90b - Sedatives and Hypotonics (Silinsky <3) Flashcards
Can benzos on their own be deadly?
In what situations?
Yes
Anyone with a breathing disorder (OSA, COPD)
Usually, the biggest danger of benzos is mixing with other drugs and/or alcohol -> respiratory depression
Hypnotic and sedative doses are usually pretty safe on their own
Dealkylation of which kinds of benzodiazepines results in a long-acting metabolite?
Which enzyme is the dealkylate-er?
What are the implications?
-azepams are dealkylated by CYP2C19
This metabolite is long-acting and will hang out for awhile, especially in anyone with slower liver metabolism
Avoid the -azepams* in anyone taking multiple drugs that could have deathly synergy, the elderly, and anyone who might have impaired hepatic function
*Except the LOTs: They are okay
(Lorazepam, oxazepam, temazepam)
How are the -zazoles metabolized?
- Phase I: CYP3A4
- Phase II: Glucuronidation
Are the benzos or -zazoles better agents for insomnia?
Why?
-zazoles
- They increase sleep quantity AND normalize sleep architecture (including slow wave and REM sleep)
- vs. benzos, which suppress slow wave and REM sleep
Which benzos are safest for use by elderyly patients?
the LOTs
- Lorazepam
- Oxazepam
- Temazepam
These are pre-lubed and can go directly to glucuronidation; no active metabolites are produced
Which benzodiazepine would you use to treat a patient with alcohol withdrawal and liver disese?
One of the LOTs (Lorazepam, Oxazepam)
Metabolites will not accumulate
How does melatonin induce sleep?
When there is no light hitting the SCN…
- Melatonin is synthesized and released from the pineal gland
-
Melatonin acts on the SCN via MT1 receptors to inhibit neurons in the SCN
- MT1 receptors activation activates K+ channels, resulting in membrane hyperpolarization
- Also inhibits Ca2+ channels and decreases cAMP, but to a lesser degree
- This induces sleep
- Melatonin assists darkness in inhibiting the SCN?
What is the action of penicillin on the GABAA receptor?
At high doses, penicillin is an uncompetitive inhibitor at the GABAA receptor
- Blocks the channel after its been opened by GABA
- Results in seizures
- Newborns, people with renal impairment are susceptible
What si the difference in structure between the -azepams and
-azolams?
- -azepam: Diazepine ring with 2 benzenes
- -azolam: has extra 5-membered ring
How do benzodiazepines affect the action of the GABAA receptor?
Increase the frequencey of Cl- channel opening
Requires endogenous GABA
(Vs. barbituates, which increase the duration of opening and can activate the receptor without endogenous GABA)
What is the pharmacological target of sedative-hypnotics?
GABAA receptors
(The GABAA receptors is a ligand-gated Cl- channel)
Which receptors do the -zazoles act on?
Where do they bind?
Benzodiazepine receptor
Bind to omega1 sites on BDZ1 receptors
- These only exist when gamma subunits are next to alpha1 subunits
How do the -zazoles affect sleep?
- Reduce sleep latency
- Fewer awakenings
- Do not suppress slow wave or REM sleep!
- vs. Benzos that do suppress slow wave and REM
These characteristics make the -zazoles good for treating sleep disorders!
What is the effect of combining ethanol and benzos?
Life-threatening synergy ->
Respiratory and cardiac depression
How do scopolamine/other antimuscarinics affect sleep?
- Decrease sleep latency
- Decrease # of awakening
- Increase slow wave sleep
- Decrease REM sleep
Same as diphenhydramine
How does light influence melatonin production?
Light inhibits melatonin synthesis by stimulating GABAA receptors in the PVN
- Light -> Retina -> Suprachiasmatic nucleus (SCN) -> GABAA receptors in the PVN
Darkness removes this inhibition
- Melatonin is synthesized and released from the pineal gland
- Acts on the SCN via MT1 receptors to inhibit neurons in the SCN
- This induces sleep
Describe the interaction between the SCN and the VLPO
- Light -> Retina -> SCN
- The SCN feeds the subparaventricular zone (SPZ)
- The SPZ feeds the dorsomedial hypothalamus (DMH)
- The DMH inhibits the VLPO and stimulates orexin neurons
Basically, when the SCN is stimulated by light orexin is released (wakefulness!) and the VLPO is inhibited (no sleepiness!)
When activated:
[MT1/MT2] receptors induce a phase shift and can re-set the circaidan clock
[MT1/MT2] receptors control sleepiness
When activated:
MT2 receptors induce a phase shift and can re-set the circaidan clock
MT1 receptors control sleepiness
Note:
Ramelteon binds the MT1 receptor
Tasimelteon binds the MT2 receptor
Melatonin binds both equally
How are the -azepams metabolized?
-
Dealkylation by CYP2C19
- Produces a long acting active metabolite
- Can cause problems if other drugs are involved bc it hangs out for so long!
- Hydroxylation by CYP3A4
- Produces an intermediate-acting metabolite similar to the LOTs
- Remember, the LOTs are “pre-lubed” - ready for glucuronidation
- Glucuronidation
Where do benzodiazepines bind to the GABAA recpetor?
Junction of the alpha and gamma subunits
This is called either BDZ1 or BDZ2, depending on which kind of GABAA receptor it is
- BDZ1 = alpha1 and gamma1
- BDZ2 = alpha2 and gamma2
What is the difference between a sedativve and a hypnotic?
- Sedative
- Reduces the excitatory response -> calmness
- Hypnotic
- Causes drowsiness and sleep
Sedative-hypnotic produces calmness at low doses, sleep at high doses
(anesthesia, coma, death at even higher doses)
How does diphenhydramine/other antihistamines affect sleep?
- Decrease sleep latency
- Decrease # of awakenings
- Increase slow wave sleep
- Decrease REM sleep
Same as scopolamine
What are the therapeutic uses of ramelteon?
Treat sleep-onset insomnia
Will not reduce number of awakenings
Not good for non-24h sleep/wake disorder (use tasimelteon for this)
Describe the melatonin prduction pathway
How is it influenced by light?
- Paraventricular nucleus (PVN) of the hypothalamus sends axons to the spinal cord
- Preganglionic sympathetics from the spinal cord synapse in the sympathetic cervical ganglion
- Postganglionic sympathetics go to the pineal gland
- NE is released onto B1 receptors
- Increased melatonin synthesis
Light inhibits melatonin synthesis by stimulating GABAA receptors in the PVN
- Light -> Retina -> SCN -> GABAA receptors in the PVN
How does alcohol affect sleep?
- Some normalization of sleep
- Suppression of REM sleep in the first 1/2 of the sleep period
- Increases slow wave sleep
- Effects on sleep latency, awakenings is variable
What are the drugs of choice for sleep?
-zazoles
zaleplon, zolpidem, eszopiclone
They bind to the benzodiazepine receptor, but are NOT benzos
- -zazoles normalize both sleep duration AND sleep architecture
- vs. benzos, which inhibit slow wave and REM sleep
Which drug is a benzodiazepine antagonist that can help reverse the effect in case of overdose?
Flumazenil
How is ramelteon metabolized?
CYP1A2
What are the indications for tasimelteon?
Non 24h sleep-wake disorder
but v expensive :(
Ramelteon has affinity for [MT1 receptors/MT2 receptors]
Tasimeltion has affinity for [MT1 receptors/MT2 receptors]
Melatonin has affinity for [MT1 receptors/MT2 receptors]
Ramelteon has affinity for MT1 receptors
Tasimeltion has affinity for MT2 receptors
Melatonin has affinity for Both
What is the mechanism of action of suvorexant?
What is it used for?
Suvorexant is an orexin receptor antagonist
- Orexins are wakefulness neuropeptides
- Blocking orexin signaling = inactivation of wakefulness
- All arousal amine cell bodies have orexin receptors (5HT, NE, ACh, DA)
Used to treat insomnia - improves sleep duration and maintenence
Drawback = long half-life
List some of the clinical uses of benzodiazepines
- Anxiety/aggression
- Severe anxiety w/panic
- Sedationa and amnesia during medical procedures
- Anticonvulsants
- Muscle spasm
- Alcohol withdrawal
But shoudl not be used long term - tolerance and dependence can build!
Often used as a bridge until SSRIs can kick in
Which benzodiazepines do not produce active metabolites when they are metabolized?
The LOTs
Lorazepam, oxazepam, temazepam
They are glucuronidated directly = no active metabolites
