Anticonvulsant – Anxiolytic – Hypnotic – Sedative

Action And Clinical Pharmacology: Benzodiazepines are glycoproteins with an affinity for benzodiazepine receptors which act as specific binding sites for gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. Although various mechanisms of action have been proposed, the precise sites and mechanisms of action have not been completely established. It is believed that benzodiazepines produce their effect within the CNS by interacting with a macromolecular protein complex in the neuronal membrane which includes GABAa receptors, high-affinity benzodiazepine receptors and chloride channels.

Occupation of the benzodiazepine receptor increases the affinity of the GABAa receptor for GABA. GABA potentiates the direct opening of the chloride ion channel, allowing an increased influx of chloride into the neuron. The inward shift of chloride ions hyperpolarizes and stabilizes the membrane, resulting in a net inhibitory effect on neuronal firing. Benzodiazepines alone have little effect on chloride ion channel permeability and depend upon the presence of GABA in the synapse for their actions.

Benzodiazepines with very similar chemical structures can differ in their potency, rate of absorption and other pharmacological parameters. The potency of a benzodiazepine is correlated with its affinity for its binding site, the benzodiazepine receptor. In therapeutic use, the benzodiazepines, while differing in potency, have similar pharmacologic profiles.

It is believed that there are different types of benzodiazepine receptors in different areas of the CNS which produce the various pharmacological actions of the drugs. As the dose of benzodiazepine is increased, anxiolytic effects are first produced, followed by anticonvulsant effects, a reduction in muscle tonus, and finally sedation and hypnosis.

Clinically, benzodiazepines are used in the management of anxiety disorders, insomnia, seizure disorders, skeletal muscle spasticity, alcohol withdrawal, panic disorder and as premedicants prior to surgical or diagnostic procedures. Benzodiazepines have also been used in the management of nausea and vomiting associated with emetogenic cancer chemotherapy.

Pharmacokinetics: Following oral administration, benzodiazepines are well absorbed from the gastrointestinal tract. Absorption of diazepam or chlordiazepoxide after i.m. injection is slow and erratic. Following i.m. administration of lorazepam or midazolam, absorption appears to be rapid and complete. Lorazepam is well absorbed after sublingual administration, reaching peak levels in 60 minutes.

Benzodiazepines are widely distributed in the body and accumulate preferentially in lipid rich areas such as the CNS and adipose tissue. The more lipophilic agents have the fastest rates of absorption and onset of clinical effects. Benzodiazepines and their metabolites are highly bound to plasma proteins.

Steady state plasma concentrations of benzodiazepines and their metabolites are reached after about 5 elimination half-lives, usually a few days to 2 weeks after initiation of therapy.

Benzodiazepines or active metabolites with very long elimination half-lives can accumulate with chronic dosing and produce prolonged effects, especially in elderly or obese patients, those with liver disease, or with concurrent use of other drugs that compete for hepatic oxidation. Benzodiazepines that undergo hepatic glucuronide conjugation and do not have active metabolites are unlikely to accumulate with chronic administration and require multiple daily dosing for sustained effects.

Most of the benzodiazepines are excreted almost entirely in the urine in the form of oxidized and glucuronide-conjugated metabolites. Benzodiazepines are not significantly removed by hemodialysis.

The primary differences among the benzodiazepines are in their pharmacokinetic properties, and these often are among the main factors considered in drug selection.

Indications And Clinical Uses: Benzodiazepines have similar pharmacologic actions; however, clinical applications of specific agents may reflect differences in their pharmacokinetic profiles, the availability of evidence-based data, or the labeled indications for a particular agent.

Contra-Indications: Patients with known hypersensitivity to this class of drugs or to any component of the product in question. The manufacturers advise against the use of benzodiazepines in patients with myasthenia gravis and acute closed angle glaucoma, but they may be used in patients receiving appropriate therapy for open angle glaucoma. Specific product monographs should be consulted as individual products may have additional contraindications to their use.

Manufacturers’ Warnings In Clinical States: Benzodiazepines are not recommended for use in patients with a major depressive disorder or psychosis in which anxiety is not a prominent feature.

Benzodiazepines should be used with extreme caution in patients with severe pulmonary insufficiency or sleep apnea, especially the elderly or very ill patients, and those with limited pulmonary reserve.

Resuscitative facilities and equipment should be available when benzodiazepines are administered parenterally, particularly i.v. These agents should not be administered i.v. to patients in shock, coma, acute alcohol intoxication, or to patients who have recently received other respiratory depressant drugs.

Benzodiazepines must be used with caution in severely depressed patients or those in whom there is any sign of impending depression with an associated anxiety disorder, particularly in patients at risk of increased suicidal tendencies. Appropriate protective measures may be necessary during benzodiazepine therapy in these patients. Consideration should be given to the quantity of medication prescribed at any one time.

Patients should be informed about possible negative effects on memory and advised to report to their physician any mental or behavioral changes that develop during benzodiazepine therapy (see Precautions).

Occupational Hazards: Patients should be warned about the potential impairment of mental alertness or physical coordination which may decrease their ability to perform hazardous tasks such as driving or operating machinery. Elderly patients may be at particular risk for these CNS depressant effects.

Dependence and Withdrawal: Tolerance and the risk of psychological and physical dependence may occur following prolonged use of benzodiazepines at therapeutic doses. The possibility that such effects also may occur following short-term use of benzodiazepines, particularly at higher doses, should also be considered. Tolerance to the hypnotic and sedative effects develops rapidly. In contrast, clinically significant tolerance to the anxiolytic effect usually does not occur even after prolonged use.

Risk of benzodiazepine dependence can be minimized by titrating the dose, close observation and follow up, proper screening for possible risk factors and education of the patient. Benzodiazepine use should be avoided in patients with a history of alcohol or substance abuse.

Abrupt withdrawal of benzodiazepines may lead to symptoms such as anxiety, insomnia, irritability, gastrointestinal discomfort, anorexia, diaphoresis, photophobia or increased sensitivity to noise. More severe symptoms may occur such as confusion, depersonalization, myoclonus, delirium, psychosis or seizures. Rebound insomnia may occur, particularly following abrupt discontinuation of a benzodiazepine with a short elimination half-life.

Withdrawal can also be precipitated by dosage tapering or inadvertent withdrawal, e.g., due to forgotten doses or admission to hospital. Such effects can also emerge in the early morning following bedtime administration of a short-acting agent. In addition, an increase in daytime anxiety and/or restlessness may be observed between doses of short-acting agents. Rebound or symptom re-emergence may occur after as little as 4 to 6 weeks therapy. It is more likely if the drug is short-acting, taken regularly for >3 months and abruptly discontinued. Symptoms may be similar to those experienced by the patient prior to initiation of the benzodiazepine, but may be more intense.

Choice of withdrawal regimen may depend on the setting of detoxification, severity of dependence and concurrent drug or substance abuse. Patients should follow a structured discontinuation program. When discontinuing benzodiazepines in patients on prolonged therapy, dosage should be gradually decreased over about 6 to 12 weeks, especially in patients with a history of seizures or epilepsy, regardless of their concomitant anticonvulsant drug therapy. If the patient had been taking a short-acting agent, a longer-acting benzodiazepine may be substituted, to provide a gradual decrease in drug concentration and decrease the possibility of withdrawal symptoms. Adjunctive agents such as propranolol, clonidine and carbamazepine have been useful in some patients in suppressing withdrawal symptoms which continue to be severe despite gradual reduction in benzodiazepine dosage.

Precautions: Benzodiazepines may cause psychologic or physical dependence (see Warnings).

Elderly or debilitated patients, children, and patients with liver disease or low serum albumin are most likely to experience CNS adverse effects. Generally it is recommended that therapy be initiated with low dosages and gradually titrated up to the lowest effective dose, to minimize the possibility of ataxia, dizziness and oversedation. Benzodiazepines can produce prolonged CNS depression in neonates because of the inability to convert the benzodiazepine into inactive metabolites. Reversible dementia has also been reported in the elderly after prolonged administration of benzodiazepines.

Differences in the degree of residual and cumulative CNS depressant effects among the benzodiazepines may be particularly important in elderly patients, in patients with potentially impaired elimination of drugs and in individuals whose occupation or life style requires unimpaired intellectual or psychomotor function. There is some evidence that ataxia and the risk of falling and associated hip fracture in elderly patients is greatest with the use of long-acting benzodiazepines as compared to short-acting agents.

Benzodiazepine therapy should be individualized and closely monitored in elderly patients, and the need for continued therapy with these drugs should be re-evaluated frequently.

Anterograde amnesia has occurred following therapeutic doses of benzodiazepines. The degree of severity and duration of effects may vary depending on the drug, dosage, route of administration or individual patient (e.g., elderly patients may be at particular risk). Although amnesic effects have been more commonly associated with midazolam, triazolam and lorazepam, these effects have occurred with other benzodiazepines. Data suggest that anterograde amnesia and next day memory loss occur at a higher rate with triazolam, generally at a 0.5 mg dose. Cases of transient global amnesia and “traveler’s amnesia” have also been associated with triazolam in patients taking the drug to induce sleep while traveling. These amnesic effects are unpredictable and not necessarily dose related. The manufacturers advise warning patients not to take triazolam under circumstances in which a full night’s sleep and clearance of the drug from the body are not possible before they will need to resume full activity and alertness, e.g., an overnight flight of less than 7 to 8 hours.

Paradoxical stimulant reactions have occurred in psychiatric patients and hyperactive, aggressive children. Such reactions include restlessness, anxiety, mania, insomnia, sleep disturbances, increased muscle spasticity, acute rage and hyperactivity, and have appeared early in therapy, usually in the first 2 weeks. Benzodiazepine therapy should be discontinued if CNS stimulation occurs.

Serious behavioral changes and abnormal thinking have occasionally been associated with benzodiazepine use. Some of these changes may be characterized by hallucinations, depersonalization, agitation, bizarre behavior and decreased inhibition manifested as aggression or excessive extroversion, similar to that seen with alcohol and other CNS depressants.

Caution is advised during parenteral administration of benzodiazepines to elderly patients as they may be more likely to experience apnea, hypotension, bradycardia or cardiac arrest.

Patients with compromised renal or hepatic function should be monitored and the dose carefully titrated to avoid accumulation of these agents.

Because of isolated reports of blood dyscrasias and abnormal liver function tests, periodic blood counts and liver function tests may be of benefit during long-term therapy.

Drug Interactions:

Pregnancy: Benzodiazepines should be avoided during pregnancy. Benzodiazepines have been associated with an increased risk of congenital malformations after first trimester exposure. Hypotonia, lethargy and sucking difficulties have been reported in infants whose mothers received benzodiazepines during labor. Chronic use of benzodiazepines during pregnancy has also been associated with neonatal withdrawal. The use of benzodiazepines solely as hypnotics is contraindicated during pregnancy. A women planning a pregnancy or who becomes pregnant should be encouraged to discontinue benzodiazepine therapy.

Lactation: Benzodiazepine use in lactating women is not recommended. Because the ability of neonates to metabolize these drugs is limited, accumulation may occur.

Occupational Hazards: Because of the CNS depressant effect of benzodiazepines, patients should be cautioned with regard to driving or performing other hazardous tasks which require mental alertness and physical coordination.

Adverse Reactions: The most common adverse effects reported with the use of benzodiazepines are dose dependent CNS effects. Ataxia, dizziness, lightheadedness, drowsiness, including residual daytime drowsiness when used as a hypnotic, weakness, and fatigue usually occur in the first few days of therapy and may decrease with continued therapy. If these effects are persistent, a reduction in dosage may be necessary. Elderly or debilitated patients, children, and patients with liver disease or low serum albumin may be unusually sensitive to the CNS effects.

The more serious, occasionally reported adverse reactions are hypersensitivity reactions, mental depression, behavioral problems, paradoxical stimulant reactions, leukopenia, jaundice, hypotension, memory impairment, phlebitis or venous thrombosis, and seizures.

Other adverse effects less frequently reported include: abdominal or stomach cramps or pain, blurred vision or diplopia, sexual dysfunction, constipation, diarrhea, dry mouth or increased thirst, vertigo, syncope, confusion, vivid or disturbing dreams, slurred speech, euphoria, headache, increased bronchial secretions or watering of mouth, muscle spasm, nausea or vomiting, incontinence, urinary retention, tachycardia or palpitations, trembling and unusual tiredness or weakness.

Symptoms And Treatment Of Overdose: Symptoms: Symptoms of mild overdose include drowsiness, impaired coordination, diminished reflexes, confusion and lethargy. In more serious overdose, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, seizures and coma. Although cardiac arrest has been reported, death from overdose of benzodiazepines in the absence of concurrent ingestion of alcohol or other CNS depressants is rare.

Treatment: Management consists of appropriate supportive and symptomatic therapy. In the case of a recent oral overdose, if vomiting has not occurred spontaneously and if the patient is fully conscious, emesis may be induced with ipecac. If the patient is unconscious, gastric lavage should be considered. Activated charcoal and a saline cathartic may be administered after gastric lavage and or emesis to remove any remaining drug. Vital signs and fluid balance should be monitored. With normal renal function, i.v. fluids may be administered. An adequate airway should be maintained and respiration assisted as required. Hypotension may be controlled by i.v. administration of vasopressors.

Flumazenil is used as an adjunct for the management of benzodiazepine overdosage and for the complete or partial reversal of benzodiazepine-induced sedation. The hypnotic-sedative effects of benzodiazepines are rapidly reversed. However, the residual effects may reappear gradually within a few hours, depending on the dose of flumazenil, the time elapsed since the benzodiazepine was administered, and elimination half-life of the benzodiazepine in question. Flumazenil should be administered only when continued observation of the patient, for recurrence of sedation, can be assured. Its effects on respiratory depression are inconsistent; in some studies residual respiratory depressant effects were still present despite reversal of sedation. Improved consciousness is expected within the first several minutes of flumazenil administration, but ventilatory support may be required for respiratory depression. Flumazenil does not consistently reverse benzodiazepine-associated amnesia. In patients treated for long periods of time with high doses of benzodiazepines (e.g., patients physically dependent, or those maintained on benzodiazepines for control of seizure disorders or intracranial pressure), flumazenil may trigger withdrawal symptoms including convulsions. Rapid i.v. injections should therefore be avoided. The flumazenil product monograph should be consulted for complete prescribing information.

Dialysis is of limited value in benzodiazepine overdose.

Dosage And Administration: The dosage of benzodiazepines should be individualized and carefully titrated to avoid excessive sedation and mental or motor impairment. The lowest effective dose should be used and the need for continued therapy reassessed frequently. The risk of dependence may increase with the dose and duration of treatment. Individual product monographs may contain recommendations for maximum duration of use or maximum quantity per prescription, e.g., in the treatment of insomnia or anxiety.

Geriatrics: Elderly patients may be particularly sensitive to the CNS effects of benzodiazepines, and may have longer elimination half-lives due to decreased hepatic metabolism. In general, dosages of benzodiazepines for elderly patients tend to be approximately one-third to one-half of the recommended dose for younger adults.

Please refer to individual product monographs for dosage recommendations for specific indications or specific patient groups such as children, elderly or debilitated patients, or those with hepatic or renal failure.

BENZODIAZEPINES AlprazolamBromazepamChlordiazepoxideClobazamClonazepamClorazepateDiazepamFlurazepamLorazepamMidazolamNitrazepamOxazepamTemazepamTriazolam Anticonvulsant – Anxiolytic – Hypnotic – Sedative

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