Lecture 51: Sedatives, Hypnotics, Anxiolytics, and Alcohol Flashcards by Claire Mann

Anxiolytic

Reduce anxiety, cause calm

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Sedative

Induce sedation by reducing irritability/excitement; calming

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Hypnotic

Induce sleep or unconsciousness

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Benzodiazepines are considered safe why?

Flatter dose-response curve (less likely to cause fatal overdose)

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Why are barbituates dangerous?

Dose as low as 10x hypnotic dose may be fatal if not discovered in time due to resp/cardio depression

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All sedative hypnotics interact with what receptor? What does this receptor do?

GABAa; chloride ion channel

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Sedative-hypnotic withdrawal includes…

Arousal/excitability: anxiety, agitation, tachycardia, seizure

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Barbituates we need to know (3) and their length of action

Phenobarbital** (long acting), secobarbital* and butalbital (intermediate acting)

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Barbituates are now primarily prescribed for what? Which drug in particular?

Epilepsy (phenobarbital)

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What can butalbital be used for?

Combination headaches

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What are the mild adverse effects of barbituates? How about the severe ones?

Mild sedation, dizziness, impaired coordination –> coma, hypotension, cardio/respiratory failure

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Absolute barbituate contraindication

Porphyria (barbituates induce ALA synthase in heme pathway)

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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

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Important point about barbituate metabolism

CYP450 inducer (many drug interactions)

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Short-acting (

Midazolam* (Versed)

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Medium-acting (8-16 hours) benzo we need to know (2)

Alprazolam* (Xanax), lorazepam*

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Long-acting (>16 hour) benzo we need to know (3)

Clonazepam* (Klonopin), Diazepam** (Valium), Chlordiazepoxide*

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Describe the mechanism of benzos

Binds directly to GABAa receptor and increase potency of endogenous GABA signaling by increasing frequency of Cl- channel openings

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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

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Benzos are prescribed for…(5)

Anxiety, epilepsy, alcohol withdrawal, muscle relaxant, anesthesia induction

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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)

1. 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

1. 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