Midazolam
Discover related
5 sources
🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Translocator protein | — | Ki 2 nM | CHEMBL | TargetTranslocator protein Action— AffinityKi 2 nM SourceCHEMBL |
| GABA-A receptor; anion channel | — | Ki 2 nM | CHEMBL | TargetGABA-A receptor; anion channel Action— AffinityKi 2 nM SourceCHEMBL |
| Cytochrome P450 3A4 | — | Ki 2470 nM | CHEMBL | TargetCytochrome P450 3A4 Action— AffinityKi 2470 nM SourceCHEMBL |
| Solute carrier family 22 member 1 | — | Ki 3700 nM | CHEMBL | TargetSolute carrier family 22 member 1 Action— AffinityKi 3700 nM SourceCHEMBL |
Mechanism of action
The actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening. These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system.
Midazolam has neurotoxic properties when administered neuraxially in vivo. Furthermore, midazolam induces neurodegeneration in neonatal animal models in combination with other general anesthetics. Therefore, this study focuses on the mechanism of neurotoxicity by midazolam in neuronal and nonneuronal cells. The study aims to evaluate the apoptotic pathway and to investigate the protective effects of the benzodiazepine antagonist flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone. The apoptosis-inducing effect of preservative-free midazolam on human lymphoma and neuroblastoma cell lines was evaluated using flow cytometric analysis of early apoptotic stages (annexin V/7AAD) and caspase 3 activation. B-cell lymphoma (Bcl2) protein overexpressing and caspase 9-deficient lymphoma cells were used to determine the role of the mitochondrial (intrinsic) pathway. Caspase 8-deficient and Fas-associated protein with death domain (FADD)-deficient cells were used to evaluate the death receptor (extrinsic) pathway. The protective effects of flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone were investigated in neuroblastoma cells and primary rat neurons using metabolic activity assays (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and immunofluorescence microscopy. Midazolam induced apoptosis in all investigated cell types in a concentration-dependent manner, indicated by flow cytometry. Bcl2-overexpression and caspase 9 deficiency protected against toxicity, whereas caspase 8 or FADD deficiency had no effect. Pancaspase inhibition had a strong protective effect, whereas flumazenil did not inhibit midazolam-induced apoptosis. Midazolam induces apoptosis via activation of the mitochondrial pathway in a concentration-dependent manner. The mechanism of midazolam toxicity switches from caspase-dependent apoptosis to necrosis with increasing concentrations. The induction of apoptosis and necrosis by midazolam is presumably unrelated to GABAA receptor pathway signaling.
A consummatory conflict procedure that involves an abrupt reduction in magnitude of an expected reward (negative contrast) has been shown to be particularly sensitive to the effects of anxiolytic agents. Midazolam released suppressed consummatory performance in a dose-dependent manner. This effect was not due to a general appetite stimulation effect of the drug. The effects of three 5-HT antagonists on negative contrast were examined to evaluate the role serotonin may play in the anxiolytic action of benzodiazepine. Methysergide was found to be ineffective, cinanserin tended to reduce contrast at two intermediate doses, and cyproheptadine eliminated the contrast effect in a similar fashion as midazolam. The effectiveness of cyproheptadine may not be attributed to its anticholinergic or antihistaminergic actions since scopolamine and pyrilamine did not produce similar efects. The results are discussed in terms of the role serotonin may play in the anti-conflict action of benzodiaepine, as well as possible interactional effects of gamma-aminobutyric acid.
The exact sites and mode of action of the benzodiazepines have not been fully elucidated, but the effects of the drugs appear to be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. Benzodiazepines are capable of producing all levels of CNS depression-from mild sedation to hypnosis to coma. /Benzodiazepines/
Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking excitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function. /Benzodiazepines/
For more Mechanism of Action (Complete) data for Midazolam (6 total), please visit the HSDB record page.
Pharmacodynamics
**General effects** Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepine drugs, include sedative, anxiolytic, amnestic, muscle relaxant, as well as hypnotic activities. Benzodiazepines enhance the inhibitory action of the amino acid neurotransmitter gamma-aminobutyric acid (GABA). Receptors for GABA are targeted by many important drugs that affect GABA function and are commonly used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, and aggressive behavior. **Sedation and memory** The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection. In one study of adults, when tested the following day, 73% of the patients who were administered midazolam intramuscularly had no recollection of memory cards shown 30 minutes following drug administration; 40% had no recollection of the memory cards shown 60 minutes after drug administration. Onset time of sedative effects in pediatric patients begins within 5 minutes and peaks at 15-30 minutes depending upon the dose administered. In the pediatric population, up to 85% had no memory of pictures shown after receiving intramuscular midazolam compared to 5% of the placebo control group. Sedation in both adult and pediatric patients is reached within 3 to 5 minutes post intravenous (IV) injection. The time of onset is affected by the dose administered and the simultaneous administration of narcotic pre-medication. Seventy-one (71%) percent of the adult patients in clinical endoscopy studies had no memory of insertion of the endoscope; 82% of the patients had no memory of withdrawal of the endoscope. **Anesthesia induction** When midazolam is administered intravenously (IV) for anesthetic induction, induction of anesthesia occurs in about 1.5 minutes when narcotic pre-medication has been given and in 2 to 2.5 minutes without narcotic pre-medication/ other sedative pre-medication. Impairment in a memory test was observed in 90% of the patients.
Pharmacokinetics
Half-life
**Intravenous**: Six single-dose pharmacokinetic studies involving healthy adults yield an elimination half-life of 1.8 to 6.4 hours (mean of approximately 3 hours). **Intramuscular** Following IM administration of 10 mg midazolam, the mean (±SD) elimination half-life of midazolam was 4.2 (±1.87) hours. **Intranasal** Following the administration of NAYZILAM in clinical trials, median midazolam and 1-hydroxy-midazolam elimination half-lives ranged from 2.1 to 6.2 hours and 2.7 to 7.2 hours, respectively, independent of dose. **Oral** The mean elimination half-life of midazolam ranged from 2.2 to 6.8 hours following single oral doses of 0.25, 0.5, and 1.0 mg/kg of midazolam HCl syrup. **Buccal* The initial and terminal elimination half-lives are 27 and 204 minutes, respectively.
Midazolam is extensively protein bound (more than 95%). With an intravenous dose of 0.075 mg/kg, the half-life is 68 min, the apparent volume of distribution is 0.23 L/kg, and the clearance is 13 mL/kg/min. The half-life is prolonged in patients with cirrhosis.
...Most elimination half-life ranged from 2.9-4.5 hours in pediatric patients (6 months to less than 16 years of age) receiving IV midazolam 150 ug/kg. In seriously ill neonates, the terminal elimination half-life is substantially prolonged (ie. 6.5-12 hours).
Following a single IV dose in health adults, the half-life of midazolam in the initial distribution phase (t 1/2 alpha) averages 6-20 minutes, and the half-life in the terminal elimination phase (t 1/2 beta) averages 1-4 hours (range: 1-12.3 hours). Limited data suggest that the half-life of midazolam may be prolonged in obese patients (presumably secondary to an increased volume of distribution), geriatric individuals, and patients with impaired hepatic function or with congestive heart failure. The half-life of midazolam is also repeatedly prolonged in patients receiving the drug for induction of anesthesia associated with major surgical procedures...
Absorption
**Intramuscular** Following IM administration of a single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median Tmax (range) of 0.5 (0.25 to 0.5) hours; midazolam's mean (±SD) Cmax and AUC0-∞ were 113.9 (±30.9) ng/mL and 402.7 (±97.0) ng∙h/mL, respectively. **Rectal** After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50%. **Intranasal Administration** Following the nasal administration of a single 5 mg midazolam dose to healthy adults, midazolam was absorbed with a median Tmax (range) of 17.3 (7.8 to 28.2) minutes; midazolam's mean (±SD) Cmax and AUC0-∞ were 54.7 (±30.4) ng/mL and 126.2 (±59) ng∙h/mL, respectively. The mean absolute bioavailability is approximately 44%. **Oral** In pediatric patients from 6 months to <16 years old, the mean Tmax values across dose groups (0.25, 0.5, and 1.0 mg/kg) range from 0.17 to 2.65 hours. Midazolam also exhibits linear pharmacokinetics within this dose range (up to a maximum dose of 40 mg). Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. Due to first-pass metabolism, only 40-50% of the administered oral dose reaches the circulation. The absolute bioavailability of midazolam is about 36%, which is not affected by pediatric age or weight. Cmax and AUC0-∞ were also calculated to range from 28 to 201 ng/mL and 67.6 to 821 ng∙h/mL respectively. **Buccal** After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about 75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions. Cmax and AUC0-∞ were also calculated to range from 87 to 148 ng/mL and 168 to 254 ng∙h/mL respectively.
The _α-hydroxymidazolam_ glucuronide conjugate of midazolam is excreted in the urine. No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates. The amount of midazolam excreted unchanged in the urine when given intravenously is less than 0.5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate. The principal urinary excretion products are glucuronide conjugates of hydroxylated derivatives. Plasma clearance of midazolam is higher in patients that remain in the supine position, because of a 40-60 percent increase in hepatic blood flow during supination. Pregnancy may also increase the metabolism of midazolam.
Female gender, old age, and obesity may increase the volume of distribution. Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid. **Intravenous administration** In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg. For healthy adult patients, the volume of distribution determined from six single-dose pharmacokinetic studies ranged from 1.0 to 3.1 L/kg. **Intramuscular administration** The mean (±SD) apparent volume of distribution (Vz/F) of midazolam following a single IM dose of 10 mg midazolam was 2117 (±845.1) mL/kg in healthy subjects. **Intranasal** The estimated total volume of distribution of midazolam is 226.5 L. **Buccal** The steady-state volume of distribution following oromucosal administration is estimated to be 5.3 l/kg.
**Intramuscular** Following IM administration of 10 mg midazolam, the apparent total body clearance (CL/F) of midazolam was 367.3 (±73.5) mL/hr/kg. **Intravenous**: Six single-dose pharmacokinetic studies involving healthy adults yield a total clearance (Cl) of 0.25 to 0.54 L/hr/kg. **Intranasal** Midazolam clearance was calculated to be 1.9 mL/min/kg **Oral** Following a group of patients receiving the 0.15 mg/kg IV dose, the mean total clearance ranged from 9.3 to 11.0 mL/min/kg. **Buccal* Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min.
Following iv administration of midazolam hydrochloride in animals, the drug is widely distributed, with highest concentrations occurring in liver, kidneys, lungs, fat, and heart. The drug crosses the blood-brain barrier and distributes into cerebrospinal fluid in humans and animals. In animals, equilibration of midazolam between plasma and cerebrospinal fluid occurs within a few minutes following iv administration, and cerebrospinal fluid:plasma ratios of the drug are highly correlated with unbound midazolam once equilibrium is reached. Distribution of the drug into human lumbar cerebrospinal fluid may be slow and erratic. Distribution may be altered in geriatric patients.
Absorption of midazolam hydrochloride from IM injection sites is rapid and nearly complete (mean absolute bioavailability is greater than 90%). Im bioavailability of the lactate appears to be similar to or slightly less than that of the hydrochloride; however, any such difference does not appear to be clinically important. Pharmacologic effects of midazolam usually are apparent within 5-15 min but may not be maximal until 15-60 min following IM administration; the duration of action usually is about 2 hr (range: 1-6 hr). Peak plasma midazolam concentrations generally are attained within 45 minutes following IM administration. Following administration of a single 12.5 mg (of midazolam) dose of the hydrochloride in healthy adults, peak plasma midazolam concentrations of approximately 200 ng/mL (range: 88-269 ng/mL) are attained. Peak plasma concentrations of midazolam and 1-hydroxymethylmidazolam (an active metabolite) attained following IM injections are approximately 50% of those attained following iv injection of a dose.
Metabolism
In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4). This enzyme is present in gastrointestinal tract mucosa, as well as in the liver. The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected, but not quantified. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes. Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxymidazolam is at least as potent as the parent compound, and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam.
... Midazolam has a rapid onset of action following intravenous, intramuscular, oral, nasal, and rectal administration. Only 50% of an orally administered dose reaches the systemic circulation due to extensive first-pass metabolism. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites including an active metabolite, alpha-hydroxymidazolam. Cytochrome P450 inhibitors such as cimetidine can profoundly reduce the metabolism of midazolam...
Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, alpha-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. /This study reports on/ five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated alpha-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated alpha-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1.4 nmol/L) or unconjugated alpha-hydroxymidazolam (2.2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.
The kinetics and dynamics of midazolam were investigated in 20 female patients undergoing lower abdominal surgery. The relation between the plasma concentrations of midazolam and pharmacokinetic end points was evaluated after an intravenous infusion regimen in 10 patients given an epidural anesthetic. The remaining 10 patients were anesthetized with a totally intravenous anesthetic technique with midazolam and alfentanil. The effect was assessed by means of a rating scale divided into degree of sedation and amnesia. A good correlation was found between plasma level of midazolam and pharmacodynamic response. The relation between the quantal response data and the plasma concentration was represented by an s-shaped concentration-effect curve. Despite similar kinetics of midazolam in the two groups, the postoperative drowsiness was more pronounced in the group receiving total intravenous anesthesia. The concomitant administration of alfentanil shifted the concentration-effect curve regarding sedation to the left.
Midazolam is metabolized extensively in the liver and intestine by cytochrome P-450 CYP3A4. The drug rapidly undergoes hydroxylation via hepatic microsomal enzymes to form 1-hyroxymethylmidazolam (alpha-hydroxymidazolam), the principal metabolite, and 4-hydroxymidazolam; a small portion of 1-hydroxymethylmidzaolam is further hydroxylated to 1-hydroxymethyl-4-hydroxymidazolam (alpha,4-dihydroxymidazolam). These metabolites undergo rapid conjugation with glucuronic acid in the liver. Although the elimination half-life of the principal metabolite, 1-hydroxymethylmidazolam, is not clearly established, it is estimated to be about 60-80 min. The 1-hydroxymethyl and 4-hydroxy metabolites are reportedly pharmacologically active, but their potencies at equivalent molar concentrations appear to be substantially less than that of midazolam. The 1-hydroxymethyl-4-hydroxy metabolite appears to have little, if any, pharmacologic activity.
For more Metabolism/Metabolites (Complete) data for Midazolam (6 total), please visit the HSDB record page.
Protein binding
In adults and pediatric patients, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, 1-hydroxy midazolam is bound to the extent of 89%.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.