CNS Depressants: Sedatives-Hypnotics/Anxiolytics

Question 1

alprazolam (Xanax) 
clorazepate (Tranxene)
diazepam (Valium)
flurazepam (dalmane)
lorazepam (Ativan)
midazolam (Versed)
oxazepam (Serax)
temazepam (Restoril)
triazolam (Halcion)
flunitrazepam (Rohypnol

Answer 1

Benzodiazepines

MOA:
1) potentiate GABA effects at GABAa receptor
increase frequency of Cl- channel opening–>hyperpolarization–>neuronal inhibition
2)bind multiple selective binding sites
alpha 1- sedation, amnesia, ataxic effect
alpha 2 & 3- anxiolytic and muscle-relaxing action

Use: acute anxiety state and rapid control of panic attacks
anxiolytic, sedative/hypnotic, conscious/preop sedation, antispasmodic, acute alcohol withdrawal, depression, bipolar depression, seizures

Pharmokinetics:
absorbed: in GI
metabolized: hepatic via P450s
influence of age: advanced age, decreased lean body mass–>increased volume distribution
drug interactions: additive CNS depression with other depressant drugs (lethal respiratory depression)

Adverse effects: drowsiness, sedation, ataxia, dizziness, headache, nausea, respiratory depression, anterograde amnesia, tolerance, dependence, withdrawal

Contraindications: pregnancy, elderly, pts susceptible to substance abuse, when alertness needed

Flunitrazepam= date rape drug

Question 2

flumazenil (Romazicon)

Answer 2

Benzodiazepine antagonist

MOA: competitive antagonist to benzodiazepine receptor

Use: terminate benzodiazepine induced sedation

Metabolism: IV administration, hepatic metabolism, short duration of action

Effects: CNS arousal, anxiogenic, withdrawal if dependent on benzos, seizures if using barbituate, TCA, or ethanol

Question 3

eszopiclone (Lunesta)
zolpidem (Ambien)
zaleplon (Sonata)

Answer 3

Benzodiazepine related (the Z-drugs)- newer hypnotics

MOA: Bind to GABAa receptor more selectively that benzos (interact with receptors containing alpha 1)
potentiate GABA effects at GABAa receptor
increase frequency of Cl- channel opening–>hyperpolarization–>neuronal inhibition
bind alpha 1- sedation, amnesia, ataxic effect

Use: manage insomnia (difficulty falling asleep)

Metabolism: oral admin, metabolized in liver to inactive form via P450 (short half-life)

Drug interaction: additive CNS depression with EtOH

Adverse effects: extension of CNS depressant effects, dependence

Question 4

Pentobarbital
Phenobarbital
Thiopental

Answer 4

Barbiturates

MOA: bind GABAa receptors to increase duration of GABA-gated Cl- channel opening
Enhance membrane hyperpolarization and neuronal inhibition
Less selective, high conc. may be GABA mimetic, bind AMPA receptors–>inhibit excitatory neurotransmission

Use: anesthesia, sedative/hypnotic–>insomnia, anticonvulsant, medically induced coma

Metabolism: slow hepatic metabolism via P450, excreted as glucuronide conjugates in urine (half life 18-48 hrs but wide varying range)

Drug interactions: extension of CNS depressant, dependence, additive CNS depression with alcohol, induction of hepatic drug-metabolism enzymes, similar to benzos

Question 5

ramelteon (Rozerem)

Answer 5

Melatonin receptor agonist

MOA: agonist to MT1 and MT1 melatonin receptors
Receptors in suprachiasmatic nuclei of brain
No effects on GABAergic system
Receptors in regulation of circadian rhythm

Use: management of insomnia (difficulty falling asleep), rapid onset with min rebound or withdrawal

Metabolism: oral admin, first-pass metabolism forming active metabolite (long half life)

Drug interaction: NOT combined with CYP1A2 or CYP2C9 inhibitors, or pts with liver dysfunction

Adverse effects: dizziness, somnolence, fatigue, decrease in testosterone, increase in prolactin, NO depedence

Question 6

buspirone (BuSpar)

Answer 6

5-HT receptor agonist (non-sedating anxiolytic)

MOA: partial agonist at 5-HT1a receptors
Increase K+ conductance–>hyperpolarize membrane–>inhibit Ca2+ channels–>reducing release of 5-HT–>decrease neuronal firing

Use: selective for anxiety without causing marked sedative, hypnotic, and euphoric effects

Metabolism: oral admin, first-pass metabolism via hydroxylation and dealkylation forming active metabolites

Drug interactions: does NOT potentiate effects, BP may rise in pts using MAOIs

Adverse effects: nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, GI distress, NO abuse

Question 7

propranolol

Answer 7

Beta blocker (1st generation)

MOA: beta 1=beta 2
NOT anxiolytic, diminishes somatic manifestations

Question 8

hydroxyzine (Vistaril)

diphenhyrdarmine (Benadryl)

Answer 8

Antihistamine

MOA: anxiolytic via sedative action

Use: mild sedative/relaxant for procedures

OTC drug

Question 9

ethanol
chloral hydrate (Noctec)

Answer 9

Alcohols

MOA: anxiolytic via sedative action