Sedative-Hypnotic Drugs Flashcards
BASIC PHARMACOLOGY OF THE SEDATIVE-HYPNOTIC DRUGS
An effective sedative drug should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. The degree of CNS depression caused by a sedative should be the minimum consistent with therapeutic efficacy.
A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.
Graded dose-dependent depression of the CNS function is a characteristic of sedative- hypnotics. However, individual drugs differ in the relationship between the dose and the degree of CNS depression.
Older sedative-hypnotics, including the barbiturates and alcohols show a linear slope in their dose-response relationship. An increase in dose above that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death.
Deviations from a linear dose-response relationship will require proportionately greater dosage increments in order to achieve CNS depression more profound than hypnosis. This appears to be the case for most drugs of the benzodiazepine class, and the greater margin of safety this offers is an important reason for their extensive clinical use to treat anxiety states and sleep disorders.
BENZODIAZEPINES
Mechanism of Action
Alprazolam, Clonazepam, Diazepam, Flurazepam, Lorazepam, Midazolam, Oxazepam, Temazepam, Triazolam
Benzodiazepines have replaced barbiturates in the treatment of anxiety because they are safer and more effective.
MECHANISM OF ACTION
The benzodiazepines bind to GABAa receptors in neuronal membranes in the CNS. The GABAA receptor functions as a chloride channel, and is activated by the inhibitory neurotransmitter GABA.
The GABAa receptor has a pentameric structure: α2β2γ. Each subunit has four spanning domains. Multiple isoforms of each subunit have been identified.
The binding sites for GABA are located between adjacent α and β subunits. Benzodiazepines bind to a site located between an α subunit and the γ subunit. These binding sites are sometimes called benzodiazepine receptors.
Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptor depending on whether their composition includes the α1 subunit or the α2 subunit, respectively.
GABA is the major inhibitory neurotransmitter in the CNS. Binding of GABA to its receptor opens the chloride channel, leading to an increase in chloride influx. The influx of chloride ions causes a hyperpolarization that moves the postsynaptic potential away from its firing threshold and, thus, inhibits the triggering of action potentials.
Benzodiazepines potentiate GABAergic inhibition. Benzodiazepines don’t directly activate GABAA receptors: they enhance GABA’s effects allosterically. This enhancement takes the form of an increase in frequency of channel opening events.
BENZODIAZEPINES
Actions and Pharmacokinetics
ACTIONS OF THE BENZODIAZEPINES
All of the benzodiazepines exhibit the following actions to a greater or lesser extent.
Sedation: Benzodiazepines exert calming effects with concomitant reduction of anxiety at relatively low doses.
Anticonvulsant effects: several benzodiazepines, including clonazepam, nitrazepam, lorazepam and diazepam, have selective actions that are clinically useful in the management of seizure states.
Muscle relaxation: benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord.
Anesthesia: certain benzodiazepines, including diazepam and midazolam, are used IV in anesthesia but are not capable of producing surgical anesthesia by themselves.
PHARMACOKINETICS
ABSORPTION AND DISTRIBUTION
The benzodiazepines are lipophilic and are rapidly and completely absorbed after oral administration and are distributed throughout the body.
DURATION OF ACTION
The half-lives of the benzodiazepines are very important clinically, since the duration of action may determine the therapeutic usefulness. The benzodiazepines can be roughly divided into short-, intermediate- and long-acting groups. The longer acting agents form active metabolites with long half-lives.
Long-Acting (1-3 days)
Diazepam, Flurazepam
Intermediate-acting (10-20 h)
Alprazolam, Lorazepam, Temazepam
Short-acting (3-8 h)
Oxazepam, Triazolam
FATE
Benzodiazepines are metabolized, mainly in the liver.
Most benzodiazepines undergo phase I reactions, mainly by CYP3A4. The metabolites are then conjugated in phase II to form glucuronides that are excreted in the urine.
Inhibitors of CYP3A4 can inhibit the metabolism of benzodiazepines.
Oxazepam, lorazepam and temazepam are conjugated directly to their glucuronides, mainly in the liver, and are not metabolized by the P450 system. Their plasma levels are not significantly affected in liver disease. Other benzodiazepines may need dose adjustment in liver disease.
Many phase I metabolites of benzodiazepines are pharmacologically active. For these benzodiazepines, the apparent half-life of the drug represents the combined actions of the parent drug and its metabolites.
THERAPEUTIC USES OF THE BENZODIAZEPINES
ANXIETY DISORDERS
Benzodiazepines are effective for most forms of anxiety but produce pharmacologic dependence and have limited benefit in OCD or PTSD. They are generally recommended only for short-term or intermittent use in anxiety disorders.
Alprazolam is effective and widely used for panic disorder but may cause rebound anxiety between doses and has been associated with a withdrawal syndrome, including seizures.
MUSCULAR DISORDERS
Diazepam is useful in the treatment of skeletal muscle spasms such as occur in muscle strain, and in treating spasticity from degenerative disorders, like multiple sclerosis and cerebral palsy.
SEIZURES
Clonazepam: used for some types of epileptic seizures.
Lorazepam: drug of choice in status epilepticus.
DRUG WITHDRAWAL
Chlordiazepoxide, clorazepate, diazepam, oxazepam: useful in the management of withdrawal states in persons physiologically dependent on ethanol.
ANESTHESIA
Certain benzodiazepines (eg diazepam, midazolam) are used as components of anesthesia protocols.
SLEEP DISORDERS
The three most prescribed for sleep disorders are long-acting flurazepam, intermediate-acting temazepam and short-acting triazolam.
All of the sedative-hypnotics will induce sleep if high enough doses are given.
The effects of sedative-hypnotics on patterns of normal sleep are as follows:
- Latency of sleep onset is decreased.
- Duration of stage 2 NREM sleep is increased.
- Duration of REM sleep is decreased.
- Duration of stage 4 NREM slow-wave sleep is decreased.
1 and 2 are useful effects. The significance of the changes in REM and slow-wave sleep is not clear.
BENZODIAZEPINES ADVERSE EFFECTS
Drowsiness and confusion: the two most common side effects.
Ataxia (An inability to coordinate muscle activity during voluntary movement): occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile.
Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur with use of benzodiazepines.
Adverse Psychological Effects
Benzodiazepines may cause paradoxical effects. For example, they may occasionally increase the incidence of nightmares and sometimes causes garrulousness, anxiety, irritability, tachycardia, and sweating. Amnesia, euphoria, restlessness, hallucinations, and hypomanic behaviour have been reported to occur with use of various benzodiazepines. Bizarre uninhibited behaviour is noted by some users, while hostility and rage may occur in others. Collectively, these are sometimes called disinhibition or dyscontrol reactions. Paranoia, depression and suicidal ideation also occasionally may accompany the use of benzodiazepines. The incidence of such reactions is rare and appears to be dose-related.
DEPENDENCE
Psychological and physical dependence can develop if high doses are given over prolonged period. Abrupt discontinuation leads to withdrawal symptoms: confusion, anxiety, agitation, restlessness, insomnia, tension.
PRECAUTIONS
Benzodiazepines should be used with caution in patients with liver disease.
Benzodiazepines potentiate alcohol and other CNS depressants.
Benzodiazepines are considerably less dangerous than other anxiolytics and hypnotic drugs. As a result, a drug overdose is seldom lethal, unless other central depressants such as alcohol are taken concurrently.
Flumazenil
BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL
Only benzodiazepine receptor antagonist available for clinical use.
It blocks the actions of benzodiazepines and BZRAs. It doesn’t antagonize the CNS effects of other sedative-hypnotics, such as ethanol, opioids, or general anesthetics.
Approved for use in reversing the CNS depressant effects of benzodiazepines overdose and to hasten recovery following use of these drugs in anesthetics and diagnostic procedures.
Available by IV administration only. Onset is rapid but duration is short, with a half-life of about 1 hour, due to rapid hepatic clearance. Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepines. Adverse effects include dizziness, confusion, nausea, vomiting and agitation.
Flumazenil may precipitate withdrawal in physiologically dependent patients or may cause seizures if a benzodiazepine is used to control seizure activity. In patients who have ingested benzodiazepines with TCAs, seizures and cardiac arrhythmias may occur following flumazenil administration.
Thiopental
BARBITURATES
Phenobarbital, Pentobarbital, Thiopental
BARBITURATES
Mechanism of Action
The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines and NBBRAs, mainly because barbiturates induce tolerance, drug- metabolizing enzymes, physical dependence, are associated with very severe withdrawal symptoms, and can cause coma in toxic doses.
Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia.
MECHANISM OF ACTION
The sedative-hypnotic action of the barbiturates is also due to their interaction with GABAa receptors, which enhances GABAergic transmission. The binding site of barbiturates is different from that of the benzodiazepines.
Barbiturates potentiate actions of GABA, but in contrast to the benzodiazepines they increase the duration of the GABA-gated chloride channel openings. In addition, barbiturates can block glutamate receptors. Anesthetic concentrations of pentobarbital also block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity.
The 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 which result in their low margin of safety compared with benzodiazepines.
BARBITURATES
Actions and Uses
Barbiturates are classified according to their duration of action.
Thiopental which acts within seconds and has a duration of action of about 30 min is used in the IV induction of anesthesia.
Phenobarbital, which has a duration of action of >1 day is useful in treatment of seizures.
Pentobarbital, secobarbital and amobarbital are short-acting barbiturates (3-8 hours), effective as sedative and hypnotic agents.
DEPRESSION OF CNS
At low doses, the barbiturates produce sedation. At higher doses hypnosis, followed by anesthesia, and finally coma and death. Thus, any degree of CNS depression is possible, depending on the dose. Barbiturates don’t raise the pain threshold and have no analgesic properties.
RESPIRATORY DEPRESSION
Barbiturates suppress the hypoxic and chemoreceptor response to CO2 and overdosage is followed by respiratory depression and death.
ENZYME INDUCTION
Barbiturates induce P-450 microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P- 450 metabolism to reduce their concentration.
THERAPEUTIC USES
ANESTHESIA
The ultra short acting barbiturates, such as thiopental are used IV to induce anesthesia.
ANTICONVULSANT
Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus and eclampsia.
HEPATIC METABOLIC USES
Because hepatic glucuronyl transferase and the bilirubin-binding Y protein are increased by the barbiturates, phenobarbital has been used successfully to treat hyperbilirubinemia and kernicterus in the neonate. The nondepressant barbiturate phetharbital (N-phenylbarbital) works equally well.
Phenobarbital may improve the hepatic transport of bilirubin in patients with hemolytic jaundice.
BARBITURATES
Adverse Effects
ADVERSE EFFECTS
CNS: barbiturates cause drowsiness, impaired concentration and mental and physical sluggishness.
Paradoxical excitement: in some persons, barbiturates repeatedly produce excitement rather than depression, and the patient may appear inebriated.
Hypersensitivity: allergic reactions occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions.
Drug hangover: hypnotic doses of barbiturates produce a feeling of tiredness well after the patient awakes. This drug hangover leads to impaired ability to function normally for many hours after waking. Occasionally nausea and dizziness occur.
Precautions: barbiturates induce the P450 system and therefore may decrease the effect of drugs that are metabolized by these hepatic enzymes.
Barbiturates increase porphyrin synthesis and are absolutely contraindicated in patients with acute intermittent porphyria, variegate porphyria, hereditary coproporphyria or symptomatic porphyria.
In the presence of pulmonary insufficiency, serious respiratory depression may occur with administration of barbiturates; barbiturates are contraindicated in this situation.
Rapid IV injection of a barbiturate may cause cardiovascular collapse before anesthesia ensues. Blood pressure can fall to shock levels; even slow IV injection of barbiturates often produces apnea and occasionally laringospasm, coughing, and other respiratory difficulties.
Addiction: abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death.
Poisoning: barbiturate poisoning has been a leading cause of death among drug overdoses for many decades. Severe depression of respiration is coupled with central cardiovascular depression and results in a shock-like condition with shallow, infrequent breathing. Alkalinization of the urine often aids in the elimination of phenobarbital.
THE NON-BENZODIAZEPINE BENZODIAZEPINE- RECEPTOR AGONISTS (NBBRA)
These drugs act only on the BZ1 subtype of benzodiazepine receptors; these are GABAa receptors that contain α1 subunits.
Zolpidem
Zaleplom
Eszopiclone
Zolpidem
ZOLPIDEM (NBBRA)
Zolpidem binds to the GABAA receptor and facilitates GABA-mediated neuronal inhibition.
Antagonized by flumazenil.
Hypnotic. Short duration of action. Elimination half life is 1.5 - 3.5 h.
It has minimal muscle relaxing and anticonvulsant effects.
It shows few withdrawal effects, and exhibits minimal rebound insomnia, and little or no tolerance occurs with prolonged use.
Extensively metabolized to inactive metabolites mainly by CYP3A4.
Indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
Adverse effects include nightmares, agitation, headache, gastrointestinal upset, dizziness, and daytime drowsiness.
Zaleplon
ZALEPLON (NBBRA)
Zaleplon is very similar to zolpidem in its hypnotic actions.
Causes fewer residual effects on psychomotor and cognitive functions compared to zolpidem or the benzodiazepines. This may be due to its rapid elimination, with a half-life of approximately 1 hour.
Metabolized by aldehyde oxidase and CYP3A4.
Eszopiclone
ESZOPICLONE
(S)-Entantiomer of zopiclone. Pharmacologically active enantiomer of zopiclone. It has about a 50-fold higher affinity for its receptor target site as compared to R- zopiclone.
FDA-approved for treatment of insomnia.
Decreases sleep latency and improves sleep maintenance.
Elimination half-life is approximately 6 hours.
Adverse events reported with eszopiclone include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste.
Buspirone
5-HT1A PARTIAL AGONISTS
BUSPIRONE
5-HT1A partial agonist.
No hypnotic, anticonvulsant or muscle relaxant properties. Only anxiolytic.
Doesn’t interact with GABA receptors.
Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.
Second-line agent for GAD, due to inconsistent data regarding its efficacy.
Onset: 2 - 3 weeks.
The slow onset has led to belief that buspirone works by adaptive neuronal and receptor events, rather than simply by acute occupancy of 5HT1A receptors. Therefore, mechanism of action appears to be analogous to antidepressants.
Advantages:
Less psychomotor impairment than diazepam.
No drug interactions with EtOH
No drug interactions with benzodiazepines and other sedative-hypnotics
No rebound anxiety or withdrawal signs on abrupt discontinuance
No dependence
