Flashcards in Anxiolytics and Hypnotics Deck (61):
What are the benzos considered to have long half lives?
- chlordiazepoxide, diazepam, prazepam, clorazepate, flurazepam
What are the benzos with short half lives?
lorazepam and oxazepam (without active metabolites)
alprazolam and triazolam (with active metabolites)
What is an anxiolytic?
- has calming effects
- relieves anxiety
What is a hypnotic?
- promotes drowsiness
- promotes onset and maintenance of sleep
What is the chemical classification of benzos?
- basic foundation is a benzene ring fused with a diazepine ring
What is the chemical classification of barbiturates?
- all barbiturates are related to the structure of barbituric acid (thiopental, pentobarbital)
What is a GABA receptor?
- action site: GABA-A receptor
- what is GABA-A receptor
-- GABA is the primary inhibitory NT in the brain
-- GABA-A receptor is a hetero-oligomeric glycoprotein with 2xa, 2xB and 1xgamma subunits
- alpha subunit has 5 isoforms with alpha 1-5
-- alpha 1- hypnotic
--alpha 2-5- sedation, psychomotor effect
- GABA-A receptor is a chloride channel
-- activation- chloride influx; hyperpolarizes neurons and decreases neuronal activity
How do benzos bind to the GABA-A receptors?
- enhance GABA actions - reduce excitability of neurons
- increase the frequency of channel opening events
- acts as CNS depressant
- has a low affinity for GABA-B receptors
How do barbiturates bind to the GABA-A receptor?
- bind to GABA-A receptor
- increased duration of channel opening events
- GABA mimetic at high concentrations
- inhibit glutamate AMPA receptor
What affects the onset of CNS drugs? (the time requires for drugs to be effective after administration)
- lipophilicity of drugs - affects onset of action
- why? BBB
- more lipophilic= more rapid onset of action
Duration of the effect of drugs depends on what? (duration is the amount of time that a measurable drug effect persists)
- biotransformation affects the duration of action:
-- microsonal oxidation (cyt P450 isozymes: phase 1 reactions)
-- conjugation (phase II reactions)
-- metabolic conversion to more water soluble metabolites is required for clearance of CNS drugs from the body
Lipophilicity of BZDs?
triazolam> diazepam> lorazepam, oxazepam
Many __ metabolites of benzos are active
What is the main differences between benzos?
- the rate of onset and the duration of action
How do the therapeutic uses relate to the half lives of drugs
short acting: preferred as hypnotic
long acting: preferred as anxiolytic
Where are benzos excreted?
Can benzos cross the placenta? Can be detected in breast milk?
yes to both
Where are benzos redistributed in obese patients?
Where are barbiturates metabolized?
Barbiturates are ____ inducers
hepatic cyt P450 system
Are barbiturates lipophilic or hydrophilic?
What are the different duration of actions of barbiturates and what are they used for?
- ultra short acting (30 min)- thiopental for induction of anesthesia
- short acting (18-48 hrs)- secobarbital. phenobarbital for hypnotic and sedative
- long acting (4-5 days)- phenobarbital for seizures
Therapeutic used for benzos
1. for relief of anxiety
2. for treatment of insomnia
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 disorder
6. for control of ethanol withdrawal symptoms or other sedative hypnotic withdrawal states
What are some of the major symptoms of anxiety?
- feelings of panic, fear and uneasiness
- uncontrollable obsessive thoughts
- problems sleeping
- cold or sweaty hands/ feet
- shortness of breath
- dry mouth
- numbness or tingling in hands/feet
- muscle tension
what drug is the first choice for long term management of anxiety and panic disorders?
Which benzo is the first choice for panic disorders and agoraphobia?
What are the stages of sleep?
Stage 1-4 (NREM) and REM
- Stage 1: light sleep during which the muscles start to relax
-Stage 2: brain activity slows own and eye movement stops
- Stage 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
Benzos as hypnotics
- decrease the latency to sleep onset and increase stage II of NREM
- decrease both REM and slow wave sleep
Drug selection for sleeping
- for difficulty falling asleep, use fast acting but shorter duration (triazolam)
- for frequent awakenings, but falling asleep is not an issue, use a drug of medium duration (lorazepam)
- start off with very low doses always
Drug selection for sedation and amnesia before and during surgical procedures
- produce sedative effects, cause anterograde amnesia
- benzos (midazolam and lorazepam) make them first choice for these purposes
- used in conjunction with anesthetics
- use before and during surgical procedures
Using benzos for treatment of epilepsy and seizure states
- can use lorazepam and diazepam
- management of seizures such as generalized tonic-clonic status epilepticus, absence seizures, partial seizures
Use benzos for muscle relaxant in skeletal muscle spasms caused by CNS disorder
- has useful relaxant effects in skeletal muscle spasticity of central origin (diazepam is used here)
Use of benzos for alcohol withdrawal symptoms or other sedative-hypnoti withdrawal states
- substituting for alcohol or other sedative hypnotics during withdrawal states
- reducing the risk of withdrawal related seizures
How do barbiturates cause CNS depression?
- higher than benzos
- sedation -> hypnosis -> anesthesia -> coma
What are the therapeutic uses of barbiturates?
- rarely used as a sedative or a hypnotic
- these drugs have been replaced by safer agents such as benzos for the treatment of anxiety and insomnia
- used as an anticonvulsant in epilepsy and seizure. Barbiturates can be used in the treatment of generalized tonic clonic seizures, but are not the DOC
How can barbiturates be used as a component of balanced anesthesia?
- can produce anesthesia (loss of feeling or sensation)
-- can enhance the inhibitory neurotransmission
-- inhibition of excitatory neurotransmission
-- thiopental is used as an anesthetic but not as an analgesic (analgesics are only used for pain sensations)
What are the adverse effects associated with benzos?
- CNS depression: drowsiness, confusion, anterograde amnesia, dizziness, lethargy, ataxia
-- may cause persistent "hangover" or residual daytime effects
- safe, except when used in combination with other CNS depressants (alcohol, opiates)
What is drug tolerance and how does it affect benzos?
tolerance: decreased responsiveness to a drug following repeated treatment
- benzo tolerance has been associated with down regulation of brain bento receptors (pharmacodynamic tolerance)
What is drug dependence and how does it affect benzos?
dependence: an altered physiological state that requires continuous drug administration to prevent withdrawal symptoms
- benzos withdrawal symptoms include relapse or rebound anxiety, insomnia, restlessness, etc
- severity of benzos withdrawal is related to the half life
- withdrawal sx are more common and more severs in patients on benzos with short half lives as compared to long ones
- patients on long term use of benzos must be tapered
What is the abuse potential of benzos?
- among the most widely abused drugs - have effects similar to alcohol
- widespread availability
- tolerance and dependence associated with long term use of benzos increase abuse potential
- cause and risk factors: in women and the elderly age groups, environmental factors (low socioeconomic status, unemployment, stress, over adherence
What are the things we must consider when giving benzos?
- prescriptions should be written for short periods
- depressant effects on psychomotor and cognitive functions
- used in combination with alcohol or other CNS depressants
- older patients, patients with liver disease
-unauthorized dosage increases
What are the contraindications to using benzos?
- myasthenia gravis
- narrow angle glaucoma (can stop the drainage from the eye)
- severe sleep apnea (can inhibit the airways and make sx of sleep apnea worse)
- pregnant or nursing mothers
What is flumazenil used for?
- used to reverse the CNS depressant effects of benzo overdose
- has a high affinity for benzo binding site- benzo competitive antagonist
- inhibits the effects of benzos but not the effects of other sedatives, hypnotics, buspirone, ethanol, opioids or general anesthetics
- given IV it acts rapidly and has a short half life- repeated dosing is usually necessary
- caution if benzos are given for seizures
What are the adverse effects of barbiturates?
- CNS depression- can cause cardiac and vascular depression
- TI is low -- barbiturates
What is the most common reason to abuse barbiturates?
- reason to abuse is just to counteract the symptoms of other drugs
What is the difference in the action site between benzos and barbiturates?
- benzos: potentiate GABA-A receptor activation
- barbiturates: potentiate GABA-A receptor activation, GABA-mimetic at high concentration, inhibit AMPA receptor
What is the difference in pharmacokinetics between benzos and barbiturates?
- they are both lipophilic- rate of onset of action is determines by lipid lipophilicity of individual drug
- benzos: many phase 1 metabolites of benzos are active, no effect on Cyt-P450 metabolites
- barbiturates: hepatic Cyt-P450 system inducers
Benzos vs barbiturates- therapeutic uses
Benzos: anxiety, insomnia, and others
Barbiturates: rarely used for anxiety and insomnia, can be used for anesthesia (not analgesic)
benzos vs barbiturates- adverse effects
- benzos: TI is high, safe
- barbiturates: TI is low, high doses can cause cardiac and vascular depression
Dependence and withdrawal
- benzos: needs to be tapered
- barbiturates: give benzos and then needs to be tapered
-benzos: can use flumazenil
-barbiturates: no antidote
Benzos vs SSRIs - action site
benzos: GABA-A receptor
SSRIs: serotonin transporter
benzos vs SSRIs- pharmacokinetics
- onset of anxiolytic effects: factor with benzos than SSRIs
benzos vs SSRIs- therapeutic uses
benzos - anxiety caused by a temporary stressor can use benzos (days or weeks)
SSRIs - more appropriate for long term anxiety -esp. if it is a symptom of depression (months)
benzos vs SSRIs - adverse effects
- both have a high therapeutic index
- SSRIs- due to inhibition of liver enzymes
- benzos - CNS depressants including ethanol and antihistamines
- benzos - rebound anxiety, insomnia after benzo therapy, need to be tapered
- SSRIs- no dependence
- produced by benzos, not SSRIs
Describe buspirone as an anxiolytic
- act as a partial agonist at serotonin 5HT1A receptor
- acts as a presynaptic antagonist at the presynaptic dopamine D2 receptor
- does not bind GABA receptors
- is rapidly absorbed orally
- extensive first pass metabolism (phase I enzyme- cyt P450) to doe several active metabolites. Elimination half life of buspirone is 2-4 hours
- takes more than 1 week to produce therapeutic effects
What is the therapeutic use of buspirone
- relieves anxiety- takes more than 1 week to develop- unsuitably for management of acute anxiety
- has not hypnotic effects
- less psychomotor impairment than benzos
- no anticonvulsant properties
- no muscle relaxant properties
What are the adverse effects of buspirone?
-tachycardia, palpitations, dizziness and others may occur (increase in SNS activity)
- no risk of tolerance and dependence, no withdrawal effects
--- do NOT use with monoamine oxidase inhibitors
How does zopiclone work?
- targets GABA-A receptor and is specific for alpha 1
- enhances GABA- mediated neuronal inhibition
(binds to the same site as benzos, but only targets the alpha 1 isoform for is more specific and has less focus on hypnotic effects)
What are the pharmacokinetics of zopiclone?
- lipophilic, rapidly absorbed and peak plasma concentrations occur within 1-2 hours
- rapid metabolism via cyt P450 -fewer concerns with accumulation.
- half life of 3-5 hours
What is the therapeutic use of zopliclone?
- not for anxiety
- only use for insomnia
- increases total sleep time- increases stage 2 NREM sleep time
- only for short term tx
- cause less amnesia
- minimal muscle relaxing effects
- minimal anticonvulsant effectis