section name header

Introduction

  1. Pharmacology
    1. Benzodiazepines potentiate inhibitory gamma-aminobutyric acid (GABA) neuronal activity in the central nervous system (CNS) by binding to the GABAA receptor. Pharmacologic effects include reduction of anxiety, suppression of seizure activity, CNS depression, and inhibition of spinal afferent pathways to produce skeletal muscle relaxation.
    2. Benzodiazepines interact with other receptors outside the CNS, especially in the heart. Diazepam has been reported to antagonize the cardiotoxic effect of chloroquine (the mechanism is unknown, but diazepam may compete with chloroquine for fixation sites on cardiac cells).
    3. Benzodiazepines generally have little effect on the autonomic nervous system or cardiovascular system. However, enhancement of GABA neurotransmission may blunt sympathetic discharge. Additionally, diazepam may have an effect on choline transport and acetylcholine turnover in the CNS, which may be part of the basis for its beneficial effect in victims of nerve agent poisoning (eg, sarin, VX).
    4. Pharmacokinetics. All these agents are well absorbed orally and are eliminated by hepatic metabolism with varying serum elimination half-lives of 1-50 hours. The duration of CNS effects is determined by the rate of drug redistribution from the brain to peripheral tissues.
      1. Diazepam. Onset of action is fast after intravenous injection but slow to intermediate after oral or rectal administration. Of note, diazepam should not be administered intramuscularly due to poor absorption. The half-life is longer than 24 hours, although anticonvulsant effects and sedation are often shorter as a result of redistribution from the CNS. Active metabolites further extend the duration of effect of diazepam, which can be helpful in the treatment of sedative-hypnotic withdrawal.
      2. Lorazepam. Onset is rapid after intravenous injection, relatively fast after intramuscular injection and intermediate after oral administration. The elimination half-life is 10-20 hours and owing to slower CNS redistribution, the anticonvulsant effects are generally longer than those of diazepam.
      3. Midazolam. Onset is rapid after intravenous or intramuscular injection, and intermediate after oral or intranasal administration. The half-life is 1.5-3 hours, and the duration of effect is very short owing to rapid redistribution from the brain. However, after prolonged infusions, sedation may persist for 10 hours or longer as a result of saturation of peripheral sites and slowed redistribution.
  2. Indications
    1. Anxiety and agitation. Benzodiazepines often are used for the treatment of anxiety or agitation (eg, caused by sympathomimetic, anticholinergic, cannabinoid, or hallucinogenic drug, plant, or venom intoxications). Note: physostigmine is a more selective antidote for anticholingeric-induced agitated delirium.
    2. Convulsions. All three drugs can be used for the treatment of acute seizure activity or status epilepticus resulting from idiopathic epilepsy, and they are the first-line therapy for drug- or toxin-induced seizures. Midazolam and lorazepam have the advantage of rapid onset of anticonvulsant action after intramuscular injection. Also, the duration of anticonvulsant action of lorazepam is longer than that of the other two agents.
    3. Hypertension and tachycardia. These drugs can be used for the initial treatment of hypertension and tachycardia caused by sympathomimetic agents.
    4. Muscle relaxant. These drugs can be used for relaxation of excessive muscle rigidity and contractions (eg, strychnine poisoning, black widow spider envenomation, tetanus, serotonin syndrome, neuroleptic malignant syndrome).
    5. Chloroquine poisoning. Diazepam may antagonize cardiotoxicity.
    6. Alcohol or sedative-hypnotic withdrawal. Diazepam and lorazepam are first-line therapies for alcohol and sedative-hypnotic withdrawal signs and symptoms (eg, anxiety, tremor, seizures).
    7. Conscious sedation. Midazolam is used to induce sedation and amnesia during brief procedures and in conjunction with neuromuscular paralysis for endotracheal intubation.
    8. Nerve agents. These drugs can be used for the treatment of agitation, muscle fasciculations, and seizures associated with nerve agent poisoning (Warfare Agents—Chemical). They may have an additive or synergistic effect with other nerve agent antidotes (pralidoxime, atropine).
  3. Contraindications. Do not use in patients with a known sensitivity to benzodiazepines.
  4. Adverse effects
    1. CNS-depressant effects may interfere with evaluation of neurologic function. They also may cause a paradoxical reaction (restlessness, agitation) in less than 1% of patients (adults and children). Flumazenil has been used successfully to manage this effect.
    2. Excessive or rapid intravenous administration may cause respiratory arrest, especially when combined with other sedating agents such as opioids.
    3. The drug may precipitate or worsen hepatic encephalopathy.
    4. Rapid or large-volume intravenous administration of lorazepam or diazepam may cause cardiotoxicity similar to that seen with phenytoin because of the diluent propylene glycol. Continuous infusions with this vehicle may also result in hyperlactatemia, increased osmolar gap, and renal dysfunction. Infusions of lorazepam (1 mL of injection solution contains 0.8 mL or 834 mg of propylene glycol) exceeding 4 mg/h or with cumulative 24-hour doses exceeding 100 mg are associated with potentially toxic serum propylene glycol levels (>25 mg/dL). Several injectable benzodiazepine products contain up to 2% benzyl alcohol as a preservative (may cause toxicity in neonates known as neonatal gasping syndrome).
    5. Use in pregnancy. FDA Category D. All these drugs readily cross the placenta. However, this does not preclude their acute, short-term use for a seriously symptomatic patient (Introduction).
  5. Drug or laboratory interactions
    1. Benzodiazepines will potentiate the CNS-depressant effects of opioids, ethanol, and other sedative-hypnotic and depressant drugs.
    2. Flumazenil will reverse the effects of benzodiazepines, but may trigger an acute withdrawal syndrome in patients with benzodiazepine dependence. Patients who have received flumazenil will have an unpredictable, but reduced or absent response to benzodiazepines.
  6. Dosage and method of administration
    1. Anxiety or agitation, muscle spasm or hyperactivity, hypertension
      1. Diazepam. Give 2-10 mg (children aged 30 days to 5 years: 1-2 mg) IV initially (no faster than 5 mg/min in adults; administer over 3 minutes in children), depending on severity (tetanus requires higher doses); may repeat every 1-4 hours as needed. The oral dose is 2-10 mg (geriatric patients: lower doses, not to exceed 2.5 mg and given at less frequent intervals; children older than 6 months: 1-2.5 mg). Doses should be adjusted according to tolerance and response. Caution: Do not give intramuscularly because of erratic absorption and pain on injection. Use lorazepam or midazolam if IM administration is necessary.
      2. Lorazepam. Give 1-2 mg (children: 0.04 mg/kg) IV, not to exceed 2 mg/min or 0.05 mg/kg IM (maximum, 4 mg). The usual adult oral dose is 2-6 mg daily.
      3. Midazolam. Give 0.05 mg/kg (up to 0.35 mg/kg for anesthesia induction) IV over 20-30 seconds (usual adult dose: varies from 1 mg to a maximum of 5 mg given in increments of 2.5 mg every 2 minutes; geriatric patients: lower dose with maximum at 3.5 mg) or 0.07-0.1 mg/kg IM. Repeat after 10-20 minutes if needed. Continuous infusions have also been used to maintain effect with initial rates of 0.02-0.1 mg/kg/h (usual adult dose: 1-7 mg/h; children: 1-2 mcg/kg/min) that are then titrated to effect. Caution: There have been several reports of respiratory arrest and hypotension after rapid intravenous injection, especially when midazolam was given in combination with opioids. Prolonged continuous infusion may lead to persistent sedation after the drug is discontinued because midazolam accumulates in tissues.
    2. Convulsions. Note: If convulsions persist after initial doses of benzodiazepines, consider alternative anticonvulsant drugs such as phenobarbital, pentobarbital, and propofol, and give pyridoxine for isoniazid or hydrazine-containing mushroom intoxications. Also, see “Seizures”.
      1. Diazepam. Give 5-10 mg IV, not to exceed 5 mg/min, every 5-10 minutes (children 5 years of age or older: 1-2 mg; children younger than 5 years: 0.2-0.5 mg) to a maximum total of 30 mg (adults) or 10 mg (older children) or 5 mg (young children). If no IV access, may give rectally (adults and children older than 12 years: 0.2 mg/kg; children 6-11 years: 0.3 mg/kg; children 2-5 years: 0.5 mg/kg).
      2. Lorazepam. Give 1-2 mg (neonates: 0.05-0.1 mg/kg; older children: 0.04 mg/kg) IV, not to exceed 2 mg/min; repeat if needed after 5-10 minutes. Usual dose for status epilepticus is up to 4 mg slow IV push over 2 minutes (dilute with an equal volume of saline). If seizure recurs, repeat dose after 10-15 minutes. The drug can also be given IM (0.05 mg/kg; maximum, 4 mg), with onset of effects after 6-10 minutes.
      3. Midazolam. Give 0.05 mg/kg (up to 0.2 mg/kg for refractory status epilepticus) IV over 20-30 seconds or 0.1-0.2 mg/kg IM; this may be repeated if needed after 5-10 minutes or maintained with a continuous infusion (see “Note” above). The drug is absorbed rapidly after IM injection and can be used when IV access is not readily available. Other available routes of administration in children include intranasal (0.2-0.5 mg/kg) and buccal (0.3 mg/kg or 10 mg in older children and adolescents).
    3. Chloroquine and hydroxychloroquine intoxication. There is reported improvement of cardiotoxicity with high-dose administration of diazepam at 1-2 mg/kg IV (infuse over 30 minutes), followed by an infusion of 1-2 mg/kg/24 h. Caution: This will likely cause apnea; the patient must be intubated, and ventilation must be controlled.
    4. Alcohol and sedative-hypnotic withdrawal
      1. Diazepam. Administer 5-10 mg IV initially, then 5 mg every 10 minutes until the patient is calm. Large doses may be required to sedate patients with severe withdrawal. The oral dose is 10-20 mg initially, repeated every 1-2 hours until the patient is calm.
      2. Lorazepam. Administer 1-2 mg IV initially, then 1 mg every 10 minutes until the patient is calm. Large doses by intermittent IV bolus or with high rates of administration by continuous infusion may be required to sedate patients in severe withdrawal. (Caution: Multiple-dose vials may contain diluents and preservatives such as propylene glycol and benzyl alcohol, which can be toxic in high doses; see Item IV.D above.) The usual oral dose is 2-4 mg, repeated every 1-2 hours until the patient is calm.