Psychotherapy: 90b - Sedatives and Hypotonics

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

-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)

• Phase I: CYP3A4

• Phase II: Glucuronidation

-zazoles

• They increase sleep quantity AND normalize sleep architecture (including slow wave and REM sleep)
  

  • vs. benzos, which suppress slow wave and REM sleep

the LOTs

• Lorazepam

• Oxazepam

• Temazepam

These are pre-lubed and can go directly to glucuronidation; no active metabolites are produced

One of the LOTs (Lorazepam, Oxazepam)

Metabolites will not accumulate

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?

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

• -azepam: Diazepine ring with 2 benzenes

• -azolam: has extra 5-membered ring

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)

GABAA receptors

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

Benzodiazepine receptor

Bind to omega1 sites on BDZ1 receptors

• These only exist when gamma subunits are next to alpha1 subunits

• 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!

Life-threatening synergy ->

Respiratory and cardiac depression

• Decrease sleep latency

• Decrease # of awakening

• Increase slow wave sleep

• Decrease REM sleep

Same as diphenhydramine

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

• 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:

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

• 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

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

• 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)

• Decrease sleep latency

• Decrease # of awakenings

• Increase slow wave sleep

• Decrease REM sleep

Same as scopolamine

Treat sleep-onset insomnia

Will not reduce number of awakenings

Not good for non-24h sleep/wake disorder (use tasimelteon for this)

• 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

• 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

-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

Flumazenil

CYP1A2

Non 24h sleep-wake disorder

but v expensive :(

Ramelteon has affinity for MT1 receptors

Tasimeltion has affinity for MT2 receptors

Melatonin has affinity for Both

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

• 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

The LOTs

Lorazepam, oxazepam, temazepam

They are glucuronidated directly = no active metabolites