Lecture 1: Sedative Hypnotics and Anti-Anxiety Drugs

Question 1

How do Sedative-Hypnotics and Anxiolytics generally work?

a. What does this cause?

Answer 1

They Bind to a MODULATORY SITE on the GABAa Receptor Complex.

a. Intensifies or Prolongs the Actions of GABA

Question 2

GABAa Receptor Complex

1. When GABA binds to the GABAa Receptor complex, what channels open up?
   a. What does this do?

Answer 2

1. Cl- channels

a. Hyperpolarizes the membrane, DEPRESSING Synaptic Transmission.

Question 3

Sedative Hypnotics act as what?

Answer 3

As DEPRESSANTS of the CNS

Question 4

Barbituates

1. How do they work?
   a. What does this do?
   b. What is another way they could work INDEPENDENT of GABA?

Answer 4

1. Bind to GABAa Receptor
   a. Increases DURATION of GABA action
   b. They could Increase Cl- Influx, causing INHIBITION w/o GABA

Question 5

Barbituates

1. Marked CNS Depressant: What 2 things can they produce?
2. Margin of Safety level?
   a. What are 2 major problems?
   b. What do they DECREASE at HIGH Doses?

Answer 5

1. Hypnosis and Surgical Anesthesia
2. Low
   a. Toxicity and Overdose
   b. Respiratory Drive

Question 6

Barbituates

1. Are they abusive?
   a. Why?
   b. Type of Scheduled drug?

Answer 6

1. Yes
   a. Cause EUPHORIA
   b. 2 or 3

Question 7

Barbituates

1. Effects of CNS depressants are what?
   a. what does this mean?
   b. This is especially true when combined with what?

Answer 7

1. Super-Additive
   a. Depression caused by 2 drugs together is more than what we would predict w/a similar dose of one.

b. ALCOHOL

Question 8

Barbituates: Pharmacokinetics

1. Best way to get them into the body?
   a. How about getting into the CNS?
2. What determines duration and rate of Onset?
3. Metabolized by what?
   a. What do they induce?

Answer 8

1. Oral
   a. They simply enter the CNS quickly and Easily
2. Degree of LIPID SOLUBILITY
3. Liver
   a. Hepatic Enzymes w/Chronic Use…has a SIGNIFICANT ALTERATION on the METABOLISM of OTHER DRUGS, esp. Alcohol, hormones, and other barbituates.

Question 9

Barbituates: Uses

1. Phenobarbital
   a. Length of duration?
   b. Use?
2. Thiopental
   a. Length of Duration?
   b. Use?

Answer 9

1. a. Long-acting
   b. Anticonvulsants
2. a. Short
   b. Induction of ANESTHESIA

Question 10

Barbituates: Side Effects

1. CNS Depression: Name the 4?
2. What can it do to sleep?
3. What other side effect is important to note?

Answer 10

1. Distortion of Mood, Drowsiness, Impaired Judgement, Impaired Motor Skills
2. Decrease REM Sleep
3. Paradoxical Excitement

Question 11

Barbituates: Side Effects (2)

1. They’re especially dangerous when combined with what?
2. Severe Overdose is marked by what 3 things?
3. Best Tx for Overdose is Supportive Therapy; However, what can actually INCREASE the Mortality Rate?
4. How are they cleared from the system?

Answer 11

1. Alcohol
2. Coma, Decreased BP, and Respiratory Depression
3. Stimulants
4. Diuresis and Alkalinization of the urine.

Question 12

Barbituates: Contraindications

1. Barbituates Enhance the Synthesis of what?
   a. So what are they CONTRAINDICATED in?
2. What other thing are they Contraindicated in?
3. Withdrawal can be LIFE THREATENING
   a. What are the symptoms (6)
   b. Severity of Withdrawal depends on what?

Answer 12

1. of Porphyrin
   a. in any form of Porphyria (Abnormal heme Synthesis)
2. In the Presence of Pulmonary Insufficiency (can cause major Respiratory Depression)
3. a. Anxiety, Hyperactive reflexes, Orthostatic Hypotension, Restlessness, Seizures, and Weakness
   b. Increases w/Dose and the Amt of time it’s been used.

Question 13

Benzodiazepenes: General

1. Most commonly used group of what?
2. Produce CNS Depression with what 2 things accompanied?
3. At Higher doses, what can occur?
4. What drug can cause MUSCLE RELAXATION?
5. What 3 Drugs have ANTICONVULSANT Effects?

Answer 13

1. Anxiolytics and Sedative-Hypnotics
2. Decrease in Anxiety that’s usually accompanied by Drowsiness
3. Hypnosis
4. Diazepam
5. Clonazepam, Lorazepam, and Diazepam

Question 14

Benzodiazepenes: Mechanism of Action

1. What do they bind to?
2. What do they do to the Actions of GABA?
   a. When do they work?
3. As concentration of the Drug INCREASES, what happens to GABA?
   a. What does cause?
   b. Which means what for these drugs?

Answer 14

1. a SPECIFIC RECEPTOR Associated w/the GABAa Receptor Complex
2. they INTENSIFY the actions of GABA by Enhancing its Binding to the GABAa Receptor
   a. ONLY when GABA is Present
3. It’s Release is INHIBITED
   a. a CEILING EFFECT, thus respiratory Depression is less likely than w/barbituates

b. They’re RELATIVELY SAFE!

Question 15

Benzodiazepenes: Pharmacokinetics

1. Best way to administer?
   a. Other way and reason to do so?
   b. Rapid uptake into what first?

Answer 15

1. Oral
   a. IV for Emergencies and Pre-Anesthesia

b. Brain, then redistribution to other tissues, like Fat…thus, Duration of Action may not always reflect BLOOD LEVELS or Metabolism

Question 16

Benzodiazepenes: Pharmacokinetics

1. They’re converted to ACTIVE METABOLITES. What does this do to metabolism?
   a. Example: What are Diazepam and Chlordiazepoxide converted to? and what is the Half-life?
   b. What is this converted to?
   c. This provides what kind of response to occur?
   d. What does this help do?

Answer 16

1. Causes VERY SLOW METABOLISM which leads to Long duration of Action
   a. Desmethyldiazepam (Nordiazepam); More than 24 hours
   b. Oxazepam. 8 Hours
   c. Tapering Response as drug is lowered or stopped
   d. Helps to combat withdrawal symptoms from Alcohol, barbituates, or other Benzodiazepines

Question 17

Benzodiazepenes: Pharmacokinetics

1. Flurazepam: Converted to what?
   a. Half life?
2. Oxazepam and Lorazepam: Conjugated directly to what?
   a. Half life?
3. Alprazolam and Triazolam: Converted to what?
   a. Half lives?
4. Midazolam: Action time?

Answer 17

1. Long-acting active metabolite
   a. by itself, has a half life of 74 hrs, and active metabolites will accumulate if it’s taken daily
2. to INACTIVE METABOLITES
   a. 6-24 hrs.
3. Short acting active metabolites (less than 6 hr half lives)
   a. A: 12 hrs; T: Short duration of action and Half Life of less than 3 hrs.
4. VERY SHORT Duration of Action (less than 2 hrs)

Question 18

Benzodiazepenes: Drug Interactions

1. Major site of Metabolism?
   a. However, unlike Barbituates, what do they NOT do?
2. What drug Lengthens Elimination Half-Life of DIAZEPAM? How?

Answer 18

1. Liver (but kidney also)
   a. They DO NOT INDUCE LIVER ENZYMES! So fewer drug interactions
2. CIMETIDINE! Decreases metabolism of it.

Question 19

Benzodiazepenes: Uses:

1. Treatment of Anxiety: What dose should be used?
2. Anxiety Disorders when NOT to use Benzodiazepines
   a. OCD
   b. Agoraphobia and Panic Disorders
   c. PTSD
   d. Anxiety in Children and Adolescents

Answer 19

1. Lowest EFFECTIVE DOSE for the SHORTEST DURATION…this translates to MAX BENEFIT w/FEWEST SIDE EFFECTS
2. a. SSRIs
   b. SSRIs or other antidepressants
   c. Antidepressants
   d. Antidepressants

Question 20

Benzodiazepenes: Insomnia

1. What 3 drugs are commonly used as HYPNOTICS?
   a. Why?
2. Which drug is the Longer-acting drug?
   a. What might it do to the patient the next day?
3. Shorter-Acting Drug?
   a. Helpful for what people?
   b. What could it cause?

Answer 20

1. FTT
   a. Cause LESS Depression of REM sleep than Barbituates
2. Flurazepam
   a. Drug “Hangover.” Makes them feel Sluggish…Best for Pt’s that wake up too early in the morning
3. Triazolam
   a. that have trouble falling asleep, but then stay asleep.
   b. REBOUND INSOMNIA…don’t use chronically…could cause Psychosis

Question 21

Benzodiazepenes: Epilepsy and Seizures

1. What drug is used to Prevent ABSENCE SEIZURES?
2. What 2 drugs can be used to Treat STATUS EPILEPTICUS?
   a. How is it given?

Answer 21

1. Clonazepam
2. Diazepam and Lorazepam
   a. IV

Question 22

Benzodiazepenes: Sedation, Amnesia, and Anesthesia

1. What VERY SHORT ACTING DRUG is used for Preparation for Anesthesia and short surgical procedures?
   a. How is it normally given
   b. When is it given orally?
   c. What can it also cause?

Answer 22

1. Midaolam
   a. IV
   b. to relieve anxiety prior to dental and other procedures, esp in children.
   c. ANTEROGRADE AMNESIA (pt can’t remember events that happened after the drug was given)

Question 23

Benzodiazepenes: Muscle Relaxation

1. What drug can be used for Acute Muscle Spasm and Pain as a result of Injury?

Answer 23

1. Diazepam

Question 24

Benzodiazepenes: Withdrawal from Alcohol and Barbituates

1. What 2 drugs can be used to provide a more TAPERED withdrawal?
2. Tx w/these can prevent what things?

Answer 24

1. Diazepam and Chlordiazepoxide (DC): they’re longer-acting benzodiazepines
2. SEIZURES in alcohol or barbituate withdrawal

Question 25

Benzodiazepenes: Side Effects Major Side Effects? 2. When can they become MORE PROFOUND? 3. When should they be used in children?

Answer 25

1. CNS Depression: dizzy, drowsy, sedation, confusion, impaired motor coordination, memory loss, loss of REM sleep. They DECREASE as Tolerance Develops 2. When combined w/Alcohol 3. ONLY when really needed. Why? Because they IMPAIR LEARNING and MEMORY

Question 26

Benzodiazepenes: Side Effects 1. Who are really sensitive to CNS effects?

Answer 26

1. Elderly...Esp memory loss and confusion.

Question 27

Benzodiazepenes: Contraindications 1. Women? 2. Children? 3. Sleep Apnea: Why?

Answer 27

1. During Pregnancy (Category D...Definite evidence of Birth Defects) 2. Can impair learning and memory 3. Can decrease Tone of UPPER AIRWAY and WORSEN APNEA

Question 28

Benzodiazepenes: Overdose 1. What does it usually cause? 2. When does fatalities happen? 3. What drug is considered the "Date rape" drug?

Answer 28

1. Long deep sleep (24-48 hrs) 2. Respiratory difficulties, children, combined w/alcohol 3. FLUNITRAZEPAM (Short-acting, high sedation)

Question 29

Benzodiazepenes: Other issues 1. When can tolerance and dependence develop? a. Type of Schedule? 2. ABRUPT DISCONTINUATION can cause what to happen? a. Best to do what? 3. Use in High Doses for a LONG time, what can occur?

Answer 29

1. When used chronically. a. Schedule 4 2. Can Cause REBOUND Increases in Insomnia and Anxiety a. Switch to a longer acting drug for a more GRADUAL TAPER if short acting has been used chronically. 3. WITHDRAWAL SYMPTOMS can be SEVERE. Taper them VERY SLOWLY after chronic use.

Question 30

Benzodiazepine Antagonist: Flumazenil 1. Where does it antagonize? 2. Given how? a. Doses are given in what way? Why? 3. What does it do? 4. Duration of Action? 5. Major Adverse Effect? 6. What can it do to patients dependent on BARBITUATES or ALCOHOL? 7. Can CAUSE SEIZURES in whom? 8. DO NOT GIVE if there is ANY SIGN of WHAT?

Answer 30

1. At the GABA receptor... Competes for it. 2. IV a. SLOWLY (series of small injections over 3 minutes). Or it may cause seizures in some people 3. REVERSES CNS Depressant effects 4. 30 minutes 5. Can cause WITHDRAWAL and SEIZURES in patients that are physically dependent on benzos 6. seizures 7. those with Barbiturate and tricyclic antidepressant overdose 8. SEIZURES!

Question 31

Other Sedative-Hypnotic Agents 1. What 2 drugs bind to the BZ1 subtype of the Benzo receptor? 2. What drug binds to all 3 subtypes? 3. Type of action? 4. What do they preserve? 5. What drug is used for LONG-TERM Tx of INSOMNIA? 6. What Drugs are used for SHORT-TERM use?

Answer 31

1. Zaleplon and Zolpidem 2. Eszopiclone 3. GABA-mediated inhibition. VERY STRON and RAPID SEDATIVE ACTIVITY 4. Deep Sleep w/only minor effect on REM SLEEP 5. Eszopiclone 6. Zaleplon and Zolpidem (7-10 days)...but are frequently used chronically * Tolerance is RARE, and Sleep Benefit may persist after the drugs are STOPPED

Question 32

Other Sedative-Hypnotic Agents Pharmacokinetics 1. Best Absorption way? a. Peak Levels? 2. How does the body get rid of them? 3. Which has the SHORTEST HALF LIFE? 4. Which has the next shortest half life? 5. Longer Half life? 6. When should they only be used?

Answer 32

1. Oral a. 30 min to 1 hr 2. Liver and Kidney 3. Zaleplon (1 hr) and lasts for about 4 hrs 4. Zolpidem (2 hrs). Extended release form now used 5. Eszopiclone (6hrs)...can cause morning drowsiness 6. when at LEAST 8 hrs is available for sleep.

Question 33

Other Sedative-Hypnotic Agents Side-Effects 1. Major side effects? 2. Use with caution in patients with a history of what? 3. Withdrawal Symptoms?

Answer 33

1. CNS-Drowsiness and Dizziness; "Blackouts" (Sleep-walking/driving, night eating) 2. of drug and alcohol abuse 3. Anxiety, seizures, and psychosis after long-term use with eszopiclone

Question 34

Ramelteon 1. Agonist what what receptor(s) a. What does it do (2 things)? 2. What does it shorten? (2) 3. Best way to get into the body? 4. How is it taken out? 5. CAUTION use in peeps with what? 6. When should they NOT be USED

Answer 34

1. MT1 and MT2 receptor a. Regulate sleepiness and resets circadian rhythym 2. delay to sleep onset and total sleep time 3. Oral. MAJOR FIRST PASS METABOLISM 4. CYP1A2 in the liver 5. w/mild to moderate liver disease 6. In Severe Liver disease (due to decreased metabolism)

Question 35

Ramelteon: Drug Interactions 1. Additive sedation w/what 2 things? 2. What INCREASES METABOLISM of RAMELTEON? Side Effects 3. What are the 3 most common?

Answer 35

1. Alcohol and other Sedative hypnotics 2. Rifampin 3. Dizziness, Drowsiness, and Nausea

Question 36

Antihistamines 1. When are they useful? 2. Most commonly used drug?

Answer 36

1. Occaisional Insomnia, or for someone that's been addicted to benzos or alcohol 2. Diphenhydramine

Question 37

Chloral Hydrate 1. Converted to what in the body? 2. Where does it act? 3. Margin of Safety? 4. Used in Children for what reasons? 5. Use as a Sedative-Hypnotic it NOT RECOMMENDED. But it is used sometimes. Why?

Answer 37

1. Trichloroethanol (causes sedation) 2. at GABAa receptor; Like Barbituates do. 3. LOW. High doses = respiratory and vasomotor depression 4. for Conscious Sedation during Pediatric dental procedures 5. It's super Cheap...used in Nursing Homes

Question 38

Other Anxiolytics: Buspirone 1. What does it do? 2. Where does it act? 3. Does NOT Affect what 2 Receptor Types? 4. How long does it take to kick in? 5. What about overdose...is there a sedative effect? 6. Addiction potential? 7. Does it do anything to CNS depression w/Alcohol or Benzos?

Answer 38

1. Relieves Anxiety w/o SEDATION! 2. Partial Agonist at 5-HT1a receptors (esp in Hippocampus) 3. Benzo and GABA receptors 4. About 2 Weeks 5. Little to none. 6. VERY LOW: good to relieve Anxiety in recovering alcoholics or addicts 7. Doesn't Potentiate CNS depression with these, BUT it WONT PREVENT SYMPTOMS of BENZO or Alcohol withdrawal.

Question 39

Other Anxiolytics: Buspirone Pharacokinetics 1. Absorbed how? 2. How does the body rid of it? 3. Best use for what? Side Effects 4. Safe at High Doses? 5. What may occur in some peeps? 6. Can INCREASE BP in peeps taking what?

Answer 39

1. Oral 2. Liver and Kidney 3. Treating Anxiety in RECOVERING ALCOHOLICS or ADDICTS, or ELDERLY 4. Safe 5. RESTLESSNESS 6. MAOIs. These DRUGS SHOULD NOT BE COMBINED!!