Lecture 51: Sedatives, Hypnotics, Anxiolytics, and Alcohol Flashcards
Anxiolytic
Reduce anxiety, cause calm
Sedative
Induce sedation by reducing irritability/excitement; calming
Hypnotic
Induce sleep or unconsciousness
Benzodiazepines are considered safe why?
Flatter dose-response curve (less likely to cause fatal overdose)
Why are barbituates dangerous?
Dose as low as 10x hypnotic dose may be fatal if not discovered in time due to resp/cardio depression
All sedative hypnotics interact with what receptor? What does this receptor do?
GABAa; chloride ion channel
Sedative-hypnotic withdrawal includes…
Arousal/excitability: anxiety, agitation, tachycardia, seizure
Barbituates we need to know (3) and their length of action
Phenobarbital** (long acting), secobarbital* and butalbital (intermediate acting)
Barbituates are now primarily prescribed for what? Which drug in particular?
Epilepsy (phenobarbital)
What can butalbital be used for?
Combination headaches
What are the mild adverse effects of barbituates? How about the severe ones?
Mild sedation, dizziness, impaired coordination –> coma, hypotension, cardio/respiratory failure
Absolute barbituate contraindication
Porphyria (barbituates induce ALA synthase in heme pathway)
This short-acting barbituate (name) is no longer used in the US. What was it used for? What odd use does it have in the US today?
Thiopental; preanesthetic sedative; part of the capital punishment cocktail
Important point about barbituate metabolism
CYP450 inducer (many drug interactions)
Short-acting (
Midazolam* (Versed)
Medium-acting (8-16 hours) benzo we need to know (2)
Alprazolam* (Xanax), lorazepam*
Long-acting (>16 hour) benzo we need to know (3)
Clonazepam* (Klonopin), Diazepam** (Valium), Chlordiazepoxide*
Describe the mechanism of benzos
Binds directly to GABAa receptor and increase potency of endogenous GABA signaling by increasing frequency of Cl- channel openings
Describe the method of action for barbituates
Binds directly to GABAa receptor and increase potency of endogenous GABA signaling by increasing duration of Cl- channel openings
Benzos are prescribed for…(5)
Anxiety, epilepsy, alcohol withdrawal, muscle relaxant, anesthesia induction
Benzo consideration for older patients? Why is this important?
Hepatic metabolism slows with age; greater risk for dangerous SEs (cardio/resp depression)
What “key drug” benzo should be prescribed for patients with liver disease and why?
Lorazepam; no Phase I metabolism so half lives are not increased in patients with hepatic disease.
Where are benzos better than barbituates? (5)
- Rapid onset; 2. Higher therapeutic index; 3. Flumazenil* for overdose; 4. Lower risk of drug interaction; 5. Minimal effects on cardio/ANS functions
SEs of benzos and a notable psych risk
Drowsiness, impaired judgment, decreased motor skills; dependence
Benzo toxicity…(5)
Ataxia, slurred speech, somnolence, diplopia, hallucinations, coma
What is the one non-benzo (new) hypnotic we need to know? Two other drugs in this category?
Zolpidem** (Ambien); Zalepon* and Eszopiclone* (Lunesta)
Describe mechanism of non-benzo hypnotics and relationship to produced effects
Bind to specific GABAa receptor subtype (w/ alpha 1 subunits) so only produces sedation/anxiolytic effects w/out producing muscle relaxant/anticonvulsant effects
What SEs of non-benzo hypnotics led to FDA labeling? (2)
- Next-morning impairment and 2. Abnormal nocturnal behavior
Zolpidem is prescribed for…Why?
Short-term treatment of insomnia; 1-2 weeks leads to tolerance to sleep effects
How does Zolpidem effect sleep?
Decrease latency to sleep, decrease REM but little change on slow-wave sleep
How would you treat a benzo overdose?
With Flumazenil*!
What is the mechanism of Ramelteon* and its clinical use. Advantages?
Melatonin receptor agaonist; insomnia; does not effect sleep architecture w/ minimal risk of abuse
What is the mechanism of Buspirone** and its clinical use. Significant SE?
Partial 5-HT1A agonist; GAD; tachycardia
What is the mechanism of dexmedetomidine* and its clinical use. Advantage/disadvantage
Presynaptic alpha2 agonist –> downregulation of NE; perioperative sedation, analgesia. Advantage: no respiratory depression; disadvantage: caution in patients with heart dysfunction
All sedative-hypnotics cross the what? Discuss the issue.
Placental barrier; complicated to use during pregnancy (may cause defects, dependence), must weight risks vs benefits
Why do women have a higher peak concentration of ethanol? (2)
Lower total body water content and difference in first-pass metabolism
How much of ethanol is oxidized by the liver? What is the rate? Where else is it excreted?
90%; zero-order kinetics (independent of time/drug concentration); kidneys/lungs
Ethanol is oxidized to what by what enzyme? Then to what by what enzyme?
Acetaldehyde, alcohol dehydrogenase; acetate, alcohol dehydrogenase (again)
Where does disulfiram exert its effect? Causes? What else might cause this reaction in a person?
Acetaldehyde –> acetate; flushing, nausea, vomiting, headaches, hypotension; genetic ALDH deficiency
How else is alcohol metabolized? What is the relevance of this?
CYP2E1/CYP450 enzymes; normally only a small amount but increases with chronic alcohol exposure –> induction of metabolism of other drugs (acetaminophen contraindication)
Two main receptor effects of alcohol
Enhances GABAa activity and inhibits NMDA activity
At what BAC does what possibly black out? BAC of Death?
0.15; >0.40
Alcohol does what to myocardial contractility? Smooth muscle?
Depresses; vasodilator
Chronic alcohol increases the risk of death for these reasons (5)
Liver disease, cardiovascular disease, cancer, accidents, and suicide
Course of alcohol liver damage
Fatty liver –> alcoholic hepatitis –> cirrhosis –> liver failure
Effects of alcohol on the cardiovascular system (4)
Dilated cardiomyopathy, arrhythmias, hypertension, coronary artery disease
Four broad categories of chronic alcohol effects on the CNS
- Tolerance/dependence (receptor changes, DA in NA); 2. Neurotoxicity; 3. Wernicke-Korsakoff (ataxia, opthalmoplegia, confusion –> memory disorder); 4. Eye damage
Describe alcohols effects on the blood, endocrine system, immune system, cancer
Blood: impairs hematopoiesis; Endocrine: androgen problems; Immune: inhibits in some places (lung) and increases in other (liver); Cancer: upper GI, liver
What three drugs are approved for treatment of alcohol dependence?
Naltrexone, acomprosate, disulfiram
What two other alcohols cause poisoning? Treatment?
Ethylene glycol (antifreeze) and methanol; IV ethanol or an ALDH inhibitor to prevent toxic aldehydes
