Midazolam

8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Overview

Midazolam belongs to Depressants / Benzodiazepines.

Key safety note: Midazolam is a potent sedative used mainly in hospitals, and its central danger is dose-dependent respiratory depression and hypotension: greatly amplified when it is combined with opioids, alcohol or other CNS depressants, which is the usual mechanism of benzodiazepine-related death.[2]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • Rapid calming, drowsiness and sleep, anxiolysis and muscle relaxation, with pronounced anterograde amnesia for the period of peak effect.
  • Physical effects: slowed breathing, lowered blood pressure, slurred speech and impaired coordination and balance.
  • Paradoxical excitement (agitation, disinhibition, aggression) can occur. Recovery brings grogginess, and prolonged use is followed by a rebound/withdrawal syndrome (anxiety, insomnia, tremor, seizures).
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Parenteral (IV/IM), intranasal, buccal/oromucosal or oral: administered and titrated by clinicians. The notes below are clinical context, NOT a recreational guide.. Midazolam is a hospital medicine given and titrated by trained staff with airway and resuscitation equipment and the antidote flumazenil to hand. There is no safe self-administered or recreational dose. Its potency, fast onset and steep respiratory-depression curve, especially with opioids or alcohol, make non-medical use particularly dangerous. Dosing is highly individualised (e.g. small IV increments titrated to effect for procedural sedation, weight-based buccal/IM dosing for seizures), which is why numeric self-dosing tiers are deliberately not given here.

Dose ranges

Procedural sedation (clinical, IV)

Small increments titrated to effect (e.g. ~0.5–2.5 mg, repeated cautiously): clinician-administered only

Seizures / status epilepticus

Weight-based buccal/IM/intranasal dosing per protocol (e.g. buccal Buccolam by age band)

Duration

Chemical & Physical Properties
FormulaC18H13ClFN3
Molar mass325.8 g/mol
StateSolid (free base, the medicinal injection is the water-soluble hydrochloride or maleate at acidic pH)
Melting point158–160 °C
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKa≈6.2 (the ring-opening equilibrium, also reported ~5.5 calc.)
LogP2.73 (predicted), highly lipophilic at physiological pH
SolubilityFree base: poorly water-soluble (~54 mg/L), Formulated as an acidic aqueous solution in which the ring-open form is freely water-soluble: the basis of the injectable/intranasal products
Refractive indexNot reported
Identifiers & Synonyms
CAS59467-70-8
CAS (enantiomer)
PubChem CID4192
InChIKeyDDLIGBOFAVUZHB-UHFFFAOYSA-N
InChIInChI=1S/C18H13ClFN3/c1-11-21-9-13-10-22-18(14-4-2-3-5-16(14)20)15-8-12(19)6-7-17(15)23(11)13/h2-9H,10H2,1H3
SMILESCC1=NC=C2N1C3=C(C=C(C=C3)Cl)C(=NC2)C4=CC=CC=C4F

Synonyms

  • Dormicum
  • Versed
  • Hypnovel
  • Buccolam
Pharmacodynamics & Biochemistry

Midazolam is a short-acting imidazobenzodiazepine. Like other benzodiazepines it is a high-affinity positive allosteric modulator at the benzodiazepine site of the GABA-A receptor (the interface between an α1/2/3/5 and the γ2 subunit): it does not open the channel itself but, in the presence of GABA, increases the frequency of chloride-channel opening, enhancing inhibitory neurotransmission to produce sedation, anxiolysis, anterograde amnesia, muscle relaxation and anticonvulsant effects. Its benzodiazepine-site affinity is high, in the low-nanomolar range, reported as comparable to clonazepam and greater than diazepam, though a single clean numeric Kᵢ is not consistently tabulated across databases, so no binding table is shown here. Its defining feature is a pH-dependent ring equilibrium: in the acidic aqueous solution of the ampoule the fused imidazole ring is open, making midazolam water-soluble (so it can be given without irritant solvents). At physiological pH the ring closes to a highly lipophilic form that crosses the blood–brain barrier rapidly. This gives a fast onset (IV ~5 min) and, together with rapid redistribution and metabolism, a short duration: the basis of its use for procedural sedation and anaesthesia. It is cleared hepatically by CYP3A4/CYP3A5 to α-hydroxymidazolam (about 10% as active, then glucuronidated and renally excreted), with an elimination half-life of roughly 1.5–2.5 hours, because CYP3A is so central, strong CYP3A inhibitors and inducers markedly change its effect. (GtoPdb lists only low-affinity off-target interactions for midazolam and no benzodiazepine-site Ki, so no receptor-binding table is shown here rather than presenting misleading off-target rows.)

Biological targets

  • GABA-A

Binding & functional measurements

TargetMeasurementSpecies
GABA-A α1β2γ2 receptorEC50 71 ± 5.8 nM
Emax 203 ± 17.6%		Human
GABA-A α2β2γ2 receptorEC50 51 ± 5.0 nM
Emax 169.6 ± 49.9%		Human
GABA-A α3β2γ2 receptorEC50 46 ± 7.4 nM
Emax 267.8 ± 20.3%		Human
GABA-A α5β2γ2 receptorEC50 53 ± 3.5 nM
Emax 107.9 ± 20.3%		Human
Pharmacokinetics
BioavailabilityNot reported
TmaxNot reported
Half-life≈1.5–2.5 h in healthy adults (longer in the elderly, the critically ill, and with CYP3A inhibitors)
VdNot reported
Protein bindingNot reported
MetabolismHepatic CYP3A4/CYP3A5 hydroxylation to α-hydroxymidazolam (~10% active), then glucuronidation
ExcretionRenal (mainly as the glucuronide)
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Midazolam is a potent sedative used mainly in hospitals, and its central danger is dose-dependent respiratory depression and hypotension: greatly amplified when it is combined with opioids, alcohol or other CNS depressants, which is the usual mechanism of benzodiazepine-related death. It should only be given where airway support, oxygen and the reversal agent flumazenil are available, with monitoring. It reliably causes anterograde amnesia (patients often do not remember the procedure), and can cause paradoxical reactions: agitation, restlessness or aggression, especially with IV use and in children and older people. Tolerance and physical dependence develop with continued use. Abrupt withdrawal after prolonged administration can cause anxiety, insomnia, seizures and psychosis, so it is tapered. It is misused recreationally (and used in drug-facilitated crime because of the amnesia). Older and frail patients and those with respiratory disease or sleep apnoea are especially vulnerable.[2]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

Opioids Additive respiratory depression and sedation: a leading cause of benzodiazepine-related death (regulatory boxed warnings).[2]
Alcohol, Benzodiazepines, Gabapentinoids (gabapentin, pregabalin) Additive sedation and respiratory depression, including with barbiturates and sedating antihistamines.[2]
CYP3A4 inhibitors (ritonavir, azole antifungals, macrolides, grapefruit) Ketoconazole/itraconazole, clarithromycin/erythromycin, ritonavir or grapefruit juice markedly raise midazolam levels and prolong its effect.[2]
CYP3A4 inducers (rifampicin, carbamazepine) Rifampicin, carbamazepine, phenytoin or St John's wort lower midazolam levels and reduce its effect.[2]

Contraindications

Significant respiratory depression or acute severe asthma severe respiratory insufficiency or acute respiratory depression.[2]
Combining with alcohol or other CNS depressants concurrent opioids or other CNS depressants without monitoring, or acute alcohol intoxication with depressed vitals.[2]
Respiratory disease or sleep apnoea obstructive sleep apnoea.[2]
Myasthenia gravis[2]
Known hypersensitivity to the drug benzodiazepine hypersensitivity.[2]
Kidney or liver impairment caution in the elderly, the frail and in hepatic impairment.[2]
Usage & Context
  • A hospital/clinic benzodiazepine used for procedural ('conscious') sedation, induction and maintenance of anaesthesia, sedation of ventilated patients in intensive care, premedication before surgery, and palliative sedation for end-of-life agitation.
  • A first-line treatment for prolonged seizures and status epilepticus: given intramuscularly, intranasally or into the cheek (buccal, e.g. Buccolam) when intravenous access is not available, exploiting its water-soluble formulation and fast onset.
  • Because it is fast-acting and causes amnesia it is also misused recreationally and implicated in drug-facilitated assault. Controversially, it has been used in some US lethal-injection protocols.
Sources & Evidence

Further Information