Lecture 12: Anxiolytics and hypnotics

Question 1

What does anxiolytic mean?

Answer 1

Calming effects

Relief of anxiety

Question 2

What does hypnotic mean?

Answer 2

Promotes drowsiness

Promotes onset and maintenance of sleep

Question 3

What is the basic foundation of benzodiazepines?

Answer 3

Benzene ring

Diazepine ring

Question 4

Structure of barbiturates

Answer 4

Related to structure of barbituric acid

Question 5

What is the action size for BZD? Structure?

Answer 5

GABA-A receptor (chloride channel)

hetero-oligomeric glycoprotein with 2 alpha subunits, 2 beta subunits and 1 gamma subunit

Question 6

What is GABA?

Answer 6

GABA is primary inhibitory neurotransmitter in brain

Question 7

Isoforms of alpha subunit of GABA-A receptor

Answer 7

alpha 1: hypnotic

alpha 2-5: sedation, psychomotor effect

Question 8

What happens when GABA-A receptor is activated?

Answer 8

Chloride influx

Hyperpolarization of neurons and decrease in neuronal activity

Question 9

What happens when BZDs bind to GABA-A receptor?

Answer 9

Enhance GABA actions (not direct activation of receptor)

Increases frequency of channel opening events

Reduces excitability of neurons (CNS depressant)

Question 10

Affinity of BZD for GABA-B receptors

Answer 10

Low affinity

Question 11

What happens when barbiturates bind to GABA receptor?

Answer 11

Increase duration of channel-opening events

Question 12

Effect of barbiturates at high concentration

Answer 12

GABA-mimetic effect

Question 13

Other effect of barbiturates

Answer 13

Inhibit glutamate AMPA receptor

Question 14

General concept of PK

Answer 14

Absorption

Distribution

Metabolism

Elimination

See figure

Question 15

What are factors that affect onset of CNS drugs?

Answer 15

Onset: time for drugs to be effective after administration

Lipophilicity affects this (due to BBB)

Question 16

What are factors that affect duration of CNS drugs?

Answer 16

Duration: the amount of time that a measurable drug effect persists

Biotransformation affects this

Question 17

Biotransformation reactions that have effect on duration of CNS drugs

Answer 17

Microsomal oxidation (Cytochrome P450 isozymes: phase I reactions)

Conjugation (phase II reactions)

Metabolic conversion to more water-soluble metabolites is required for clearance of CNS drugs from the body

Question 18

What are factors that affect onset of BZDs?

Answer 18

Lipophilicity

Triazolam > diazepam > lorazepam, oxazepam

Question 19

BZDs with long half-lives

Answer 19

Chlordiazepoxide

Diazepam

Prazepam

Clorazepate

Flurazepam

Question 20

BZDs with short half-lives

Answer 20

Lorazepam and oxazepam (Without active metabolites)

Alprazolam and triazolam (With active metabolites but short half-lives)

Question 21

Therapeutic uses of BZDs related to half life

Answer 21

Short acting: preferable for hypnotic

Longer acting: preferable for anxiolytic

Question 22

Consideration with BZDs with long half-lives

Answer 22

Cause cumulative effects with multiple doses

Question 23

Where are BZDs excreted?

Answer 23

Kidney

Question 24

Clinical considerations regarding BZD PK

Answer 24

Can cross placental barrier: pregnant patients

Can be detectable in breast milk: Infants

Older patients, patients with liver diseases

Redistributed to adipose tissue: obese
patients

Question 25

Lipophilicity of barbiturates

Answer 25

Lipophilic: absorbed and distributed rapidly.

Question 26

Where does metabolism of barbiturates occur?

Answer 26

Liver ``` but slowly (with the exception of thiopental) ```

Question 27

What do barbiturates induce?

Answer 27

Cyt-P450

Question 28

Duration of action of barbiturates

Answer 28

Ultra-short-acting (30 min) --- thiopental for induction of anesthesia Short-acting (18-48 hours) --- secobarbital, pentobarbital for hypnotic and sedative Long-acting (4-5 days) --- phenobarbital for seizures

Question 29

Therapeutic uses of BZDs

Answer 29

1) For relief of anxiety (sedative) 2) For treatment of insomnia (hypnotic) 3) For sedation and amnesia before and during surgical procedures 4) For treatment of epilepsy and seizure states 5) For muscle relaxation in specific neuromuscular disorders 6) For control of ethanol withdrawal symptoms or other sedative-hypnotic withdrawal states

Question 30

Examples of anxiety disorders

Answer 30

Generalized anxiety disorder (GAD) Panic disorder Social phobia Post-traumatic stress disorder (PTSD) Obsessive-compulsive disorder (OCD)

Question 31

Symptoms of anxiety disorders

Answer 31

vary depending on the type of anxiety disorder, but general symptoms include: Feelings of panic, fear and uneasiness Uncontrollable, obsessive thoughts Nightmares Problems sleeping Cold or sweaty hands and/or feet Shortness of breath Palpitations Dry mouth Numbness or tingling in the hands or feet Nausea Muscle tension Dizziness

Question 32

Management of acute anxiety vs long term

Answer 32

Acute: Use BZDs for rapid control Long term: SSRIs

Question 33

Symptoms of insomnia

Answer 33

trouble falling or staying asleep, which leads to sleep deprivation. Lying awake for a long time before falling asleep Sleeping for only short periods Being awake for much of the night Waking up too early

Question 34

Physiology of sleep

Answer 34

NREM (stage 1-4) and REM Stage 1: light sleep during which the muscles begin to relax Stage 2: brain activity slows down and eye movement stops. Stages 3/4: deep sleep during which all eye and muscle movement ceases. REM (rapid eye movement): paradoxical sleep, rapid eye movement where most muscles are paralyzed See figure

Question 35

BZDs as hypnotics

Answer 35

decrease the latency to sleep onset and increase Stage II of NREM decrease both REM and slow wave sleep.

Question 36

How to select drugs for difficulty falling asleep? Frequent awakenings?

Answer 36

Difficulty falling asleep: Fast-acting, shorter duration drug (triazolam) Frequent awakenings: drug of medium duration (lorazepam)

Question 37

Drugs used for sedation and amnesia before and during surgery

Answer 37

Cause anterograde amnesia Midazolam and lorazepam

Question 38

CNS depression: barbiturates vs BZDs

Answer 38

Barbiturates cause higher CNS depression than BZDs Sedation -> hypnosis -> anasthesia -> coma

Question 39

Therapeutic uses of Barbiturates

Answer 39

Rarely used as sedatives and hypnotics (replaced bu BZDs for anxiety and insomnia) Used as anticonvulsant in epilepsy and seizure (phenobarbital) Component of balanced anesthesia (thiopental)

Question 40

Adverse effects of BZDs

Answer 40

CNS depression: Drowsiness, confusion, anterograde amnesia, dizziness, lethargy, ataxia May persist and cause "hangover" Safe, except when used in combination with other CNS depressants

Question 41

BZDs and tolerance

Answer 41

Pharmacodynamic tolerance down-regulation of brain BZD receptors

Question 42

What is tolerance?

Answer 42

decreased responsiveness to a drug following repeated treatment.

Question 43

What is dependence?

Answer 43

an altered physiologic state that requires continuous drug administration to prevent withdrawal symptoms.

Question 44

What are the withdrawal symptoms of BZD?

Answer 44

relapse or rebound anxiety, insomnia, restlessness, etc.

Question 45

Which type of BZDs produce worse withdrawal symptoms?

Answer 45

Withdrawal symptoms are more common and more severe in patients on BZDs with short half-lives

Question 46

What does chronic use of BZDs produce?

Answer 46

Tolerance and dependence Patients on long term BZD must be tapered

Question 47

Considerations with BZDs

Answer 47

Prescriptions should be written for short periods. Depressant effects on psychomotor and cognitive functions. Used in combination with alcohol or other CNS depressants (e.g. alcohol). Older patients, patients with liver diseases Obese patients Unauthorized dosage increases

Question 48

Contraindications with BDZs

Answer 48

Myasthenia gravis Narrow-angle glaucoma Alcoholism Severe sleep apnea Pregnant or nursing mothers