Sedative Hypnotics Flashcards
What are sedative hypnotics?
- Sedative-hypnotics cause sedation or encourage sleep.
* These drugs are among the most widely prescribed worldwide.
What constitutes an effective sedative agent?
SEDATIVES
• An effective sedative agent 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.
What constitutes effective hypnotics?
HYPNOTICS
• A hypnotic drug should produce drowsiness
and encourage the onset and maintenance of a
state of sleep that resembles the natural sleep
state.
• Hypnotic effects involve more pronounced
depression of the CNS than sedation.
• This can be achieved with most sedative drugs
by increasing the dose.
Sedative-hypnotic effect on CNS function?
- Sedative-hypnotics cause a graded dose dependent depression of CNS functions.
- Individual drugs differ in the relationship between the dose and the degree of CNS depression.
DOSE-RESPONSE RELATIONSHIPS FOR
SEDATIVE-HYPNOTICS?
• Older sedative-hypnotics (barbiturates) show a
linear dose-response curve.
• An increase in dose above that needed for hypnosis may lead to a state of general anesthesia.
• At still higher doses they may depress respiratory and vasomotor centers in the
medulla, leading to coma and death.
• Benzodiazepines show a non-linear dose response relationship. They are safer drugs.
SEDATIVE-HYPNOTICS classes?
Benzodiazepines Barbiturates Non-benzodiazepine benzodiazepine receptor agonists 5HT1A receptor partial agonists Melatonin agonists Other classes
What are benzodiazepines and what receptor do they bind to?
• Benzodiazepines are the most widely used
anxiolytic drugs.
• They have replaced barbiturates in the treatment
of anxiety, because they are safer and more
effective.
• 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.
GABAa receptor constituents and gaba binding site?
• The GABAA receptor has a pentameric structure: alpha2beta2gamma.
• 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.
• 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.
BENZODIAZEPINES: MECHANISM OF ACTION
• Benzodiazepines bind to a site located between
an α subunit and the gamma subunit.
• These binding sites are sometimes called benzodiazepine receptors.
• Two benzodiazepine receptor subtypes commonly found in the CNS have been designated BZ1 and BZ2.
• Benzodiazepines enhance GABA’s effects allosterically.
• This enhancement takes the form of an increase
in frequency of channel opening events.
BDZ decrease the
EC50 for the GABAinduced Cl- influx
BENZODIAZEPINE-RECEPTOR INTERACTIONS with
Agonists
• Are positive allosteric modulators of receptor
function.
• These are the clinically useful benzodiazepines,
which exert anxiolytic and anticonvulsant effects.
BENZODIAZEPINE-RECEPTOR INTERACTIONS with antagonists and inverse agonists?
Antagonists
• Flumazenil: blocks actions of benzodiazepines.
Inverse Agonists
• Negative allosteric modulators of GABA
receptor function.
• They can cause anxiety and seizures.
ACTIONS OF THE BENZODIAZEPINES?
- Reduction of anxiety.
- Sedative and hypnotic actions.
- Anticonvulsant.
- Muscle relaxant.
- Anesthesia.
ABSORPTION AND DISTRIBUTION of benzodiazepines?
• Benzodiazepines are lipophilic.
• Rapidly and completely absorbed after oral
administration.
• Distributed throughout the body.
DURATION OF ACTION of benzodiazepines?
- The half-lives of the benzodiazepines are very important clinically: duration of action may determine the therapeutic usefulness.
- Benzodiazepines can be divided into short-, intermediate- and long-acting groups.
- Longer acting agents form active metabolites with long half-lives.
DURATION OF ACTION OF BENZODIAZEPINES?
Long-Acting (1-3 days) Diazepam
Flurazepam
Intermediate-acting (10-20 h)
Alprazolam
Lorazepam
Temazepam
Short-acting (3-8 h) Oxazepam
Triazolam
Discuss liver metabolism of benzodiazepines?
- Most benzodiazepines undergo phase I reactions, mainly by CYP3A4.
- The metabolites are then conjugated to form glucuronides that are excreted in the urine.
- Desmethyldiazepam, with a half-life of over 40 hours, is an active metabolite of several benzodiazepines used clinically.
- Desmethyldiazepam is then metabolized to the active compound oxazepam.
- Oxazepam, lorazepam and temazepam are conjugated directly and are not metabolized by the P450 system.
- Flurazepam is oxidized by liver enzymes to active metabolites with half-lives ranging from 30 to 100 hours.
THERAPEUTIC USES OF BENZODIAZEPINES in regards to anxiety and muscle disorders?
Anxiety Disorders
• Recommended only for short-term or intermittent
use in anxiety disorders.
Muscular Disorders
• Diazepam is useful in the treatment of skeletal muscle spasms and in treating spasticity from degenerative disorders, like MS and cerebral
palsy.
THERAPEUTIC USES OF BENZODIAZEPINES with seizures and drug withdrawl?
Seizures
• Clonazepam: used for some types of epileptic seizures.
• Midazolam, Lorazepam & Diazepam: used in
status epilepticus.
Drug Withdrawal
• Diazepam & oxazepam: useful in the management of withdrawal from ethanol
THERAPEUTIC USES OF BENZODIAZEPINES with anesthesia and sleep disorders?
Anesthesia
• Certain benzodiazepines are used as components of anesthesia protocols.
Sleep Disorders • The three most prescribed for sleep disorders are: • long-acting flurazepam • intermediate-acting temazepam • short-acting triazolam
BENZODIAZEPINES: ADVERSE EFFECTS list 3
- Drowsiness and confusion.
- Ataxia
- Cognitive impairment.
Adverse Psychological Effects of Benzodiazepines?
• Benzodiazepines may cause paradoxical effects:
Anxiety, irritability, hostility and rage, paranoia,
depression and suicidal ideation.
• The incidence of such reactions is rare.
Dependence on Benzodiazepines?
- Dependence can develop if high doses are given over prolonged period.
- Abrupt discontinuation leads to withdrawal symptoms: confusion, anxiety, agitation, restlessness, insomnia, tension.
Name a BENZODIAZEPINE ANTAGONISTS and uses?
FLUMAZENIL
• Only benzodiazepine receptor antagonist available for clinical use.
• It blocks effects of benzodiazepines.
• Approved for reversing the CNS depressant effects of benzodiazepine overdose.
• Approved to hasten recovery following use of
benzodiazepines in anesthetic and diagnostic
procedures.
FLUMAZENIL pk?
• Rapid onset.
• Short duration: half-life about 1 hour, due to
rapid hepatic clearance.
• Frequent administration may be necessary to
maintain reversal of long-acting benzodiazepines.
• May precipitate withdrawal in physiologically
dependent patients.
• May cause seizures if a benzodiazepine is used
to control seizures.
What are barbiturates?
• Replaced by the benzodiazepines as sedative hypnotics.
• Barbiturates induce tolerance, drug-metabolizing
enzymes, physical dependence and cause very
severe withdrawal symptoms.
• They can cause coma in high doses.
barbiturates moa?
• Barbiturates also act on GABAA receptors, and
enhance GABAergic transmission.
• The binding site of barbiturates is different from
that of the benzodiazepines.
• Barbiturates increase the duration of the GABA gated chloride channel openings.
• Barbiturates can also block glutamate receptors
and sodium channels.
• The multiplicity of sites of action of barbiturates
may explain their ability to induce full surgical
anesthesia and their more pronounced central
depressant effects.
BARBITURATES: ACTIONS?
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.
Respiratory depression
• Barbiturates suppress the hypoxic and chemoreceptor response to CO2. Overdosage causes respiratory depression and death.
Enzyme induction
• Barbiturates induce liver cytochrome P450 enzymes
BARBITURATES: USES?
Anesthesia
• Ultra short acting barbiturates, such as thiopental are used IV to induce anesthesia.
Anticonvulsant
• Phenobarbital can be used in long-term management of tonic-clonic seizures, status epilepticus and eclampsia.
BARBITURATES: ADVERSE EFFECTS
• Drowsiness, impaired concentration
• Paradoxical excitement
• Hypersensitivity
• Hangover
• Respiratory: In the presence of pulmonary
insufficiency they may cause serious respiratory
depression.
• Pain: May worsen perception of pain.
• Dependence: Severe withdrawal syndrome.
• Poisoning: severe respiratory depression and
central CV depression.
NON-BENZODIAZEPINE
BENZODIAZEPINE RECEPTOR AGONISTS
- ZOLPIDEM
- ZALEPLON
- ESZOPICLONE
moa of NON-BENZODIAZEPINE
BENZODIAZEPINE RECEPTOR AGONISTS?
- These drugs act only on the BZ1 subtype of benzodiazepine receptors.
- Hypnotics.
- Minimal muscle relaxing and anticonvulsant effects.
- Little or no tolerance.
- Low incidence of adverse effects
pk of zolpidem and indications?
- Short duration of action.
- Short half life = 1.5 - 3.5 h.
- Indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
pk of zaleplon and indications?
- Rapid onset and very short duration of action.
- Elimination half life = 1 h.
- Indicated for the short-term treatment of insomnia.
Eszopiclone pk and indications?
- (S)-Enantiomer of zopiclone.
- Pharmacologically active enantiomer of zopiclone.
- Approved for treatment of insomnia.
- Decreases sleep latency and improves sleep maintenance.
- Half-life = 6 hours.
Name a 5-HT1A partial agonist, actions, indications, pk, moa?
BUSPIRONE
• No hypnotic, anticonvulsant or muscle relaxant properties.
• Only anxiolytic.
• Indicated for management of anxiety disorders.
• Onset: 2 - 3 weeks.
• Mechanism of action may be analogous to
antidepressants.
Advantages of a 5-HT1A agonist?
• Less psychomotor impairment than BZ.
• 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
MELATONIN RECEPTOR AGONISTS name example, action, and indication?
RAMELTEON
• Agonist at MT1 & MT2 melatonin receptors.
• Indicated for the treatment of insomnia characterized by difficulty with sleep onset.
Name 4 drugs from other classes possible used as sedatives?
HYDROXYZINE
• Antihistamine with antiemetic activity.
• Approved for symptomatic relief of anxiety.
PROPRANOLOL
• Widely used to control performance anxiety.
• Clonidine may also modify autonomic expression of anxiety.
• Nonprescription antihistamines with sedating
properties, such as diphenhydramine and
doxylamine, are effective in treating mild types
of insomnia.
• However, these drugs are usually ineffective for
all but the milder forms of situational insomnia.
