Psychotherapy: 90b - Sedatives and Hypotonics

Increase the frequencey of Cl- channel opening

Requires endogenous GAB...

GABAA receptors

(The GABAA receptors is a ligand-gated Cl- channel)

Benzodiazepine receptor

Bind to omega1 sites on BDZ1 receptors

• How do the -zazoles affect sleep?

  • Reduce sleep latency

  • Fewer awakenings

  • 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

  • How does light influence melatonin production?

    Light inhibits melatonin synthesis by stimulating GABAA receptors in the PVN

    • Describe the interaction between the SCN and the VLPO

      • Light -> Retina -> SCN

      • The SCN feeds the subparaventricular zone...

    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 ...

    How are the -azepams metabolized?

    • Dealkylation by CYP2C19
      

      • Produces ...

    Where do benzodiazepines bind to the GABAA recpetor?

    Junction of the alpha and gamma subunits

    This is called either BDZ1 or BDZ2, depending ...

    What is the difference between a sedativve and a hypnotic?

    • Sedative
      

      • Reduces the excitatory response -> calmness

    How does diphenhydramine/other antihistamines affect sleep?

    • Decrease sleep latency

    • Decrease # of awakenings

    • What are the therapeutic uses of ramelteon?

      Treat sleep-onset insomnia

      Will not reduce number of awakenings

      Describe the melatonin prduction pathway

      How is it influenced by light?

      • Paraventricular nucleus (PVN) of the hypothalamus sends axons to the spinal cord

      • How does alcohol affect sleep?

        • Some normalization of sleep

        • Suppression of REM sleep in the fi...

      What are the drugs of choice for sleep?

      -zazoles

      zaleplon, zolpidem, eszopiclone

      They bind to ...

      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 ...

      What is the mechanism of action of suvorexant?

      What is it used for?

      Suvorexant is an orexin receptor antagonist

      • Orexins are wakefulness neuropeptid...

      List some of the clinical uses of benzodiazepines

      • nxiety/aggression

      • Severe anxiety w/panic

      • Which benzodiazepines do not produce active metabolites when they are metabolized?

        The LOTs

        Lorazepam, oxazepam, temazepam

        They are glucu...

      View all 33 terms

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      Psychotherapy: 90b - Sedatives and Hypotonics

      Term	Definition
      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	nxiety/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