Lecture 12: Anxiolytics and hypnotics Flashcards
What does anxiolytic mean?
Calming effects
Relief of anxiety
What does hypnotic mean?
Promotes drowsiness
Promotes onset and maintenance of sleep
What is the basic foundation of benzodiazepines?
Benzene ring
Diazepine ring
Structure of barbiturates
Related to structure of barbituric acid
What is the action size for BZD? Structure?
GABA-A receptor (chloride channel)
hetero-oligomeric glycoprotein with 2 alpha subunits, 2 beta subunits and 1 gamma subunit
What is GABA?
GABA is primary inhibitory neurotransmitter in brain
Isoforms of alpha subunit of GABA-A receptor
alpha 1: hypnotic
alpha 2-5: sedation, psychomotor effect
What happens when GABA-A receptor is activated?
Chloride influx
Hyperpolarization of neurons and decrease in neuronal activity
What happens when BZDs bind to GABA-A receptor?
Enhance GABA actions (not direct activation of receptor)
Increases frequency of channel opening events
Reduces excitability of neurons (CNS depressant)
Affinity of BZD for GABA-B receptors
Low affinity
What happens when barbiturates bind to GABA receptor?
Increase duration of channel-opening events
Effect of barbiturates at high concentration
GABA-mimetic effect
Other effect of barbiturates
Inhibit glutamate AMPA receptor
General concept of PK
Absorption
Distribution
Metabolism
Elimination
See figure
What are factors that affect onset of CNS drugs?
Onset: time for drugs to be effective after administration
Lipophilicity affects this (due to BBB)
What are factors that affect duration of CNS drugs?
Duration: the amount of time that a measurable drug effect persists
Biotransformation affects this
Biotransformation reactions that have effect on duration of CNS drugs
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
What are factors that affect onset of BZDs?
Lipophilicity
Triazolam > diazepam > lorazepam, oxazepam
BZDs with long half-lives
Chlordiazepoxide
Diazepam
Prazepam
Clorazepate
Flurazepam
BZDs with short half-lives
Lorazepam and oxazepam (Without active metabolites)
Alprazolam and triazolam (With active metabolites but short half-lives)
Therapeutic uses of BZDs related to half life
Short acting: preferable for hypnotic
Longer acting: preferable for anxiolytic
Consideration with BZDs with long half-lives
Cause cumulative effects with multiple doses
Where are BZDs excreted?
Kidney
Clinical considerations regarding BZD PK
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
Lipophilicity of barbiturates
Lipophilic: absorbed and distributed rapidly.
Where does metabolism of barbiturates occur?
Liver
but slowly (with the exception of thiopental)
What do barbiturates induce?
Cyt-P450
Duration of action of barbiturates
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
Therapeutic uses of BZDs
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
Examples of anxiety disorders
Generalized anxiety disorder (GAD)
Panic disorder
Social phobia
Post-traumatic stress disorder (PTSD)
Obsessive-compulsive disorder (OCD)
Symptoms of anxiety disorders
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
Management of acute anxiety vs long term
Acute: Use BZDs for rapid control
Long term: SSRIs
Symptoms of insomnia
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
Physiology of sleep
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
BZDs as hypnotics
decrease the latency to sleep onset and increase Stage II of NREM
decrease both REM and slow wave sleep.
How to select drugs for difficulty falling asleep? Frequent awakenings?
Difficulty falling asleep: Fast-acting, shorter duration drug (triazolam)
Frequent awakenings: drug of medium duration (lorazepam)
Drugs used for sedation and amnesia before and during surgery
Cause anterograde amnesia
Midazolam and lorazepam
CNS depression: barbiturates vs BZDs
Barbiturates cause higher CNS depression than BZDs
Sedation -> hypnosis -> anasthesia -> coma
Therapeutic uses of Barbiturates
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)
Adverse effects of BZDs
CNS depression: Drowsiness, confusion, anterograde amnesia, dizziness, lethargy, ataxia
May persist and cause “hangover”
Safe, except when used in combination with other CNS depressants
BZDs and tolerance
Pharmacodynamic tolerance
down-regulation of brain BZD receptors
What is tolerance?
decreased responsiveness to a drug following repeated treatment.
What is dependence?
an altered physiologic state that requires continuous drug administration to prevent withdrawal symptoms.
What are the withdrawal symptoms of BZD?
relapse or rebound anxiety, insomnia, restlessness, etc.
Which type of BZDs produce worse withdrawal symptoms?
Withdrawal symptoms are more common and more severe in patients on BZDs with short half-lives
What does chronic use of BZDs produce?
Tolerance and dependence
Patients on long term BZD must be tapered
Considerations with BZDs
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
Contraindications with BDZs
Myasthenia gravis
Narrow-angle glaucoma
Alcoholism
Severe sleep apnea
Pregnant or nursing mothers
