90. Sedatives, Hypnotics

Question 1

What is the primary target for many sedatives and hypnotics?

How do benzos, general anesthetics, and barbituates act on this target?

Answer 1

GABA-a receptor: ligand-gated Cl- channel AGONISTS (GABA binds b/w a + b subunits)

Benzo: bind b/w a+g subunits to increase frequency of channel openings - enhance GABA effect, requires them to be open first

Gen Anesthetics: increase duration of openings; higher doses can open channel w/o GABA

Barbituates: increase duration of openings; higher doses can open channel w/o GABA

(antagonists are convulsants)

Question 2

Why do some GABA receptor agonists lead to death and others have a ceiling effect/saturate?

Answer 2

Barbituates: more dose = more effect = death
Benzos: more dose = saturate (b/c channels only increase freq of opening - reach max rate of opening/closing) - reduced risk of death by OD

Question 3

What Benzos are used to treat different diseases?

Answer 3

1. Gold standard tx of EtOH withdrawal (all)
2. Anxiety/Depression: Diazepam (acts in limbic system)
3. Severe Anxiety/Panic: Clonazepam/Alprazolam (target limbic)
4. Insomnia: Clonazepam (also tx REM sleep behavior disorder!)
5. Sedation/Amnesia for procedures: Midazolam
6. Anticonvulsants: Diazepam, Lorazepam, Clonazepam
7. Muscle Spasms form SC interneurons: Diazepam or Clonazepam

Question 4

What are the major side effects of Benzos (4)?

Answer 4

1. Anterograde Amnesia (all)
2. Panic Attacks once they wear off (Alprazolam)
3. Tolerance (need to increase dose)
4. Withdrawal (anxiety, agitation, cramps/myoclonus, sleep problems, dizziness) severe high doses: seizures/delirium

Question 5

How are benzo’s metabolized? How does their metabolism affect different patient groups?

Answer 5

Most: Phase I CYP3A4 hydroxylation (CYP2C19 helps for -azePAMs); Phase II Glucuronidation

LOT drugs: no CYPs needed, only glucuronidation - makes them good for elderly or asians (high rate of mutant cyp2c19 allele)
Lorazepam, Oxazepam, Temazepan

Question 6

Flumazenil
Flunitrazepam
-mechanism

what drugs are used for sleep aides? What is their mechanism?

Answer 6

Flumazenil - reverse benzo ODs (benzo-binding site antagonist) - may cause seizures by blocking benzo

Flunitrazepam - Roofies, high affinity for benzo site, drug of abuse

ZAZOLES: Zaleplon, Zolpidem, Eszopiclone (selective for w1 sites - tx sleep/insomnia)

Question 7

How does EtOH interact with benzos?

What drug is preferred for EtOH withdrawal tx?

Answer 7

EtOH: increases GABA receptor currents after acute exposure = SYNERGY with Benzos (and increased absorption rate) = too much sedation/fatal OD

Use benzos to tx EtOH withdrawal: anxiety, tremors, seizures (DIAZEPAM, or a LOT drug)

Question 8

What are the differences between benzos and ZAZOLES in terms of sleep?

Answer 8

Benzos: decrease latency, improve sleep duration, but decrease slow-wave/REM sleep!

ZAZOLES: CAN NORMALIZE SLEEP (no change to slow-wave/REM); dependent on CYP3A4 metabolism, SE: sleep-related eating/driving/amnesia, date-rape drug

Question 9

How do the following drugs tx insomnia?

• Scopolamine
• Sedating Antihistamines
• Ethanol
• Ramelteon
• Tasimelteon
• Suvorexant

Answer 9

Scopolamine, Antihistamines, EtOH cause antimuscarinic effects: easier to fall asleep, stay asleep, but LESS REM sleep

Ramelteon: MT agonist (MT1 > MT2); MT1 inhibits SCN to induce sleep (membrane delimited K+ channel hyperpolarization), no abuse potential, CYP1A2 metabolism, SE: dizziness, fatigue, endocrine disorders (high prolactin)

Tasimelteon: MT agonist (MT2 > MT1); tx non-24hr sleep wake disorder (esp blind); EXPENSIVE

Suvorexant: Orexin Antagonist; increases sleep duration/maintenance; CYP3A4 metabolism, SE: long half-life - daytime sedation, sleep-eating