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.
