Anxiolytics & Hypnotics Flashcards
Long-acting BZDs:
Diazepam, Flurazepam, Clonazepam,
Intermediate-acting BZDs:
Lorazepam, Alprazolam, Temazepam,
Short-acting BZDs:
Triazolam
BZD antagonist:
Flumazenil
Barbiturates:
Thiopental
Other anxiolytic:
Buspirone
Other hypnotic:
Zopiclone
What are terms “anxiolytic” and “hypnotic”?
Anxiolytic (help pt relax)
- Calming effects
- Relief of anxiety
Hypnotic (help pt sleep)
- Promotes drowsiness
- Promotes onset and maintenance of sleep
What drugs are classified as Benzodiazepines (BZDs)?
Diazepam, Flurazepam, Clonazepam, Lorazepam, Alprazolam, Temazepam and
Triazolam
What drugs are classified as Barbiturates?
Thiopental
What drugs are classified under “Others”?
Buspirone (anxiolytic), Zopiclone (hypnotic)
What is the action site of BZDs?
GABA-A receptor
What is a GABA-A receptor?
- GABA is the primary inhibitory neurotransmitter in brain;
- GABA-A receptor is a hetero-oligomeric glycoprotein with 2X α, 2X β and 1X γ subunits.
- α subunit has 5 isoforms with α1-5
– α1 — hypnotic
– α2-5 — sedation, psychomotor effect - GABA-A receptor is a chloride channel
– Activation — chloride influx; hyperpolarizes neurons and decreases neuronal activity.
What is the action sites of the BZDs?
GABA-A receptor, Cl- channel
ENHANCE GABA actions (not directly activate receptor), increase Cl- channel opening
What is the action sites of the Barbiturates?
GABA-A receptor, Cl- channel
ENHANCE GABA actions; DIRECTLY ACTIVATE receptor at high concentration; inhibit glutamate AMPA receptor
What are the factors that affect rate of onset and duration of BZDs?
lipophilicity and biotransformation
What are the factors that affects onset (determined by absorption & distribution) of BZDs?
Lipophilicity
MORE LIPOPHILIC = MORE RAPID ONSET OF ACTION
What are the factors that affects duration (determined by biotransformations & excretion) of BZDs?
Biotransformation
MANY PHASE I METABOLITES OF BZDs ARE ACTIVE
Half-life of BZDs ↑, Duration ↑
What are the Long-acting BZDs?
Diazepam, Flurazepam, Clonazepam,
What are the Intermediate-acting BZDs?
Lorazepam, Alprazolam, Temazepam,
What are the Short-acting BZDs?
Triazolam
What is the main differences between BZDs?
rate of onset and duration of actions
What are BZDs therapeutic uses related to half-life?
- short acting is preferable for hypnotic
- longer acting preferable for anxiolytic
BZDs with long half-lives:
cause cumulative effects with multiple doses
What are the pharmacokinetics of Barbiturates?
- Lipophilic: absorbed and distributed rapidly.
- Metabolized in the liver, but slowly (with the exception of thiopental)
- HEPATIC CYT-P450 SYSTEM INDUCERS
Which Barbiturate drugs are Ultra-short-acting (30 min)?
thiopental for induction of anesthesia
Which Barbiturate drugs are Short-acting (18-48 hours)?
secobarbital, pentobarbital for hypnotic and sedative
Which Barbiturate drugs are Long-acting (4-5 days)?
phenobarbital for seizures
What are the therapeutic uses of BZDs?
1) For relief of ANXIETY (NOT 1st line drugs for chronic anxiety (SSRIs are 1st line drugs)
2) For treatment of INSOMNIA (increase stage II, but decrease deep sleep)
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 (skeletal muscle spasms)
6) For control of ethanol (alcohol) withdrawal symptoms or other sedative-hypnotic withdrawal states
What are Barbiturates used for?
rarely used, but still used for induction of ANESTHESIA, SEIZURE
What are the 6 things that BZDs are used for?
- For relief of anxiety (sedation)
- For tx of insomnia (hypnotic)
- For sedation & amnesia before & during surgical procedures
- For tx of epilepsy & seizure states - Anticonvulsant
5) Muscle relaxant – for muscle relaxation in skeletal muscle spasms caused by CNS disorder. e.g. diazepam
6) For alcohol withdrawal symptoms or other sedative- hypnotic withdrawal states
What are BZDs used for?
Used for the management of ACUTE ANXIETY
STATES and for rapid control of panic attacks.
Are BZDs the 1st-line drugs for chronic anxiety?
NO - Selective serotonin reuptake inhibitors (SSRIs) are first-line drugs FOR LONG-TERM MANAGEMENT of chronic anxiety (Generalized Anxiety Disorder) and panic disorders.
What is the drug selection of BZDs for panic disorders & agoraphobia?
Alprazolam
How do BZDs act as hypnotics?
- decrease the latency to sleep onset and increase Stage II of NREM
- decrease both slow wave and REM sleep.
Which BZD drug?
For difficulty falling asleep, use fast-acting, but shorter duration drug
i.e. triazolam
Which BZD drug?
For frequent awakenings, falling asleep is not the issue, so use a drug of medium duration
i.e. lorazepam, temazepam
What dose level should you start with for tx of insomnia (hypnotic) BZDs?
Starting with very low doses (to avoid hangover)
Why are BZDs used for sedation and amnesia before and during surgical procedures?
Produce sedative effects, cause anterograde amnesia
Use before and during medical and surgical procedures.
Which BZDs make them 1st choice for sedation and amnesia before and during surgical procedures (Produce sedative effects, cause anterograde amnesia)?
midazolam, lorazepam
Use before and during medical and surgical procedures.
Which BZDs should be used for treatment of epilepsy and seizure states – Anticonvulsant?
(lorazepam, diazepam)
- management of seizures such as generalized tonic-clonic status epilepticus, absence seizures, partial seizures…
Why should BZDs be used forMuscle relaxant – for muscle relaxation in skeletal muscle spasms caused by CNS disorder. e.g. diazepam?
has useful relaxant effects in skeletal muscle spasticity of central origin
Why should BZDs be used for alcohol withdrawal symptoms or other sedative- hypnotic withdrawal states?
- substituting for alcohol or other sedative-hypnotics during withdrawal states
- reducing the risk of withdrawal-related seizures.
What are Barbiturates?
CNS depression:
- Sedation →hypnosis →anesthesia →coma
- Higher than BZDs
What are the therapeutic uses of Barbiturates?
- Rarely used as sedative and hypnotic. These drugs have largely been replaced by safer agents such as BZDs for the treatment of anxiety and insomnia.
- Used as anticonvulsant in epilepsy and seizure. Barbiturates (phenobarbital): treatment of generalized tonic-clonic seizures, but not the drugs of first choice
- As a component of balanced anesthesia Barbiturates (thiopental): Used to induce anesthesia, often followed by inhalation agent
What are the general adverse effects of BZDs?
Safe, but produce CNS depressive effect on psychomotor and cognitive functions: drowsiness, confusion, anterograde amnesia; potentiate with alcohol, opiates CNS depressants.
What is the Tolerance of BZDs?
decreased responsiveness to a drug following repeated treatment: down-regulation of brain BZD receptors (pharmacodynamic tolerance); not induction of metabolic enzymes.
What is the Dependence of BZDs?
an altered physiologic state that requires continuous drug administration to prevent WITHDRAWAL symptoms:
A. Withdrawal symptoms: rebound anxiety, insomnia;
B. Withdrawal symptoms are more common and more severe in patients on BZDs with short half-lives as compared to long-half-lives;
C. Chronic use causes tolerance and dependence: patients on long-term BZD use MUST be tapered.
(severity of withdrawal sx’s is related in part to half-life!)
What are the considerations of BZDs?
- Prescriptions should be written for short periods
- Depressant effects on psychomotor & cognitive functions
- Used in combo with alcohol or other CNS depressants
- Older patients, patients with liver diseases
- Obese patients
- Unauthorized dosage increases
What are the contraindications of BZDs?
- Myasthenia gravis
- Narrow-angle glaucoma
- Alcoholism
- Severe sleep apnea
- Pregnant or nursing mothers
What is Flumazenil? What is the action site of Flumazenil?
has a high affinity for BZD binding site - BZD competitive antagonist
What are the therapeutic use of Flumazenil?
- Used to reverse the CNS depressant effects of BZD overdose
- Inhibits effects of BZDs, but DOES NOT inhibit effects of barbiturates, buspirone, ethanol, opioids or general anesthetics
– Given iv, it acts rapidly & has a short half-life (0.7-1.3 hours); if repeated dosing is usually necessary
– Caution: If BZDs given for seizures
What are the adverse effects of Barbiturates?
- inducer of metabolic enzymes (metabolic tolerance) & pharmacodynamic tolerance
- low therapeutic index
- not safe
- no antidote (compare with BZDs)
(CNS depression, physical dependence with more severe withdrawal sx’s, popular drug of social abuse)
BZDs vs barbiturates
Action site:
- BZDs: Potentiate GABA-A receptor activation
Barbiturates:
- Potentiate GABA-A receptor activation, GABA-mimetic at high concentration, Inhibit glutamate AMPA receptor
BZDs vs barbiturates
Pharmacokinetics:
- Lipophilic; rate of onset of action is determined by lipophilicity of individual drug
- BZDs: Many phase I metabolites of BZDs are active, no effect on Cyt-P450 isoenzymes
- Barbiturates: hepatic Cyt-P450 system inducers.
BZDs vs barbiturates
Therapeutic uses:
- BZDs: anxiety; insomnia; amnesia; epilepsy; muscle spasms; alcohol withdrawal
- Barbiturates: epilepsy, induction of anesthesia followed by inhalation agent.
BZDs vs barbiturates
Adverse effects:
Therapeutic index:
- BZDs: Therapeutic index is high, safe
- Barbiturates: Therapeutic index is low, high doses can cause cardiac and vascular depression
Dependence and withdrawal:
- Restlessness, insomnia, weakness, dizziness, nausea, sweating and anxiety.
- BZDs: need to be tapered; Barbiturates: Give BZDs and then need to be tapered
Overdose: BZDs: flumazenil; Barbiturates: No antidote
BZDs vs SSRIs in the treatment of anxiety
Action site:
BZDs: GABA-A receptor
SSRIs: serotonin transporter
BZDs vs SSRIs in the treatment of anxiety
Pharmacokinetics:
Onset of anxiolytic effects
- Faster with BZDs than SSRIs
BZDs vs SSRIs in the treatment of anxiety
Therapeutic uses:
- Anxiety caused by a temporary stressor may be better treated with a BZD
- SSRIs: more appropriate for long term anxiety, especially if anxiety may be a symptom of depression
- Recommended for days or weeks with BZD; months with SSRIs
BZDs vs SSRIs in the treatment of anxiety
Adverse effects:
- Therapeutic index: Both are high
- Drug interactions:
– SSRIs: due to inhibition of liver enzymes
– BZDs: CNS depressants including ethanol and
antihistamines - Dependence:
– BZDs: Rebound anxiety, insomnia after BZD therapy; need to be tapered
– SSRIs: No dependence - Amnesic effects:
– Produced by BZDs, not SSRIs
What are the other anxiolytics & hypnotics?
Structurally different from BZDs and barbiturates
Other anxiolytic:
- Buspirone
Other hypnotic:
- Zopiclone
What is the action site of Buspirone (Buspar): anxiolytic?
partial serotonin receptor agonist
no effect on GABA
What are the pharmacokinetics of Buspirone (Buspar): anxiolytic?
intermediate onset (takes more than 1 week)
What is the therapeutic use of Buspirone (Buspar): anxiolytic?
treat anxiety
What is the adverse effects of Buspirone (Buspar): anxiolytic?
No risk of tolerance & dependence, minimal abuse potential, no withdrawal effects
Consideration: Do not use with monoamine oxidase (MAO) inhibitors
What is the action site of Zopiclone (Imovane)?
structure is different from BZDs but GABA-A receptor binding site is same with BZDs, enhances GABA-mediated neuronal inhibition
What are the pharmacokinetics of Zopiclone (Imovane)?
rapidly metabolized
What is the therapeutic use of Zopiclone (Imovane)?
used for insomnia, not for anxiety, cause less
amnesia, minimal muscle relaxing and anticonvulsant effects
What are the adverse effects of Zopiclone (Imovane)?
drowsiness, memory impairments, but low risk for tolerance, dependence and withdrawal
Can be antagonized by flumazenil
