Sedative Hypnotics Flashcards
How are benzodiazepenes metabolized?
Hepativ. P450 enzymes especially CYP3A4
What barbiturate is excreted unchanged into the urine to a certain extent (20-30% in humans)? It also has an eliminiation half life of 4-5 days
Phenobarbital
How can the excretion of Pb be hastened?
Alkalinize the urine because Pb is weakly acidic
Where does Ramelteon act?
MT1 and MT2 melatonin receptors in the suprachiasmatic nucleus of the brain
What receptors does busiprone act on?
D2 and 5HT1A
How do benzodiazepenes and barbiturates affect liver metabolizing enzymes? State the difference
Barbiturates can increase the activity of these enzymes while benzos have no effect. So Pb can induce its own metabolism in the long run
What type of GABA receptor do benzos and barbiturates bind to?
How about baclofen?
GABA A
GABA B
How do the actions of Benzos and Barbs differ at GABA A?
Benzos increase frequency of opneing GABA gated chloride channels
Barbs increase duration
What additional effects do barbiturates have that make them have more pronounced central depressant effects compared to benzos?
Depress actions of glutamic acid via binding to the AMPA receptor
Identify the mediated actions of the different GABA A receptors.
alpha 1 sedation and amnesia
alpha 2 and 3 for anxiolysis and muscle relaxation
alpha 5 memory
What kind of amnesia do benzos and barbs produce?
Anterograde
What stages of sleep are reduced by benzos and barbs?
REM and Stage 4 NREM
Stage 2 NREM is increased
The general effects of benzodiazepines and older
sedative-hypnotics on patterns of normal sleep are as follows: (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM (nonrapid eye movement) sleep is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased.
What barbiturate is used for anesthesia owing to its high lipid solubility– great for induction?
Thiopental
What is the most dangerous effect of sedative hyponotic drug doses?
Cardiovascular and respiratory collapse
What is the expected adverse effect of benzos and barbs at doses meant to treat anxiety?
Disinhibition
What is the antidote to benzo overdose and how does it act?
Flumazenil acting as a competitive antagonist at the GABA A receptor– blocking the effects of benzos and even the newer sedatives like zolpidem
Why are zolpidem and other new sleeping pills like Zaleplon and Eszopiclone better than benzos?
Minimal change in sleep pattern. Also they have few amnestic effects and day after psychomotor depression or somnolence. Remember that Benzos decrease REM and slow wave stage 4 NREM sleep.
What disease are barbiturates contraindicated in because of enhanced porphyrin synthesis?
Porphyria: Acute intermittent, variegate, symptomatic
MOA of The newer hypnotics: Zolpidem, Zaleplon, Eszopiclone
Similar to Benzos– bind to GABA A– bind between the alpha and gamma receptors
What is the advantage of busiprone over benzos in anxiety?
Minimal psychomotor impairment and no additive CNS depression
Why do oxazepam and lorazepam have relatively short half-lives?
They are metabolized directly into inactive glucuronides VS diazepam, Flurazepam
THEY HAVE NO ACTIVE METABOLITES! LIKE ZOLPIDEM
What is the elimination half life of phenobarbital?
4-5 days!
Diazepam 1-2 days half life
What are the 3 characteristics of Ramelteon that make it ideal for use as a hypnotic substance?
- Reduced latency of persistent sleep with no effects on sleep architecture
- No rebound insomnia
- No significant withdrawal symptoms
Why is busiprone NOT suitable for the management of acute anxiety?
Effects may take more than a week to become established
How do barbiturates affect microsomal drug metabolizing enzymes?
Increased activity in stark contrast to benzodiazepenes and newer hypnotics like zolpidem
T or F: Benzodiazepenes do not substitute for GABA but appear to enhance GABA’s effects allosterically without directly activating GABAa receptors or opening the associated chloride channels.
T
T or F. Flumazenil also blocks the actions of barbiturates on the GABA receptor Cl channel.
F. It only antagonizes the actions of benzos and zolpidem
Recall that barbiturates bind in an area separate from the binding site of the benzos.
What is an example of an inverse agonist at the GABA receptor? Acts by negative allosteric modulation of the GABA receptor function
beta carboline
Which sedative hypnotics have no REM Rebound?
Zolpidem and then newer drugs
However, rebound insomnia occurs with both zolpidem and zaleplon if used at higher doses.
What are the mechanisms of tolerance for sedative hypnotics?
- Increase in the metabolism of drugs
- Down regulation of receptors (bezodiazepenes)
- Pharmacodynamic tolerance: decrease in the responsiveness of the brain to the effects of the drug
What is the advantage of benzos over SNRI and SSRI in the treatment of acute anxiety?
Benzos have a rapid onset of action.
What kind of amnesia accompanies benzos?
Anterograde
Which new hypnotic has value in those who awaken early in the sleep cycle? The drug acts rapidly and has a very short half life.
Zaleplon
What are the three new sedative hypnotics?
Zolpidem, Zaleplon, Eszopiclone
What sedative hypnotic drug is ABSOLUTELY CONTRAINDICATED against porphyria?
Baribiturates
Remember the Rrrrrrsss. baRbituRates and poRphyRias
What agents block the GABA receptor serving as CNS stimulants?
These convulsant
drugs block the channel directly (picrotoxin) or interfere with GABA binding (bicuculline).
How do new hyponotics affect sleep?
The newer hypnotics all decrease the latency
to persistent sleep. Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep. Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. Eszopiclone increases total sleep time, mainly via increases in stage 2 NREM sleep, and at low doses has little effect on sleep patterns. At the highest recommended dose, eszopiclone decreases REM sleep.
