given in table 1.
| |
Parameter |
Value |
Clearance, mL/min. |
350-500 |
Clearance, mL/kg/min. |
6.4-11.0 |
Vdss, l/kg |
0.7-1.7 |
Distribution half-life, t1/2α, min. |
25-30 |
Elimination half-life, t1/2β, hour. |
1.5-3.0 |
Elimination half-life of 1-hydroxymidazolam, hour. |
1.5-3.0 |
Bond to proteins, % |
96 |
Bioavailability in intramuscular administration, % |
90 |
tmax, min. |
30 |
Fast distribution and accelerated metabolism in comparison to other benzodiazepines interpret the peculiarities of midazolam pharmacodynamics: quick onset of action, but short duration in bolus dosing. Upon intravenous administration of the product to healthy volunteers, the decrease in its concentration is made into two phases: initial, fast, related to distribution; second, slow, depends primarily on metabolism.
The first stage of midazolam metabolism involves its fast oxidation under the effect of liver CYP3A4 and CYP3A5. The basic product is 1-hydroxymidazolam (1-hydroxymethylmidazolam, α-hydroxymidazolam). Small amounts of 4-hydroxymidazolam are produced simultaneously and even less of 1,4-dihydroxymidazolam. Both basic products conjugate quickly with glucuronic acid and are eliminated with the urine in a form of glucuronids (60–80 % from the administered dose). Less than 1% is cleared unchanged in the urine.
Metabolites circulate also in blood in unconjugated form. They have pharmacological effect [5]. 1-hydroxymidazolam activity is compatible with that of the unchanged midazolam and in high concentrations may contribute significantly to the product activity. 4-hydroxymidazolam effect is clinically insignificant.
The capacity of midazolam to be exposed to extrahepatic metabolism has also been proved. And now, as part of the study, formation of metabolites continued in the intravenous administration of midazolam during liver transplant in non-liver period[5].
Dependence of Pharmacokinetic from the Age of Patients
According to a number of researchers, midazolam clearance decreases in elderly individuals and its elimination half-life increases in comparison to young adults[5]. Age also influence on pharmacodynamics of midazolam. The same sedation level in patients over 70 y.o. is provided in less concentrations than in younger patients (younger 60 y.o.). Therefore, in unchanged midazolam parmacokinetic profile, the sensitivity to its effects increases with the age that is needed to be taken into account in choosing doses in senior and young patients (in order to avoid excessive and insufficient sedation, respectively).
As for the majority of other products, midazolam pharmacokinetics in children differs from pharmacokinetics in adults in many respects. In children under 6 months of age, t1/2β prolongs and midazolam clearance decreases. Probably, such a difference stems from the immaturity of the liver microsomal system in children under 6 months of age [8].
Bioavailability of intramuscularly injected midazolam in children does not differ from the ratio in adults (90 %), bioavailability of the product administered per os due to the first-pass effect decreases to 27 %[8].
Pharmacokinetics in Patients with Impaired Renal Function
In patients with impaired renal function, an increase in free midazolam fraction (6,5 %) is noted in comparison to healthy volunteers (3.9 %)[5]. At the same time, free midazolam clearance index, correlated as per the level of bond to proteins, does not differ in patients with or without chronic renal impairment.
α-hydroxymidazolam glucuronide - a metabolite accumulated in patients with renal impairment, leads probably to excessive sedation observed in such patients that is confirmed by a number or studies.
Midazolam and its unconjugated α-hydroxymidazolam metabolite do not eliminate in course of hemodialysis, while conjugated α-hydroxymidazolam does. It is hard to predict the response to midazolam in patients that are on hemodialysis, as stable substance and its conjugated metabolite both have pharmacological effect.
Pharmacokinetics in Patients with Hepatic Impairment
The elimination half-life in patients with liver cirrhosis is significantly increased (2,89 in average) in comparison to persons having no cirrhosis (1,65 in average). Decreased hepatic metabolism and reduced midazolam clearance, as a consequence, in serious intensive care patients require midazolam dose titration in order to avoid excessive sedation[5].
Midazolam, like other products, benzodiazepine derivatives, has hypnotic, anxiolytic, myorelaxing and anticonvulsant effect, causes antegrade amnesia.
Pharmacodynamics
Sedative and Hypnotic Effect
In course of a number of studies, midazolam hypnotic effect has been proved, moreover, no clear effect dose-dependence was noted, and its maximum was achieved in the first third of the night[5]. It has been determined that midazolam increases the time before the onset of the sleep phase - rapid eye movement, but the duration of this phase is not changed significantly[5]. Rebounding insomnia has been described resulted from the termination of midazolam intake in a dose of 20 or 30 mg, but not 10 mg. Rebounding insomnia and anxiety after benzodiazepine withdrawal, including midazolam, are a frequent occurrence. Development of tolerance to hypnotic effect is possible. Shortness of action makes it impossible to consider midazolam as a perspective sleeping aid but rapid onset of the effect and its short duration are useful properties for post-surgical sedation. In the same way as for other products with fast metabolism, development of tolerance to midazolam effect does not allow using it for revealing long proceeding anxiety and sleep disorders. At the same time, the absence of local adverse effects in the intravenous administration, rapid hypnotic effect onset and its short duration, as well as anterograde amnesia make midazolam a drug of choice for performing fast diagnostic and treatment manipulations (endoscopy, dentistry)[5].
Effects on Psychomotor Functions
In assessing the psychomotor functions as part of clinical studies, a significant decrease in psychomotor functions was noted in 1 hour after midazolam intake per os singularly or in combination with alcohol. Daily midazolam intake in a dose of 20 mg before sleep within four days was associated with the decreased psychomotor functions in 10 hours after the last intake. At the same time, the effect was less noticeable in comparison to that against flunitrazepam intake in a dose of 30 mg. After intravenous administration of midazolam in a dose of 0.07–0.15 mg/kg to healthy subjects, psychomotor functions restored in 3 hours [5].
Effects on Memory
Initial midazolam studies demonstrated already that it causes anterograde amnesia. This way, the maximum intensity of the said effect is observed in a period from 2 to 5 minutes after injection. In analysing the frequency of development and the duration of anterograde amnesia after intravenous administration of equivalent doses of various benzodiazepines, the same profile of midazolam and diazepam effect (shorter duration of midazolam effect) come under notice and differing lorazepam effect - slow onset but longer effect duration. None of the products causes retrograde amnesia.
Short-term anterograde amnesia is a useful property of midazolam used in diagnostic procedures and in dental practice. Patients forget senses of discomfort that appear, for example, in time of endoscope insertion or administration of local anesthetics, and fast restoration allows maintaining adequate unassisted breathing and other physiological functions in further manipulations.
Cardiovascular Effects
Injectable benzodiazepines, excluding flunitrazepam, have minimum effect on cardiovascular functions. This assertion is true for midazolam as well. Midazolam decreases peripheral vascular resistance in patients with coronary artery disease (CAD). The effect is especially noticeable in persons with initially increased resistance, for example, against arterial hypertension or in emotional stress before a scheduled surgical intervention. Blood depositing in veins and decreased peripheral vascular resistance under the effect of midazolam may ease pre- and afterload on the heart that may potentially improve the heart function in heart failure.
Within a number of clinical studies, a comparative assessment was performed of the effect of midazolam and diazepam on the cardiovascular system parameters in patients with CAD. Both benzodiazepines had minimum effects in anesthesia induction for carrying out the coronary artery bypass grafting (CABG). Under cardia bypass conditions, diazepam induced more expressed vein and arteriolodilatation.
Against pre-medication, the induction of anesthesia with midazolam in patients is associated with less expressed changes in the frequency of the heart rate (HR) and average blood pressure (BP) than in thiopental induction, and also provides less response to tracheal intubation in patients before CAD operative therapy. Bolus dosing of midazolam (unlike with thiopental) has no influence on its hemodynamic effects.
It was noted in Forster et al. study that the cerebral blood flow velocity in conscious healthy volunteers against midazolam administration was decreased. In patients in anesthetic condition, cerebral perfusion pressure is slightly decreased due to the decreased average BP in the aorta. In patients with brain tumours, midazolam in a dose of 0.32 mg/kg intravenously did not decrease the intracranial pressure. Midazolam decreases the renal blood flow.
Effects on Respiratory Functions
In oral intake in therapeutic doses, midazolam does not cause any respiratory disorders in healthy subjects. Midazolam effect on the respiratory system in high doses is realized via two mechanisms. Firstly, its effect on the muscular tone causes the risk of upper airway obstruction, so benzodiazepines are not recommended, and in the opinion of some experts, even prohibited to persons with obstructive sleep apnoea. Secondly, in loss of consciousness, in midazolam administration the sensitivity to carbon dioxide level increase reduces. Midazolam suppresses respiration centre, although peripheral effects cannot be excluded. In concomitant prescription of midazolam and opioids, the risk of respiratory suppression increases dramatically. The important mechanism of respiratory suppression against midazolam administration is the suppression of response to hypoxaemia under hypercapnia conditions. In patients suffering from chronic obstructive pulmonary disease, respiratory suppression under midazolam effect is more frank and continues longer that in healthy subjects. Consequently, special attention is needed while using the product in patients with chronic obstructive pulmonary disease[2].
In therapeutic doses (0.1 mg/kg), midazolam intravenous administration leads to the decreased breathing capacity, which is compensated by an increase in respiratory rate, as a result, the minute volume remains unchanged. At that, the increased respiratory rate is ensured by expiration shortening; inspiration duration remains unchanged. Under midazolam effect, the functional residual capacity and residual lung volume remain unchanged. In contrast to anaesthetic drugs, midazolam increases the lung static compliance, which decreases the load on the chest and the participation of abdominal muscles in breathing[7].
Effects on Autonomic Vegetative Nervous System and Endocrine System Functions
Benzodiazepines decrease the reaction to both physiological and psychological stress[5].
In a comparative study performed by Croizer et al. aiming at estimating endocrine changes against the induction with etomidate, midazolam and methohexital, it was revealed in patents who were exposed to minimally invasive orthopedic interventions, that adrenaline and noradrenaline levels prior to the intervention were compatible in patients of all groups. By the end of the surgery, catecholamine levels increased significantly in patients of all groups but in midazolam group, the increase level turned to be minimum. Cortisol and aldosterone level decrease, both against etomidate and midazolam administration, was compatible. The response to adrenocorticotropic hormone (ACTH) administration in midazolam group was way over expressed than in etomidate group. As a result of feedback mechanism failure, ACTH endogenous level increased in etomidate group. Midazolam does not cause adrenal suppression in post-surgical period.
In intrathecal administration, midazolam provides analgesic effect, which is confirmed by the decrease in the need for enflurane and diamorphine during surgical treatment of the abdominal cavity organs.
Drug Interactions
Pharmacokinetic Interactions
Midazolam is exposed to metabolic transformation with the participation of cytochrome Р450 (CYP3A4) primarily [4, 5]. Thus, medicinal products having the capacity to change CYP3A4 effect one way or another, may potentially influence on metabolic profile, and midazolam clinical effects, as a consequence. So, CYP3A4 inhibitors, such as erotromicyn, fluconazol, itraconazolum, sacvinavir and voriconazole, reduce midazolam clearance in its intravenous administration in healthy volunteers by 50–70 %. Therefore, in the prolonged infusion, midazolam concentration against strong inhibitors (CYP3A4) intake should increase three to four times and may cause unscheduled intensification of sedation and an increase in its duration. Propofol and intavenous hypnotics used for induction and maintenance of general anaesthesia also decrease the clearance of intravenously administered midazolam by 37% owing to CYP3A4 cytochrome inhibition in the liver. Fentanyl reduces midazolam clearance by 30%.
CYP3A4 inhibitors include also such products as calcium-channel blockers, diltiazem and verapamil, H2-histamine receptors blockers, cimetidine and ranitidine. Numerous studies have proved their effect on pharmacodynamics and pharmacokinetics of midazolam.
CYP3A4 inducers cause sharp acceleration of midazolam metabolism that decreases its concentration and effect intensity. CYP3A4 inducers include rifampin, carbamazepine and phenytoin. They accelerate midazolam metabolism and decrease midazolam pharmacological effect.
Midazolam metabolism and its pharmacodynamics, respectively, may be influenced by other products suppressing or activating CYP3A4. According to Drugs.com database, the possibility of drug interaction with midazolam is described for 1 682 medicinal products. 82 of them have significant impact on midazolam effect, 1 392 - moderate and 208 - minimum. The products that have significant impact are antiviral agents (atazanavir, darunavir, efavirenz, tenofovir, fosamprenavir, indinavir, and sacvinavir), antifungal agents (fluconazol, itraconazolum, ketoconazolum, posaconazole, and voriconazole), analgesics (sodium oxybate) and antipsychotic drugs (clozapine, droperidol, and olanzapine).
Pharmacodynamic Interactions
Clinical significance of midazolam pharmacodynamic interactions is essentially higher in comparison to pharmacokinetic. Many of them are unpredictable and can be prevented owing to rational approach to product combining. At the same time, in a number of cases, pharmacodynamic interactions of various medicinal products containing midazolam appear to be of use in clinics. In that way, combination of products with similar effect allows decreasing the dose of each product and, therefore, achieving the desired result in less quantity of adverse effects.
All benzodiazepines influence on the CNS and interact with other central action products. For example, morphine in combination with midazolam has summational sedative effect [7]. Combination of midazolam, propofol, alfentanil is accompanied by their synergistic effect. In intrathecal administration, midazolam provides analgesic effect, additional to opioid effect. We want to emphasis one more time the potentiating effect of opioids on respiratory suppression under midazolam effect [7].
According to Hong et al., midazolam and ketamine interaction shows itself in summation of their effects (additive effect). In combination of midazolam and thiopental, and also propofol and midazolam, synergism (potentiating) is noted, that is probably stipulated by their ability for various changes in the conformation of GABA-receptor complex.
Flumazenil is benzodiazepine antagonist, binds to benzodiazepine receptor and, not having own pharmacological effect, blocks all effects of benzodiazepine antagonists, including midazolam. Flumazenil dose in a range of 0.3–2.0 mg is sufficient for reducing the intensity or total elimination of pharmacological effect of benzodiazepines in their overdosing[7].
Safety
Local Adverse Effects
Pain at the injection site and post-injection thrombophlebitis are frequent complications emerging against intravenous administration of benzodiazepine (diazepam, lorazepam and flunitrazepam)[1]. Solubility in water in an acidic environment allows obtaining midazolam water solutions, which leads to a decrease in thrombophlebitis frequency after intravenous administration of midazolam (from 3 to 10 %)[4].
In intranasal administration of midazolam (convenient product administration route) there may be burning sensation in the nose, irritation, and lacrimation. After midazolam inhalation through nebulizer, bronchospasm was observed in 2 patients of 10 associated with the action of not the product itself but with acid pH of its solution[4].
System Adverse Effects
Midazolam in monotherapy does not have significant respiratory effects. Administration of combination of midazolam and fentanyl is associated with hypoventilation in 90% of cases[7]. Respiratory suppression induced by midazolam may depend on product infusion velocity: fast administration is accompanied by higher frequency of bradypnea development. Midazolam already in a doze of 0.01 mg/kg decreases the sensitivity to hypoxia and hypercapnia.
Arcos et al. reported about three cases of ventricular bigemenia and trigemenia, and about ventricular tachycardia after the premedication, which included intramuscular administration of midazolam. All arrhythmias ceased within 2-4 hours after midazolam administration[4].
Yakel et al. described a case with angioedema and bronchospasm after repeated midazolam intravenous administration. Fujita et al. also reported of allergic shock reaction to midazolam.
Also paradoxical responses to benzodiazepines were described manifestative in animosity, aggression, and irascibility. Cased of psychoemotional excitement in response to midazolam administration are described both in adults and in children[1]. The mechanism of development of delirious states in response to midazolam administration is not clear.
After termination of the prolonged (more than a few days) midazolam infusion, the withdrawal syndrome may occur, including convulsionary attacks development.
The prolonged anterograde amnesia is a frequent complication against midazolam therapy. Upon premedication with benzodiazepines, including midazolam, slow restoration of cognitive functions is noted.
Midazolam may induce other, less clinically significant adverse effects. They include hiccup, cough, nausea and vomiting[1].
Using Midazolam During Pregnancy and Lactation
Wilson et al. determined that midazolam metabolism changes during pregnancy and particularly significantly during childbirth. Maybe, an increase in bond to proteins can lead to a decrease in distribution volume and clearance of the product. Midazolam elimination half-life in pregnant women is approximately 1 hour [6]. Midazolam has the ability to penetrate the placental barrier, but the level of the product in foetus’s circulatory stream is lower than in mother’s [6]. Midazolam administration immediately before caesarean section or within the latency period leads to foetus’s heart beat disorder, hypotony, sucking disorder, hypothermia and moderate respiratory suppression in newborns.
Since midazolam in small doses penetrates into breast milk, breastfeeding women should discontinue breast-feeding for 24 hours.
No studies have been found in literature on the assessment of midazolam safety in the first trimester of pregnancy or information about fetus or newborn malformation.
Clinical Administration (Indications) in Children and Adults
Basic clinical administration of midazolam is sedation before and during diagnostic or treatment procedures. Midazolam is used in premedication, induction and as a sedative component in combined anaesthesia.
Midazolam is used for sedation under emergency treatment conditions, before endoscopic studies (fibrogastroduodenoscopy, colonoscopy and bronchoscopy), in dental practice for revealing psychomotor agitation.
Cole et al. made a comparison of the efficiency and safety of diazepam and midazolam administration in patients before endoscopic interventions. Midazolam had faster and stronger effect than diazepam - sedation occurred in 2.5 minutes in average after administration; also faster effect termination was noted. In patients treated with midazolam, less side effects were noted including less level of respiratory suppression. In a study by Coughlin et al. on the assessment of the efficiency and safety of intravenously prescribed midazolam and diazepam in maxillofacial surgery, sedation duration did not differ significantly, but clinically significant differences in pain frequency at the injection site were observed (32% in diazepam group against 6% in midazolam group). Amnesia severity was higher in midazolam group.
Midazolam relieves agitation effectively. Wyant et al demonstrated in a comparative study that midazolam in a dose of 5 mg intramuscularly overrun haloperidol by agitation relieving effect and was equal to 250 mg of sodium amylate. Barbiturates cause respiratory suppression and arterial hypertension, midazolam overruns amylate by these parameters.
One more benefit of sedation induced by benzodiazepines is the presence of antagonist – flumazenil, which allows achieving the inversability of sedative effect, if necessary, psychomotoric retardation and memory impairment within 5 minutes.
Midazolam is effective for relieving convulsion and refractory epileptic status in intravenous and intramuscular administration. Midazolam is also effectively used in muscle cramps at emergency departments and as a product for quick sedation in patients before tracheal intubation.
Midazolam can be prescribed intravenously, intramuscularly, orally, rectally and intranasally, which facilitates its use in pediatric practice, in intensive care. Dosing and routes of midazolam administration are chosen individually till reaching the required degree of the effect corresponding to clinical necessity, patient’s physical condition and age, and concomitant medication.
The major contradictions to using midazolam are hypersensitivity to benzodiazepines or product components, severe respiratory failure, angle-closure glaucoma, and latency period.
Consequently, midazolam administration in anesthesiologists-resuscitationists’ practice allows for provision of basic fundamentals of modern anaesthesiology - safety and adequacy of anaesthesia. And unique midazolam structure stipulates its differences from other benzodiazepines that are beneficial from clinician's point of view[3]:
• high affinity to benzodiazepine receptors;
• water solubility of salts, which allows preparing stable purified water solutions, the administration of which is well tolerated by patient;
• quick onset and short duration of the effect due to fast metabolism.
List of reference 1 Rational pharmacoanaesthesiology: Guidance for practising physicians/under the general editorship of A.A. Bunyatyan, V.M. Mizikov. — М.:
“Litera”, 2006. - 800 p.
2. S.A. Sumin, M.V. Rudenko, I.M. Borodinov Aesthesiology and resuscitation: Study guide in 2 volumes. Т.I. — М.: LLC Medical information agency, 2010. - 928 p.: il.
3. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol. 1983; 16 Suppl 1: 11S?16S.
4. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984 Jul; 61 (1): 27-35.
5 were revealed. Mandema JW1, Tuk B, van Steveninck AL, Breimer DD et al. Pharmacokinetic pharmacodynamicmodeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther. 1992 Jun; 51 (6): 715-28.
6. Kanto J, Sjovall S, Erkkola R, Himberg JJ et al. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther. 1983 Jun; 33 (6): 786-91.
7. Ramoska EA, Linkenheimer R, Glasgow C. Midazolam use in the emergency department. J Emerg Med. 1991; 9: 247-51. 8. Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet. 1998 Jul; 35 (1): 37-47.
Comment type is not specified in the component properties.