Time to peak plasma concentration (h)
Short- to intermediate-acting benzodiazepines
0.25–0.5 mg BID–TID for anxiety; maximum 4 mg/day
0.25–0.5 mg BID–TID for anxiety; 0.5–2 mg BID for panic disorder; maximum 4 mg/day
2–6 mg/day divided BID–TID for anxiety; maximum 10 mg/day
10–30 mg TID–QID for anxiety
7.5–30 mg QHS for insomnia
5–25 mg TID–QID for anxiety; 50–100 mg PRN for alcohol withdrawal; maximum 300 mg/day
15–60 mg/day divided BID–TID for anxiety
2–10 mg TID–QID for muscle spasm; 2–10 mg BID–QID for anxiety; 5 mg TID–QID PRN for alcohol withdrawal
Alprazolam is a short-acting, high-potency benzodiazepine used in the treatment of anxiety and panic disorders. It may also be used for pre-procedural sedation. It is highly lipid soluble and has an increased risk of amnesia. While its shorter half-life makes it an appealing drug, patients can be at risk for rebound symptoms if abruptly discontinued.
Lorazepam is another short- to intermediate-acting benzodiazepine with high potency. In addition to having less affinity for GABA-A receptors than alprazolam, it is also less lipid soluble and may therefore carry a lower risk of causing amnesia. Lorazepam is commonly used for the treatment of anxiety, agitation, and seizures. When administered intramuscularly, absorption is rapid and complete. Unlike most benzodiazepines which are metabolized by CYP450, lorazepam undergoes glucuronidation and elimination and is therefore less affected by the many drugs that may interact with CYP450.
Midazolam is a short-acting benzodiazepine with almost twice the potency of diazepam. It is commonly used preoperatively for anxiolysis and amnesia and can be administered via intravenous, intramuscular, oral, sublingual, intranasal, and rectal routes. It is highly lipophilic and therefore has a quick onset of action. Its elimination half-life is 2–6 h due to rapid reabsorption, making its effects shorter than lorazepam and suitable for use in a continuous infusion for sedation in the intensive care unit. The hypnotic effects of midazolam are due to its interference with GABA reuptake.
Clonazepam is an intermediate-acting, high-potency benzodiazepine. In addition to its effects at the GABA-A receptor, it also has some serotoninergic activity. It is used in the treatment of seizures, anxiety, panic disorder, and acute mania. It has lower lipid solubility than other benzodiazepines and tends to cause less anterograde amnesia.
Diazepam is a long-acting, medium-potency benzodiazepine prescribed for many indications, including anxiety, muscle spasms, seizures, and alcohol withdrawal. At low doses, diazepam binding to BZ2 receptors in the limbic system results in anxiolysis. At higher doses, diazepam binding to BZ2 receptors in the spinal cord and motor neurons provides muscle relaxation, but there are also increasing BZ1-mediated effects at these doses, such as sedation and anterograde amnesia. Diazepam has a number of active metabolites—oxazepam, temazepam, and desmethyldiazepam—which prolong the time in which a patient may experience sedation, amnesia, and other effects.
Most benzodiazepines are metabolized by CYP450 enzymes. A smaller group (e.g., lorazepam, oxazepam, temazepam) undergoes direct glucuronidation and is less affected by other drugs. Drugs that inhibit CYP450 enzymes (e.g., oral contraceptive pills, antifungals, some antibiotics) decrease the rate of benzodiazepine elimination and can worsen side effects or precipttate drug overdose. Drugs that induce CYP450 enzymes (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) increase the metabolism of benzodiazepines and patients may thus require higher dosages.
Respiratory depression may occur if alcohol, opioids, or other psychotropic medications are co-administered, and consideration is needed before initiation in patients with pulmonary disease, neuromuscular weakness and obstructive sleep apnea. Similarly, cardiovascular effects from peripheral vasodilation and CNS depression may be more pronounced.
Side Effects/Black Box Warnings
The most common side effects include sedation, somnolence, memory and cognitive impairment, depression, anterograde amnesia, respiratory depression, changes in weight and appetite and decreased libido. Hypotension may result from peripheral vasodilation. Thrombophlebitis and venoirritation may be seen with intravenous administration of diazepam and lorazepam and Bdue to the diluent, propylene glycol. Intensive care unit patients who receive large doses of these drugs are at risk for propylene glycol toxicity. Paradoxical reactions, including agitation, irritability, aggression and impulsivity, rarely occur but may be seen more frequently in patients with psychiatric or cognitive disorders using higher dosages of high-potency benzodiazepines or in the setting of chronic benzodiazepine use. Drug clearance may be significantly delayed in elderly patients as hepatic and renal functions are commonly impaired and there is an inability to metabolize and eliminate the dose efficiently. As a result, elderly patients are highly sensitive to benzodiazepines and their administration may lead to significant adverse outcomes such as respiratory depression, altered mental status and oversedation, which could lead to injury via falls or motor vehicle accidents.
Muscle relaxants alleviate pain caused by muscle spasms and spasticity of various origins. Both muscle spasms and spasticity involve involuntary muscular contraction that can be associated with significant pain. Many of these treatments, however, are limited by their side effect profile. The muscle relaxants described in this chapter are primarily centrally acting muscle relaxants and are distinct from agents that target the neuromuscular junction, such as succinylcholine and the non-depolarizing neuromuscular blocking agents.