Sedative-Hypnotic Drugs

An effective sedative, anxiolytic agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose. Classification: Benzodiazepines. Barbiturates. Miscellaneous drugs. Benzodiazepines are the most important sedativehypnotics. The barbiturates have been regarded as prototypes of the class because of their extensive use in the past. The motivation to develop the benzodiazepines and other newer sedative-hypnotics can be attributed to efforts to avoid undesirable features of the barbiturates, including their potential for inducing psychologic and physical dependence. Benzodiazepines: Classification of Benzodiazepines: Long-acting drugs: (24-48 hrs) Diazepam. Chlordiazepoxide. Flurazepam. Clonazepam. Medium acting drugs: (24 hrs) Alprazolam. Nitrazepam. Short acting drugs: (12-18 hrs) Lorazepam.

Oxazepam. Temazepam. Ultrashort acting drugs: (6 hrs) Triazolam. Midazolam.

Pharmacodynamics of Benzodiazepines: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Benzodiazepines potentiate GABAergic neurotransmission at all levels including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines bind to specific benzodiazepines receptors which associated with postsynaptic GABAA receptors. This binding would cause an increase in the efficiency of GABAergic synaptic inhibition by increasing the ability to open chloride channels and increasing the chloride influx causing membrane hyperpolarization, which leads to a decrease in the firing rate of critical neurons in many regions of the brain. Therefore, benzodiazepines act by augmenting GABA inhibitory action. Benzodiazepine Receptor Ligands: Three types of ligand benzodiazepine receptor interactions have been reported. This includes: (1) Agonists facilitate GABA action. These effects are typically produced by benzodiazepines, which exert anxiolytic and anticonvulsant effects. (2) Antagonists are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines but does not affect the actions of barbiturates or ethanol.

(3) Inverse agonists produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the B-carbolines, e.g. n-butyl-B-carboline-3-carboxylate (Beta-CCB). In addition to their direct actions, these molecules can block the effect of benzodiazepines. Pharmacological Effects of Benzodiazepines: Enhancing GABA action by benzodiazepines would decrease the firing rate of many neurons in the brain. The most important effects of the benzodiazepines on the central nervous system are: Reduction of anxiety and aggression Sedation and induction of sleep Reduction of muscle tone and coordination anticonvulsant effect. They do not produce any analgesic or antipsychotic activity. Reduction of anxiety and aggression: Benzodiazepines show activity and exert a marked 'taming' effect, allowing animals to be handled much more easily. benzodiazepines do not have specific antidepressant effects, though the relief of anxiety may be beneficial in depressed patients. Sedation and induction of sleep: Benzodiazepines decrease the time taken to get to sleep, and increase the total duration of sleep, though the latter effect occurs only in subjects who normally sleep for less than about 6 hours each night. Both effects tend to decline when benzodiazepines are taken regularly for 1-2 weeks. Normal sleep consists of two major stages: non-rapid eye movement (NREM) sleep, which represents approximately 70-75% of total sleep; and rapid eye

movement (REM) sleep. REM and NREM sleep occur cyclically over an interval of about 90 minutes. The effect of sedative-hypnotics on patterns of normal sleep are as follows: The latency of sleep onset is decreased (time to fall asleep). The duration of NREM sleep is increased. The duration of REM sleep is decreased. The duration of slow-wave sleep is decreased. The use of sedative-hypnotics for more than a week may lead to tolerance to their effects on sleep patterns. Withdrawal after continued use can result in a rebound increase in the frequency of occurrence and duration of REM sleep. Reduction of muscle tone and coordination: Benzodiazepines appear to reduce muscle tone by a central action that is independent of their sedative effect. A reduction of muscle tone appears to be possible without producing appreciable in-coordination. Anticonvulsant effects: All benzodiazepines have anticonvulsant activity in experimental animal tests. They are generally more effective against chemically induced convulsions caused by leptazol, bicuculline than against electrically induced convulsions, and are among the most potent agents known in preventing leptazol-induced convulsions. Several benzodiazepines, including clonazepam and diazepam are clinically useful in the management of seizure states. Diazepam, given intravenously, is effectively used in controlling the repeated seizures of status epilepticus. Anesthesia:

Certain benzodiazepines, including diazepam and midazolam, are used intravenously in anesthesia but have not proved to be very successful. Effects on Respiration and Cardiovascular Function: Sedative-hypnotics even at therapeutic doses can produce significant respiratory depression in patients with obstructive pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedativehypnotics. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Benzodiazepines produce less respiratory and cardiovascular depression compared to barbiturates.
Pharmacokinetics of Benzodiazepines:

Absorption: They are usually given orally. Benzodiazepines are weakly basic drugs that absorbed most effectively at the high pH found in the duodenum. Oral absorption of triazolam is extremely rapid. Ditribution: Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the central nervous system. Diazepam and triazolam are more lipidsoluble than chlordiazepoxide and lorazepam; thus, the central nervous system actions of the latter drugs are slower in onset. Administration of benzodiazepines during pregnancy should be done with the recognition that the placental barrier to lipid-soluble drugs is incomplete and that all of these agents are capable of reaching the fetus.

Benzodiazepines and most other sedative-hypnotics bind extensively to plasma proteins. Biotransformation: Hepatic metabolism accounts for the clearance or elimination of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) by glucuronosyltransferases to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are active, with halflives greater than the parent drugs. Desmethyldiazepam, which has an elimination half-life 40-140 hours, is an active metabolite of chlordiazepoxide, diazepam, and clorazepate. While diazepam is metabolized mainly to desmethyldiazepam, it is also converted to temazepam which is further metabolized in part to oxazepam. The alprazolam and triazolam undergo alpha-hydroxylation, and the resulting metabolites appear to exert short-lived pharmacological effects since they are rapidly conjugated to form inactive glucuronides. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as oxazepam and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Excretion: The water-soluble metabolites of benzodiazepines and other sedative-hypnotics are excreted mainly via the kidney.

Clinical Indications of Benzodiazepines: Hypnotics for insomnia. Anxiolytics. Panic attacks. For preoperative sedation. For acute alcohol withdrawal. Anticonvulsants in treatment of epilepsy. Muscle relaxants in chronic muscle spasm and spasticity. Dosage of Benzodiazepines: Drugs that used as anxiolytics and sedatives: Diazepam: 5-10mg twice daily. Chlordiazepoxide: 10-20mg 2-3 times daily. Alprazolam: 0.25-0.5mg 2-3 times daily. Lorazepam: 1-2mg twice daily. Oxazepam: 15-30mg 3 times daily. Drugs that used as hypnotics: taken at bedtime. Flurazepam: 15-30mg daily. Lorazepam: 2-4mg twice daily. Temazepam: 10-30mg daily. Triazolam: 0.125-0.5mg daily. Side Effects of Benzodiazepines: Drowsiness, confusion, amnesia and impaired motor coordination, which considerably impairs manual skills such as driving performance. An interaction with alcohol is often claimed, whereby a low plasma concentration of benzodiazepines can enhance the depressant effect of alcohol. The long and unpredictable duration of action of many benzodiazepines is important in relation to side effects. Drugs such as nitrazepam that are used as hypnotics have been shown to produce a substantial day-after impairment of job performance and driving skill.

Acute Toxicity of Benzodiazepines: Benzodiazepines in acute overdose are considerably less dangerous than other anxiolytic/hypnotic drugs. The effect of an overdose is to cause prolonged sleep, without serious depression of respiration or cardiovascular function. However, in the presence of other CNS depressants, particularly alcohol, benzodiazepines can cause severe, even life-threatening, respiratory depression. The availability of an effective antagonist, flumazenil, means that the effects of an acute overdose can be counteracted, which is not possible for most CNS depressants. Tolerance; Dependence of Benzodiazepines: Tolerance, a decrease in responsiveness to a drug following continuous exposure, is a common feature of sedative-hypnotic use. The changes in responsiveness of the central nervous system (pharmacodynamic tolerance) may explain tolerance to benzodiazepines. The consequences of abuse of these agents can be defined in both psychologic and physiologic terms. When the pattern of sedative-hypnotic use becomes compulsive, more serious complications develop, including physical dependence and tolerance. Physical dependence can be described as an altered physiologic state that requires continuous drug administration to prevent the appearance of an abstinence or withdrawal syndrome. This syndrome is characterized by states of increased anxiety, insomnia, and CNS excitability that may progress to convulsions. All sedative-hypnotics are capable of causing physical dependence when used on a chronic basis. However, the severity of withdrawal symptoms differs between individual drugs and depends also on the magnitude of the dose used immediately prior to cessation of use.

Differences in the severity of withdrawal symptoms between individual sedative-hypnotics relate in part to halflife, since drugs with long half-lives are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms. Therefore, benzidiazepines produces less intense withdrawal symptoms after stopping of therapy due to the long plasma half-life and their active metabolites. Drug Interactions of Benzodiazepine: They potentiate the CNS depressant effect of alcohol as well as the other CNS depressant drugs. Concurrent administration of benzodiazepines with liver microsomal enzyme inhibitors such as cimetidine would lead to excessive sedation and drowsiness due to the increase in benzodiazepines plasma levels. Lorazepam, temazepam and oxazepam are metabolized by a different metabolic pathway involving glucuronidation which is not affected by cimetidine. Benzodiazepine Antagonists: Flumazenil: Flumazenil is one of several 1,4-benzodiazepine derivatives with high affinity to Benzodiazepines receptors that act as competitive antagonists. It blocks many of the actions of benzodiazepines but does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids, or general anesthetics. Flumazenil is used in reversing the CNS depressant effects of benzodiazepines overdose and following use of these drugs in anesthetic and diagnostic procedures. When given intravenously, flumazenil acts rapidly but has a short half-life (0.7-1.3 hours) due to rapid hepatic clearance. Adverse effects of flumazenil include agitation, confusion, dizziness, and nausea.

Barbiturates: Pharmacodynamics of Barbiturates: Barbiturates facilitate the actions of GABA at multiple sites in the CNS, but in contrast to benzodiazepines they appear to increase the duration of the GABA-gated channel openings. At high concentrations, barbiturates may directly activate chloride channels. These effects involve a binding site or sites distinct from the benzodiazepines binding site. Barbiturates are less selective in their actions than benzodiazepines, since they also depress the actions of excitatory neurotransmitters and exert non-synaptic membrane effects in parallel with their effects on GABA neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and for their more pronounced central depressant effects compared to benzodiazepines. Pharmacological Effects of Barbiturates: CNS depressant Effect: Sedation: drowsiness, mental confusion. Hypnosis: abnormal sleep and hangover. Barbiturates inhibit the REM sleep however, after stopping administration, a rebound increase in REM sleep with nightmares may occur. Amnesia. Anesthesia: Certain sedative-hypnotics in high doses will depress the central nervous system to the point known as stage III or general anesthesia thiopental is very lipid-soluble, penetrating brain tissue rapidly following intravenous administration. Rapid tissue redistribution accounts for the short duration of action of these drugs, which are therefore useful in anesthesia practice. Anticonvulsant effects: Phenobarbital is effective in the treatment of grand mal and jacksonian epilepsy. Respiratory and circulatory depression:

High doses of barbiturates depress the respiratory and vasomotor centers leading to death. Gastrointestinal effects: They inhibit gut motility and secretion. Kidney: They cause the release of antidiuretic hormone causing oliguria and anuria. Pharmacokinetics of Barbiturates: Lipid solubility plays a major role in determining the rate at which the particular drug enters into the brain. Thiopental in which the oxygen on C2 is replaced by sulfur, is very lipid-soluble, and a high rate of entry into the CNS contributes to the rapid onset of its central effects. Redistribution of drug from the CNS to other tissues is an important feature of the biodisposition of sedativehypnotics. Thiobarbiturates have shown that they are rapidly redistributed from the brain, first to highly perfused tissues such as skeletal muscle and subsequently to poorly perused adipose tissue. These processes contribute to the termination of their major CNS effects. Redistribution to tissues other than the brain may be as important as biotransformation in terminating the CNS effects of many sedative-hypnotics. However, metabolic transformation to more water-soluble metabolites is necessary for clearance from the body of almost all drugs in this class. The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard. With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes of chemical groups attached to C5, which are different for the individual barbiturates. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different

individuals. The elimination half-life of phenobarbital in humans is 4-5 days. Multiple dosing with these agents can lead to cumulative effects. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. Clinical Indications of Barbiturates: Sedatives and hypnotics e.g. pentobarbitone. They inhibit the REM sleep, however stopping of barbiturates may cause rebound increase in the REM sleep and nightmares. Anticonvulsants in treatment of epilepsy e.g. phenobarbitone. As preanaesthetic medication e.g. thiopental for either induction of anesthesia or as I.V. anesthetic for brief operations (15 mins). To counteract the CNS stimulant effect of CNS stimulant drugs. Dosage of Barbiturate: Phenobarbital: 15-30mg 2-3 times daily. Pentobarbital: 100-200mg daily. Side Effects of Barbiturates: Drowsiness, mental confusion, hangover. Hypersensitivity reactions. Acute Toxicity of Barbiturates: Hypoxia, cyanosis, hypothermia. Respiratory, circulatory failure, coma, death. Treatment of Toxicity: Emergency treatment by supporting respiration and circulation. Inhibiting further absorption by gastric lavage (if no coma) and promoting renal excretion by forced alkaline diuresis and hemodialysis. CNS stimulant drugs can be used such as analeptics.

Contra-indications of Barbiturates: In patients with acute porphyria due to the induction of deltaaminolevulinic acid synthase that cause a significant increase in porphyrin synthesis causing hematuria, neuropathy and muscle weakness. In liver and renal impairment. In respiratory disease as bronchial asthma. Tolerance; Dependence of Barbiturates: An increase in the rate of metabolic inactivation with chronic administration may be partly responsible (metabolic tolerance) for tolerance of barbiturates. Drug dependence and withdrawal symptoms occur with barbiturates more severe compared to benzodiazepines. Drug Interactions of Barbiturates: Barbituartes would decrease the serum levels and the effect of concurrently administered drugs due to induction of liver microsomal enzymes. Concurrent use of barbiturates and the other CNS depressant drugs may lead to respiratory depression. Buspirone: Benzodiazepines continue to be the agents of choice in the treatment of anxiety and insomnia however, their pharmacological effects include sedation and drowsiness, synergistic CNS depression with other drugs (especially alcohol), and dependence with continuous use are considered the main drawbacks. New anxiolytic drugs that act through non-GABAergic systems might have a reduced propensity for such actions. Buspirone relieves anxiety without marked sedation. Unlike benzodiazepines, the drug has no hypnotic, anticonvulsant, or muscle relaxant properties.

Buspirone does not interact directly with GABAergic systems but appears to exert its anxiolytic effects by acting as a partial agonist at 5-HT1A receptors. It is not effective in blocking the withdrawal syndrome resulting from cessation of use of benzodiazepines or other sedative-hypnotics. Buspirone does not potentiate the CNS depressant effects of conventional sedative-hypnotic drugs. Buspirone is rapidly absorbed from the gastrointestinal tract but undergoes extensive first-pass metabolism. Its elimination half-life is 4 hours, with virtually no free drug appearing in the urine. Liver enzymes metabolize buspirone via hydroxylation and N-dealkylation reactions, resulting in formation of several metabolites that may retain slight pharmacological activity. Buspirone causes less psychomotor impairment than diazepam. Tachycardia, palpitations, headache, nervousness, gastrointestinal distress, and paresthesias may occur more frequently than with benzodiazepines. Its dose is 20mg daily, orally. Zolpidem: Zolpidem is an imidazopyridine derivative, structurally unrelated to benzodiazepines. The drug binds to benzodiazepines receptors and appears to have a similar mechanism of action to facilitate GABA-mediated inhibition. It is mainly used as a hypnotic. Zolpidem has an efficacy and side effect profile similar to that of triazolam. Older Sedatives and hypnotics: These drugs include chloral hydrate, meprobamate, glutethimide, paraldehyde and even inorganic bromide ion. They are rarely used in therapy. Chloral Hydrate:

Trichloroethanol is the pharmacologically active metabolite of chloral hydrate that cause hypnosis and has a half-life of 6-10 hours. However, its toxic metabolite, trichloroacetic acid, is cleared very slowly and can accumulate with the nightly administration of chloral hydrate. It causes less respiratory and circulatory depression. The main side effects of chloral hydrate include; vomiting, irritation to the stomach (avoid in patients with peptic ulcer) and jaundice.