Lecture 9 - Sedative, Hypotics, Anxiolytics, and Antidepressants

Question 1

Non-rapid eye movement sleep - Stage 1

Answer 1

• Somewhat aware of surroundings
• short
• alpha and theta waves

Question 2

Non-rapid eye movement sleep - Stage 2

Answer 2

• Unaware of surroundings
• Easily awakened
• Sleep spindles and K-complex

Question 3

Non-rapid eye movement sleep - Stages 3 and 4

Answer 3

• Deeper stages of sleep
• Delta wave (larger waves)
• important for physcial rest and restoration

Question 4

Rapid-eye movement sleep

Answer 4

-Bursts of rapid eye movement (REM)
- Increased autonomic activity
- Dreaming

AKA paradoxical sleep

Question 6

Define

Dreaming

Answer 6

The absence of motor fuction with the excpetion of the eye muscles and the diaphragm, occurs several times during sleep, and predominates towards morning

Question 7

Describe the EEG patterns observed during the stages of sleep

Answer 7

1. Awake - low voltage, random and fast waves
2. Drowsy - 8-12 cps, alpha waves (slighty taller and closer together)
3. Stage 1 - 3-7 cps, theta waves (farther apart)
4. Stage 2 - 12-14 cps, sleep spindles (very fast clump of waves) and K complexes (one very large wave)
5. Delta sleep - 1/2 to 2 cps, delta waves (very large waves), about 75 mV
6. REM sleep - low voltage, random fast sawtooth waves)

Question 8

Sedative-Hypnotic Drugs

Mechanisms of Action

Answer 8

• Brain activity is highly affected by GABA
• regulates the chloride channel –> reduces generation of action potentials
• Most hypnotic drugs bind to specific receptor sites –> increases the inhibitory effects of GABA

Question 9

Sedative-Hypnotic Drugs

Dosage (Low vs High)

Answer 9

Low Dosage - decreased activity of the reticular activation system (RAS), promotes sedation or sleep
High Dosage - depression of CNS, general anaesthesia, death

Question 10

Classification of Sedatives and Hypnotics

Barbiturate - Effects on sleep cycle

Answer 10

• Increase in stage 2 sleep
• decrease in slow-wave sleep
• Supression of REM sleep
• Altered sleep structure

Question 11

Classification of Sedatives and Hypnotics

Barbiturate - Effects and uses

Answer 11

• Prolonged use can lead to tolerance and physical dependence
• Overdose results in extensive cardiovascular and CNS depression –> hypotension and shock
• No antidote for an overdose
• No longer recommended as hypnotics

Question 12

Classification of Sedatives and Hypnotics

Barbiturate - Phenobarbital

Answer 12

Death penalty drug

Question 13

Classification of Sedatives and Hypnotics

Benzodiazepine - Mechanism and sites of action

Answer 13

• Decrease the excitability and functional activity of specific areas of the brain
• Limbic system, reticular formation, cerebral cortex, spinal cord
• Do NOT function as general anaesthetics

Question 14

Classification of Sedatives and Hypnotics

Benzodiazepines - Example drugs

Answer 14

Flurazepam, temazepam, triazolam, lorazepam

Question 15

Classification of Sedatives and Hypnotics

Benzodiazepines - Effects on sleep cycle

Answer 15

• Increased NREM stage 2 and decreased stage 4
• No suppression of REM

Question 16

Classification of Sedatives and Hypnotics

Benzodiazepines - Advantages

Answer 16

• No REM rebound
• Does not induce microsomal metabolizing enzymes
• Well tolerated

Question 17

Classification of Sedatives and Hypnotics

Benzodiazepine - Adverse effects

Answer 17

• Drowsiness, confusion
• Higher doses affect memory
• Long term usage, abuse, and abrupt termination can cause dependency
• Avoid during pregnancy

Question 18

Classification of Sedatives and Hypnotics

Benzodiazepines - Drug interactions

Answer 18

Alcohol - coma and permenant brain damage
Cimetidine - inhibits the metabolism of benzos and prolongs the effects

Question 19

Flumazenil

Answer 19

• Benzodiazepine antagonist
• may be administered intravenously to reverse depressant effects of the benzo drugs

Question 20

Why do GABAa Receptors have large diversity?

Answer 20

• GABAa recpetors exist as pentamers that form an anion selective channel
• Possible arrangments of subunits are taken from three different types; alpha, beta, and gamma
  -GABAc receptors are formed from rho-subunits and are insenstitive to benzos and barbiturates

Question 21

Subunit specific GABAa receptor agonists

Gaboxal

Answer 21

Targets benzo-insensitive alpha-4, beta-3, delta receptors
- In late stage clinical development for the treatment of insomnia

Question 22

Subunit specific GABAa receptor agonists

Alpha2/Aplha3 subunit selective agonists

Answer 22

Non-sedating anxiolytics

Question 23

Subunit specific GABAa receptor agonists

Alpha5 subunit inverse agonists

Answer 23

Memory enhancers

Question 24

Subunit specific GABAa receptor agonists

Zolpidem

Answer 24

• GABAa receptor, alpha-1 subunit-selective compound
• Short-term treatment of insomnia

Question 25

# Classification of Sedatives and Hypnotics Z-Drugs - Site of action

Answer 25

Selectively bind alpha-1 subunit of GABAa receptor

Question 26

# Classification of Sedatives and Hypnotics Z-drugs - Examples

Answer 26

Zopiclone, zaleplon, zolpidem

Question 27

# Classification of Sedatives and Hypnotics Z-drugs - Effects

Answer 27

- Increased inhibitory effects of GABA - No anticonvulsant muscle relaxing, or anxiolytic effects - Cannot be used as general anaesthetics - Do not disturb sleep stages - Less physical dependence

Question 28

# Classification of Sedatives and Hypnotics Melatonin and Ramelteon

Answer 28

Melatonin is a hormone stimulated by a lack of sunlight, 1 hour half life Ramelteon is a melatonin receptor agonist with a 2.6 hour half life

Question 29

# Use Zolpidem or Zopiclone

Answer 29

-Preferred therapy for insomnia

Question 30

# Use Flurazepam or Quazepam

Answer 30

For insomnia coupled with anxiety

Question 31

# Use Zaleplon or Ramelton

Answer 31

Helps induce sleep

Question 32

# Use Benzodiazepines

Answer 32

Sedation

Question 33

# Anxiolytics Causes of anxiety

Answer 33

Overactive limbic system and situations that are interpreted as threatening or dangerous

Question 34

# Anxiolytics Percent of the US with GAD

Answer 34

3.1%

Question 35

# Antidepressants What phenotype of mice recapitulates the core symptoms of human major depression?

Answer 35

AC3-/-

Question 36

What is the Monoamine Theory of Major Depression?

Answer 36

Decreased levels of norepinephrine or seretonin lead to depression

Question 37

# Antidepressants What amino acid is serotonin made from?

Answer 37

Tryptophan

Question 38

# Antidepressants Antidepressant drug classes

Answer 38

1. Selective serotonin reuptake inhibitors (SSRIs) 2. Serotonin-norepinephrine reuptake inhibitors (SNRIs) 3. Tricyclic antidepressants (TCAs) 4. Monoamine oxidase inhibitors (MAOIs) 5. Atypical antidepressants

Question 39

# Classification of antidepressants SSRIs - Mechanism of action

Answer 39

Blocks the reuptake of serotonin into the serotonergic nerve endings - vary in degree of CNS activation (Lexapro - low, Prozac - high, Fluvoxamine - sedating)

Question 40

# Classification of antidepressants SSRIs - Clinical indications

Answer 40

- Preffered therapy for major depression - Administered 1-2 times a day - No effect on adrenergic, cholinergic, adrenergic, or histamine receptors - Some SSRIs can treat anxiety, PTSD, and OCD

Question 41

# Classification of antidepressants SSRIs - Adverse effects

Answer 41

- GI disturbances - sexual dysfunction - OD leads to serotonin syndrome

Question 42

# Classification of antidepressants SNRIs - Mechanism of action

Answer 42

Block the reuptake of norepinephrine and serotonin - Little effect in blocking cholinergic, adrenergic, or histamine receptors

Question 43

# Classification of antidepressants SNRIs - Adverse effects

Answer 43

- Increased blood pressure, heart rate, and CNS stimulation - Sudden discontinuation can lead to discontinuation syndrome

Question 44

# Classification of antidepressants TCAs - Mechanism of action

Answer 44

Blocks the reuptake of norepinephrine and serotonin, increased serotonin and NE levels contribute to the antidepressant effect

Question 45

# Classification of antidepressants TCAs - Pharmacological actions

Answer 45

Produces varying degrees of sedation, anticholinergic effects, and alpha-adrenergic blockade

Question 46

# Classification of antidepressants MAOIs - Mechanism of action

Answer 46

Inhibits or blocks MAOs (inhibit break down of NE, serotonin, and dopamine)

Question 47

# Classification of antidepressants Where is MAO found in the body?

Answer 47

MAO-A: Liver, GI tract, brain, other tissues MAO-B: nervous system, blood platelets

Question 48

# Classification of antidepressants MAOIs - How long does it take to see the full effects?

Answer 48

2 to 4 weeks

Question 49

# Classification of antidepressants MAOIs - Dietary restrictions

Answer 49

- Avoid foods containing tyramine (substance that causes the release of ME) such as wine, beer, herring, and some cheeses - Avoid sympathetic drugs that treat cold symptoms (broncodilators)

Question 50

# Classification of antidepressants Atypical antidepressants - Bupropion

Answer 50

- NE-dopamine reuptake inhbitor - Useful for bipolar disorder - Increased dopamine and serotonin levels in the brain

Question 51

# Classification of antidepressants Atypical antidepressants - Mirtazapine

Answer 51

- Acts as a sedative - Antagonizes serotonin 5HT2a and SHT2c receptors

Question 52

# Classification of antidepressants Atypical antidepressants - ketamine

Answer 52

Unknown mechanism of action