Lec 47 Sedative Hypnotics Anxiolytics Alcohol Flashcards
What is an anxiolytic?
reduces anxiety, causes calm
What is a sedative?
induces sedation, has calming effect
What is a hypnotic?
induces sleep or unconsciouness
What are general effects of sedative hypnotics?
- anti-anxiety/calming
- sedation
- anterograde amnesia
- sleep
- anesthesia
- anticonvulsant
- muscle relaxation
- respiratory drive depression
What are possible toxicities of sedative hypnotic?
- frequently overdose
- dose-related CNS depression
- ingestion rarely fatal in benzos
- resp and cardio depression
- additive effects with other CNS depressants
Are benzos or barbiturates safer?
benzos because flatter dose response curve, harder to
- taking 10x your prescribed barbiturate dose –> can be fatal
What is struct of GABA-A receptors?
- 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
Where do benzos and newer hypnotics bind on GABA-A?
bind at site between alpha and gamma
when they are there –> more GABA can bind, more than usual hyperpolarization
Are benzos, barbiturates, newer drugs selective for specific isoforms of GABA-A?
benzos and barbs are not
newer isoforms are –> why they may have fewer side effects and harder to overdose
What is role of a1 subunit?
- mediates sedation, amnesia, ataxia
What is role of a2 and a3 subunits?
- muscle relaxing, anxiolytic
What is role of a5 subunit?
memory impairment
What are symptoms of sedative-hypnotic withdrawal?
anxiety/agitation restlessness insomnia tremor CNS excitability tachycardia, HT
abrupt cessation can be lethal
What are 2 intermediate acting barbiturates?
secobarbital, butalbital
What is one long acting barbiturate?
phenobarbital
Are barbiturates absorbed quickly or slowly?
rapidly absorbed/distrubuted , they are lipophilic
How are barbiturates metabolized/eliminated? half life?
metabolized: slowly into alcohols –> over time cause induction cyt p450 enzyme
eliminated: renal
half life = ~4-5 days
What is clinical use of barbiturates?
- epilepys [phenobarb]
- anesthesia induction
- physician assisted suicide
- lethal injection
- combo headache remedies [butalbital]
- induction agent for shock therapy for depression
What are adverse effects of barbiturates? severe?
- mild sedation, dizziness, impaired coordination, slurred speech, nystagmus, confusion, ataxia
severe: coma, HT, hypothermia, resp failure
exam: small pupils, diminished reflexes
Why aren’t barbiturates used anymore a lot?
- tolerance to hypnotic effects
- induction of CYP450 = drug interactions
- low margin of safety
- addiction
- no antidote
- effects on CV/autonomic
What is difference benzos vs barbiturates at GABA-A?
benzos –> increased frequency of Cl channel opening
barbs –> increase duration of Cl channel opening, less selective so can also depress glutamate receptor
What is clinical use of benzos?
- panic/anxiety
- insomnia (short term)
- epilepsy (acute status epilepticus)
- alcohol withdrawal
- muscle relaxation
- anesthesia
- acute agitation/psych
- parasomnias
- mania, catatonia
What is clinical use of midazolam?
induction agent of anesthesia
What is clinical use of clonazepam?
parasomnias
How are benzos metabolized/excreted?
hepatic metabolism
– usually phase 1 oxidation with CYP3A4 then phase 2 conjugation
renal excretion
3 benzos that do not undergo phase 1 metabolism? importance?
lorazema
oxazepam
temazepam
much safer to use with liver disease
How are half lives of benzos changed in older pts? pts with liver disease?
longer half life with older pts and with liver disease
Do drugs that have phase 1 metabolism have shorter or longer half life?
very long half life! > 40 hrs
What is the half life of alprazolam?
very short!
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
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
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
What are exam findings of barbituate tox [pupils; reflexes]?
- small pupils
- diminished reflexes
Which benzos are safe in liver disease?
- the ones that don’t undergo phase 1 metabolism in liver
- oxazepam, lorazepam, temazepam
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
How do you treat barb overdose? benzo overdose?
barb = supportive, no antidote benzo = treat with flumazenil
What is mech of action flumazenil?
competitive antagonist at GABA benzodiazepine receptor
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
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
Why are newer hypnotics in theory better than benzos/barbs for sleep?
- newer hypnotics do not decrease slow wave sleep which is important
What is function of ramalteon?
pt having difficulty falling asleep
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
What other types of drugs besides sedative/hypnotics can be used to manage insomnia/anxiety?
- antidepressants
- antihistamines
- atypical antipsychotics
- antiepileptics
When is peak BAC after drinking alcohol if fasting?
within 30 min
How much alcohol can typical adult metabolize per hour?
7-10 g = 1 drink
What are kinetics of ethanol elimination?
zero order kinetics = independent of time and concentration of drug
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
What is disulfram?
- inhibits aldehyde dehydrogenase [oxidation acetaldehyde to acetate]
- causes there to be accumulation of acetaldehyde = unpleasant facial flushing, N/V, dizziness, headache
At what BAC do you have coma/death? blackout?
blackout = 0.15 death = 0.4
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
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
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
What is wernicke-korsakoff?
- due to alcoholism
- paralysis external eye muscles, ataxia
- confused state
- associated with thiamine deficiency
- diabling memory disorder
What is fetal alcohol system? features?
- ethanol crosses placenta to fetus
- fetal liver has no alcohol dehydrogenase
- intrauterine growth retardation, microcephaly, poor coordination
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
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
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
What 3 FDA approved drugs for treatment of alcohol dependence?
- naltrexone
- acamprosate
- disulfiram
What is mech of naltrexone?
long acting opioid antagonist
Who should you avoid giving naltrexone to?
pts on opioids or disulfiram
pts with liver disease
What is mech of acamprosate?
weak NMDA-receptor antagonist and GABA-A receptor agonist
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
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
What are signs of methanol poisoning?
- look inebriated; visual disturbance; anion gap metabolic acidosis
How do you treat methanol poisoning?
- alkalinization [bicarb] to coutneract metabolic acidosis
- give alcohol or fomepizole to compete with methanol
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
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
