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:
q Benzodiazepines.
q Barbiturates.
q Miscellaneous drugs.
Benzodiazepines are the most important sedative-hypnotics. 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)
q Diazepam.
q Chlordiazepoxide.
q Flurazepam.
q Clonazepam.
Medium acting drugs: (24 hrs)
q Alprazolam.
q Nitrazepam.
Short acting drugs: (12-18 hrs)
q Lorazepam.
q Oxazepam.
q Temazepam.
Ultrashort acting drugs: (6 hrs)
q Triazolam.
q 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:
q Reduction of anxiety and aggression
q Sedation and induction of sleep
q Reduction of muscle tone and coordination
q anticonvulsant effect.
q 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:
q The latency of sleep onset is decreased (time to fall asleep).
q The duration of NREM sleep is increased.
q The duration of REM sleep is decreased.
q 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 sedative-hypnotics.
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 lipid-soluble 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 half-lives 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:
q Hypnotics for insomnia.
q Anxiolytics.
q Panic attacks.
q For preoperative sedation.
q For acute alcohol withdrawal.
q Anticonvulsants in treatment of epilepsy.
q Muscle relaxants in chronic muscle spasm and spasticity.
Dosage of Benzodiazepines:
Drugs that used as anxiolytics and sedatives:
q Diazepam: 5-10mg twice daily.
q Chlordiazepoxide: 10-20mg 2-3 times daily.
q Alprazolam: 0.25-0.5mg 2-3 times daily.
q Lorazepam: 1-2mg twice daily.
q Oxazepam: 15-30mg 3 times daily.
Drugs that used as hypnotics: taken at bedtime.
q Flurazepam: 15-30mg daily.
q Lorazepam: 2-4mg twice daily.
q Temazepam: 10-30mg daily.
q Triazolam: 0.125-0.5mg daily.
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