Block 2: Sedative-Hypnotics

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Gastric ulcer MI: Disease related anxiety
Treat the disease
Short term Rx of sedative-hypnotic
death of family member surgery: Situational anxiety
Short term Rx
generalized anxiety disorder panic disorder: Chronic anxiety
psychotherapy and Rx
sleep apnea: do not use hypnotics- dec arousal response to hypoxia; exacerbate obstructive sleep apnea by reducing muscle tone
circadian rhythm disturbances: hypnotics can help
disease-related insomnia (depression, anxiety, psychosis, chronic heart failure, pain): treat medical condition first
Rx/substance related insomnia (alcohol, SSRIs, anti-Parkinson's, methylxanthines, diuretics): first alter dosing regimen or medication choices
Transient insomnia: Rx for 2-3 days, not more than 2-3 wks --> than taper
chronic insomnia: first change exercise, diet, behavior
some new hypnotics are safe(r)
long term use is problematic/not recommended
Name six classes of sedative hypnotics: 1. barbituates
2. benzodiazepine receptor ligands
3. older sedative-hypnotics
4. serotonergic agents
5. OTC sleep aids
6. GHB/sodium oxybate
Where do barbituates work?: bind barbituate site on GABA-A receptor --> allosteric enhancement of GABA --> inc duration of GABA induced Cl channel opening
Where do barbituates work at higher doses?: directly activate GABA-A receptors
inhibit AMPA receptor
What is the barbituate dose dependent continuum of CNS depression?: sedation -> sleep -> coma -> anesthesia -> death
Barbituates... Do/do not induce phsyiologic sleep? High/low therapeutic index? Do/do not have drug interactions? Do/do not cause abuse and addiction?: Do not
low
significant drug interactions
yes to abuse and addiction
Mechanism of barbituate tolerance?: 1. pharmacokinetic- induces CYP450
2. pharmacodynamic- neurons less sensitive and have cross tolerance to other CNS depressants
What happens with barbituate withdrawal?: 1-2 nights rebound insomnia --> life threatening CNS excitation --> seizures --> coma --> death
When do you use long acting barbituates?: daytime, antiseizure
When do you use intermediate acting barbituates?: hypnotic, preoperative sedative, emergency management of seizures
When do you use short acting barbituates?: induction or maintenance of anesthesia
mephobarbital: long acting barbituate
10-70 hrs
phenobarbital: long acting barbituate
80-120 hrs
also used for hypnosedative withdrawal
amobarbital: intermediate acting barbituate
10-40 hrs
secobarbital: intermediate acting barbituate
15-40 hrs
pentobarbital: intermediate acting barbituate
15-50 hrs
thiopental: short acting barbituate
8-10 hrs
methohexital: short acting barbituate
3-5 hrs
Are barbituates used as anxiolytics?: no
still used as hypnotics and antiseizure agents in limited settings
How are barbituates metabolized?: metabolism/conjugation in liver --> renal excretion

short acting- highly lipophyllic--> terminated by redistribution from CNS into muscle and fat
When are older sedative-hypnotics used?: rarely, but still in some institutionalized patients
Which older sedative-hypnotic is similar to benzodiazepines (with greater abuse) instead of barbituates: meprobamate
How do they work?: bind benzodiazepine site on GABA-A receptor --> allosteric enhancement of GABA --> inc FREQUENCY of cl channel openings
chloral hydrate: older sedative-hypnotic
ethchlorvynol: older sedative-hypnotic
paraldehyde: older sedative-hypnotic
methyprylon: older sedative-hypnotic
ethinamate: older sedative-hypnotic
glutethimide: older sedative-hypnotic
meprobamate (mep-ro-ba'-mate): older sedative-hypnotic
Name two serotonergic agents: buspirone (byoo-SPY-rone)- partial 5-HT1A agonist
and
SSRIs
Name three uses of serotonergic agents?: 1. anxiety
2. depression
3. many other psych ds
3 advantages of serotonergic agents over benzodiazepines: safer
less psychomotor impairement
less abuse potential
4 disadvantages of buspirone: weak anxiolytic
dizziness
headache
nausea
4 disadvantages of SSRIs: slow onset
non-responders to anxiolytic effects
sexual dysfunction
sleep disturbances
Name 3 OTC sleep aids: antihistamines
melatonin
valerian
What's wrong with antihistamines as sleep aids: rapid tolerance
inadequate dosages
pradoxical stimulation
residual daytime sedation
Where is melatonin made?: pineal gland, controlled by light
What does melatonin do?: lightens skin pigment
suppresses ovarian function
sold to reduce jet lag/promote sleep
What exactly is valerian: dietary supplement from valerian plant- used forever to treat sleep disorders but no convincing clinical data
doxylamine: antihistamine
diphenhydramine: antihistamine
pyrilamine: antihistamine
Mechanism of action of GHB/sodium oxybate: metabolite of GABA --> CNS depressants
Why is GHB a schedule I controlled substance?: addictive, abused for euphoric/hallucinogenic properties, now more popular than rohypnol as a date rape drug
When is sodium oxybate a schedule III controlled substance?: when it is used as prescribed for tx of cataplexy in patients with narcolepsy
Adverse effects of GHB/sodium oxybate when abused?: amnesia
vomiting
respiratory and cardiovascular depression
LOC
seizures
death
Adverse effects of GHB/sodium oxybate when used as prescribed?: confusion
headacthe
nausea
vomiting
dizziness
urinary incontinence
When are spasmolytics used?: tx sk mm spasms from MS, ALS, spinal cord transection, CP, stroke or local muscle trauma
Which two benzodiazepines are spasmolytic? What is their adverse effect?: diazepam
clonazepam

sedation
Baclofen: spasmolytic
baclofen mechanism of action: GABA-B agonist
- inc K perm, dec Ca influx --> dec transmitter release
tizanidine: spasmolytic
tizanidine mechanism of action: central alpha-2 adrenergic agonist
inc pre and post-synaptic inhibition of motor neurons
dantrolene: spasmolytic
dantrolene mechanism of action: direct action of sk mm --> dec Ca release from sarcoplasmic reticulum --> inhibits excitation/contraction coupling
other uses for dantrolene: malignant hyperthermia
Name four reasons why benzodiazepines positive modulators have replaced barbituates and older agents as sedative hypnotics?: 1. higher Therapeutic index
2. lower toxicity w/ overdose
3. fewer sleep pattern alterations
4. dec. tolerance and abuse
Do benzodiazepine positive modulators work in the absence of GABA?: no
Are benzodiazepine positive modulators general CNS depressants?: no
continuum is sedation --> sleep
Why should patients on benzodiazepine modulators not take alcohol>: even though respiratory and CV function depression is rare with overdose, depressant actions are additive with other CNS depressants
alprazolam (xanax): benzodiazepine for anxiety (short acting)
chlordiazepoxide: benzodiazepine for anxiety, alcohol withdrawal, preanesthetic
(short acting)
clonazepam: benzodiazepine for seizures, mania, movement disorders
(intermediate)
clorazepate: benzodiazepine for anxiety and seizures
(very short)
PRODRUG
diazepam (valium): benzodiazepine for anxiety, status epilepticus, muscle relaxant, preanesthetic
(long)
estazolam: benzodiazepine for insomnia
(short)
flurazepam: benzodiazepine for insomnia
(very long)
lorazepam: benzodiazepine for anxiety, status epilepticus, preanesthetic
midazolam: benzodiazepine for preanesthetic and intraoperative medication
oxazepam: benzodiazepine for anxiety
(short)
quazepam: benzodiazepine for insomnia
(long)
temazapam: benzodiazepine for insomnia
(short)
triazolam: benzodiazepine for insomnia
(short)
Common benzodiazepine drug interaction?: Cyp450 3A4 inhibitors
What is the metabolism of benzodiazepines: first go to high perfusion areas (bain) than to lower areas (mm, fat)
--> metabolized in liver to other active metabolites
adverse effects of benzodiazepines: 1. alters sleep patterns
2. impaired mental/motor function, ataxia, daytime sedation, anterograde amnesia, additive with other CNS depressants
3. Abrupt withrdawal can cause anxiety, nausea, seizures
4. Abuse- flunitrazepam as date rape drug
advantages of non-benzodiazepine modulators?: no anxiolytic, mm relaxant, antiseizure properties, no rebound insomnia or other withdrawal sx
(Blind to BZ)
zolpidem (ambien): non-benzodiazepine modulator
for use as hypnotic, maintain nl sleep patterns
zaleplon (sonata): non-benzodiazepine modulator
for use as hypnotic, maintain nl sleep patterns
adverse effects of non-benzodiazepine modulators?: abuse potential like benzodiazepines
morning sedation w/ late night use of zolpidem
flumazenil: competitive benzodiazepine site antagonist for decreasede recovery time from benzodiazepine modulators
flumazenil fast or slow acting? fast or slow metabolism?: rapid onset, short half life
Adverse effects of flumazenil: agitation, confusion, dizziness, nausea
inc risk of seizures/other withdrawal sx in patients with benzodiazepine tolerance or barbituate, tricyclic antidepressant overdose

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