Lec 47 Sedative Hypnotics Anxiolytics Alcohol Flashcards
1
Q
What is an anxiolytic?
A
reduces anxiety, causes calm
2
Q
What is a sedative?
A
induces sedation, has calming effect
3
Q
What is a hypnotic?
A
induces sleep or unconsciouness
4
Q
What are general effects of sedative hypnotics?
A
- anti-anxiety/calming
- sedation
- anterograde amnesia
- sleep
- anesthesia
- anticonvulsant
- muscle relaxation
- respiratory drive depression
5
Q
What are possible toxicities of sedative hypnotic?
A
- frequently overdose
- dose-related CNS depression
- ingestion rarely fatal in benzos
- resp and cardio depression
- additive effects with other CNS depressants
6
Q
Are benzos or barbiturates safer?
A
benzos because flatter dose response curve, harder to
- taking 10x your prescribed barbiturate dose –> can be fatal
7
Q
What is struct of GABA-A receptors?
A
- 2 alpha
- 2 beta
- 1 gamma
- many different permutations of GABA-A receptors b/c different forms of each subunit
- Cl ion gated channel
- GABA binds between the alpha and Beta subunits
8
Q
Where do benzos and newer hypnotics bind on GABA-A?
A
bind at site between alpha and gamma
when they are there –> more GABA can bind, more than usual hyperpolarization
9
Q
Are benzos, barbiturates, newer drugs selective for specific isoforms of GABA-A?
A
benzos and barbs are not
newer isoforms are –> why they may have fewer side effects and harder to overdose
10
Q
What is role of a1 subunit?
A
- mediates sedation, amnesia, ataxia
11
Q
What is role of a2 and a3 subunits?
A
- muscle relaxing, anxiolytic
12
Q
What is role of a5 subunit?
A
memory impairment
13
Q
What are symptoms of sedative-hypnotic withdrawal?
A
anxiety/agitation restlessness insomnia tremor CNS excitability tachycardia, HT
abrupt cessation can be lethal
14
Q
What are 2 intermediate acting barbiturates?
A
secobarbital, butalbital
15
Q
What is one long acting barbiturate?
A
phenobarbital
16
Q
Are barbiturates absorbed quickly or slowly?
A
rapidly absorbed/distrubuted , they are lipophilic
17
Q
How are barbiturates metabolized/eliminated? half life?
A
metabolized: slowly into alcohols –> over time cause induction cyt p450 enzyme
eliminated: renal
half life = ~4-5 days
18
Q
What is clinical use of barbiturates?
A
- epilepys [phenobarb]
- anesthesia induction
- physician assisted suicide
- lethal injection
- combo headache remedies [butalbital]
- induction agent for shock therapy for depression
19
Q
What are adverse effects of barbiturates? severe?
A
- mild sedation, dizziness, impaired coordination, slurred speech, nystagmus, confusion, ataxia
severe: coma, HT, hypothermia, resp failure
exam: small pupils, diminished reflexes
20
Q
Why aren’t barbiturates used anymore a lot?
A
- tolerance to hypnotic effects
- induction of CYP450 = drug interactions
- low margin of safety
- addiction
- no antidote
- effects on CV/autonomic
21
Q
What is difference benzos vs barbiturates at GABA-A?
A
benzos –> increased frequency of Cl channel opening
barbs –> increase duration of Cl channel opening, less selective so can also depress glutamate receptor
22
Q
What is clinical use of benzos?
A
- panic/anxiety
- insomnia (short term)
- epilepsy (acute status epilepticus)
- alcohol withdrawal
- muscle relaxation
- anesthesia
- acute agitation/psych
- parasomnias
- mania, catatonia
23
Q
What is clinical use of midazolam?
A
induction agent of anesthesia
24
Q
What is clinical use of clonazepam?
A
parasomnias
25
How are benzos metabolized/excreted?
hepatic metabolism
-- usually phase 1 oxidation with CYP3A4 then phase 2 conjugation
renal excretion
26
3 benzos that do not undergo phase 1 metabolism? importance?
lorazema
oxazepam
temazepam
much safer to use with liver disease
27
How are half lives of benzos changed in older pts? pts with liver disease?
longer half life with older pts and with liver disease
28
Do drugs that have phase 1 metabolism have shorter or longer half life?
very long half life! > 40 hrs
29
What is the half life of alprazolam?
very short!
30
Categorize as short, intermediate, or long: Midazolam, alprazolam, diazepam, lorazepam, clonazepam
```
diazepam = very long
clonazepam = intermediate-long
lorazepam = intermediate
alprazolam = intermediate
midazolam = short but IV
```
31
What are adverse effects of benzos?
- drowsiness
- disinhibition
- confusion
- anterograde amnesia
- impaired motor skils
- resp/cardio depression
- dependence/abuse
- additive CNS depression with other drugs
- life threatening withdrawal
32
What is difference between benzo and z drugs in binding of GABA-A?
Z drugs = more selective, only bind isoforms of GABA-A that contain alpha 1 subunits
33
What are exam findings of barbituate tox [pupils; reflexes]?
- small pupils
| - diminished reflexes
34
Which benzos are safe in liver disease?
- the ones that don't undergo phase 1 metabolism in liver
| - oxazepam, lorazepam, temazepam
35
What are advantages of benzos?
- minimal CV and autonomic effects
- low risk of drug interactions
- availability flumazenil for treatment overdose
- high therapeutic index
- rapid onset
36
How do you treat barb overdose? benzo overdose?
```
barb = supportive, no antidote
benzo = treat with flumazenil
```
37
What is mech of action flumazenil?
competitive antagonist at GABA benzodiazepine receptor
38
What is effect of benzos and barbs on sleep [on onset, stage 2, REM, stage 4]?
- decreased latency sleep onset
- increased duration stage 2 sleep
- decreased duration REM sleep
- decreased duration stage 4 slow wave sleep
39
What is effect of zolpidem on sleep [on onset, stage 2, REM, stage 4]?
- decreased latency sleep onset
- decreased duration REM sleep
- minimal effect stage 4 slow wave sleep
40
Why are newer hypnotics in theory better than benzos/barbs for sleep?
- newer hypnotics do not decrease slow wave sleep which is important
41
What is function of ramalteon?
pt having difficulty falling asleep
42
Which are safe in pregnancy: Buspirone, barbs, non-benzo hypnotics, benzos
```
buspirone = category B
non-benzos = category C = not a lot of data
```
others are category D = more dangerous
all cross placental barrier
even though benzos = category D/X use in pregnancy b/c untreated anxiety disorder might be more damaging to pregnant woman/fetus
all can cause newborn to be dependent
43
What other types of drugs besides sedative/hypnotics can be used to manage insomnia/anxiety?
- antidepressants
- antihistamines
- atypical antipsychotics
- antiepileptics
44
When is peak BAC after drinking alcohol if fasting?
within 30 min
45
How much alcohol can typical adult metabolize per hour?
7-10 g = 1 drink
46
What are kinetics of ethanol elimination?
zero order kinetics = independent of time and concentration of drug
47
What are two paths of alcohol metabolism to acetaldehyde? final step of metabolism from acetaldehyde?
- via alcohol dehydrogenase = primary path
- via MEOS [microsomal ethanol-oxidizing system]
from acetaldehyde --> acetate by aldehyde dehydrogenase
48
What is disulfram?
- inhibits aldehyde dehydrogenase [oxidation acetaldehyde to acetate]
- causes there to be accumulation of acetaldehyde = unpleasant facial flushing, N/V, dizziness, headache
49
At what BAC do you have coma/death? blackout?
```
blackout = 0.15
death = 0.4
```
50
What is the most common complication of alcohol abuse?
- liver disease
| - --> alcoholic fatty liver = reversible but may progress to alcoholic hepatitis and cirrhosis/liver failure
51
How does chronic alcohol use affect the CV system?
- dilated cardiomopathy = right ventricle really big and doesn't pump well
- heart failure
- arrhythmias
- HT
- coronary artery disease
52
How does chronic alcohol use affect CNS?
- upregulation NMDA glut receptors + voltage-sensitive Ca channels --> seizures
- increases DA release
- peripheral nerve injury
- cerebellar tox
- wernicke-korsakoff syndrome
53
What is wernicke-korsakoff?
- due to alcoholism
- paralysis external eye muscles, ataxia
- confused state
- associated with thiamine deficiency
- diabling memory disorder
54
What is fetal alcohol system? features?
- ethanol crosses placenta to fetus
- fetal liver has no alcohol dehydrogenase
- intrauterine growth retardation, microcephaly, poor coordination
55
What are alcohol-drug interactions?
PK: chronic alcohol use --> induction hepatic cyt p450
- get increased risk hepatotoxicity w/ drugs that are metabolized by P450s [ex. acetaminophen]
- can increase level of tricyclic antidepressants, sedative-hypnotics
- additive CNS depression when alcohol combined with sedative hypnotics
56
What is goal of acute alcohol intoxication treatment?
- give thiamine to protect wernicke-korsakoff
- IVF with electrolytes if dehydrated + vomiting
- correct electrolyte imbalance
- treat hypoglycemia w/ glucose
prevent resp depression, prevent aspiration of vomit, support CV system
57
How do you manage alcohol withdrawal?
want to prevent seizures, delirium, arrhythmias
- substitute long-acting sedative hypnotic for alcohol [usually benzo --> diazepam if good hepatic function; lorazepam if not]
- taper dose of long acting drug
- give thiamine
- restore electrolytes
58
What 3 FDA approved drugs for treatment of alcohol dependence?
- naltrexone
- acamprosate
- disulfiram
59
What is mech of naltrexone?
long acting opioid antagonist
60
Who should you avoid giving naltrexone to?
pts on opioids or disulfiram
| pts with liver disease
61
What is mech of acamprosate?
weak NMDA-receptor antagonist and GABA-A receptor agonist
62
What are upsides and downsides to acamprosate?
upsides: no drug-drug interaction; safer for pt with liver disease
downsides: avoid in renal disease; poor absorption; need to give many pills / day
63
What is mech of methanol?
- found in commercial solvents
- absorbed through skin, resp, or GI
- slow ox to toxic metabolites --> 6-30 hrs before toxic
64
What are signs of methanol poisoning?
- look inebriated; visual disturbance; anion gap metabolic acidosis
65
How do you treat methanol poisoning?
- alkalinization [bicarb] to coutneract metabolic acidosis
| - give alcohol or fomepizole to compete with methanol
66
What is ethylene glycol? signs of poisoning?
- in antifreeze
- metabolized to toxic aldehyde
- get severe anion gap met acidosis; osmolar gap; oxalate crystals in urine; no visual symptoms
67
How do you distinguish methanol vs ethylene glycol poisoning?
both = osmolar gap; anion gap metabolic acidosis
methanol = visual symptoms
ethylene glycol = oxalate crystal in urine
