anxiolytic agents Flashcards
What are the different levels of “graded response” of the CNS to sedative hypnotics?
• Least to most
• Sedation, disinhibition, anxiolysis
○ Therapeutic window for possible selective anticonvulsant and muscle-relaxant
• Hypnosis
• Anestheisa
○ Benzodiazepines start leveling off in ability at about this point
• Medullary depression
• Coma
○ Barbituates get you here
○ There are times where induction of a coma is indicated
What is dangerous about really high doses of barbituates?
• As you increase the dose of these drugs above that needed for hypnosis/sleep
○ Reach general anestheia
○ Progression to depression of respiratory and vasomotor centers
• Ultimate worry is coma and death with overdose
What’s the major difference in dose considerations between beznodiazepines and barbituates?
- Benzodiazepines are non-linear in their dose response relationship
- They need much greater dosage increments to achieve CNS depression
- Greater margin of safety as a result
What are the 4 categories of drugs used in treatment of anxiety?
• Antidepressants
○ SSRIs and SNRIs are most commonly used
• Benzodiazepines
○ Useful in acute or situational anxiety
• Buspirone
○ Weaker, but fewer side effects
• Barbituates
○ Try not to use these for day-day treatment of anxiety
Sedative and hypnotic drugs are separately classified from other CNS depressants how?
- Graded, dose-dependent depressant effects
- Augment GABA neuronal inhibition and/or inhibit glutamate neuronal excitation
- Sedative - decreasing activity, moderating excitement, calming
- Hypontic - drowsiness, facilitate onset and maintenance of sleep that resembles natural sleep and from which recipient can be easily aroused
What is the most common mechanism of action for the sedative-hypnotic drugs?
• Vast majority act to facilitate the action of GABA at the GABA-a receptor
○ This is a chloride ion channel complex
• GABA is major inhibitory transmitter in the CNS
• Increasing Cl conductance will hyperpolarize the neuron
• Hyperpolarization leads to diminished neuronal excitability and neurotransmission
• Molecular level - usually facilitate opening but does not directly initiate cl current
What do benzodiazepines vs. barbituates in particular do to the GABA receptor?
• Benzos - Intensify the effect of GABA
○ Barbituates will prolong GABA effect
• Benzos - need GABA for effect (thus can’t be used for surgical anesthesia)
○ Barbituates at high concentrations will interact with GABA receptor directly
• Barbituates are less selective and also depress excitatory NT
○ Lower safety margin
Flumazenil does what?
- Antagonist of benzodiazepines
* Competitive inhibitor, binds at benzo site on GABA channel complex
Zolpidem is an example of what type of drug?
- Z drug
* Non-benzodiazepines that interact with the benzodiazepine binding site as agonists
What importance do the different alpha subunits of the GABA-a Cl channel have on drug effect?
• Alpha-1 subunit vs. alpha-2/5 subunit
• These subunits are differentially expressed in different areas of the brain and allow for more targeted treatments
• Alpha-1 is expressed in the cortex
• Alpha-2/5 is expressed in the limbic system and brain stem
○ Benzo’s - both subunit types
○ Produce sedative (sleep), amnestic, anxiolytic and anticonvulsant actions
○ Z-drugs are alpha-1 specefic and produce sleep but no anxiolysis
Anxiolysis and sedation are considered the same thing. Why?
• Described as a decrease in responsiveness to a given level of stimulation
• Allows for relief of anxiety (valence attributed to situation and stimuli)
• Anxiolysis is usually accompanied by some impairment of psychomotor function
○ Behavioral disinhibition may also occur
• Non-sedative anxiolytics exist
○ Buspirone and propanolol
How can benzo treatment help with muscle spasms?
- Action to inhibit spinal cord polysynaptic reflexes may aid in muscle spasms
- Effect requires high doses, usually accompanied by significant CNS depression
Describe the anticonvulsant effects of the sedative-hypnotic drugs.
• Higher doses of most barbiturates and some benzos inhibit formation and spread of seizure activity in cortical neurons
• Some do so at does that do not cause severe sedation or effects on mental or motor activity
○ Phenobarbital, clonazepam
• Diazepam (or lorazepam) is drug of choice for status epilepticus
Describe the use of these drugs for anesthesia
- Short-acting barbitruates (thiopental) used to induce or maintain surgical anesthesia
- Bezos are not capable of inducing or maintaining anesthesia but are used as adjuncts for their anxiolytic and amnesia producing properties
Describe the attributes of psychologic and physical dependence on the sedative-hypnotic drugs
• Desirable effects frequently lead to compulsive misuse and pscychologic dependence
○ Relief of anxeity, euphoria, disinhibition, promotion of sleep
• ALL cause physical dependence if used on a chronic basis
○ Need to titrate down if you want to get off of them
• Withdrawal syndrome includes
○ Decreased appetite, nausea, fatigue, tachycardia, insomnia, depression, weight loss
○ May also see a state of increased excitability (anxiety, tremors, hyperreflexes)
○ These excited brain functions can lead to convulsions
• The shorter the 1/2 life, the worse the withdrawal
Can tolerance to sedative and hypnotic drugs occur?
• Yes.
• Common feature when agents are used continuously in high doses
• May require increase in dose to maintain effect
• Metabolica nd pharmacodynamic components of tolerance are seen
• Occurs rapidly to sedative and anticonvulsant effects
○ Less tolerance to anxiolytic effects
Which diazepines have a fast onset of action when taken by the oral route and are therefore good for prn usage?
- Diazepam, alprazolam, triazolam
* Oxazepam and temazepam have SLOW absorption so don’t use these orally for prn use
How are the hypnotic-sedative drugs eliminated?
• As lipid soluble drugs, benzodiazepines require biotransformation to more water-soluble metabolites
○ 1/2 life depends mainly on actiivity of drug metabolizing enzymes
§ CYP2C19 and CYP3A4
• Most benzos undergo CYP450 oxidations
○ Phase I
• Then subsequent inactivation via conjugation by glucuronidation
○ Phase II
• After phase II there is renal elimination (it’s soluble enough to be eliminated renally)
• Barbiturates are oxidiezed to inactive metabolites via CYP450, excreted as glucuronide
Thiopental can lose its efficacy pretty quickly. It’s not due to 1/2 life but what is it due to?
- Super lipid soluble, so it gets into CNS quickly. BUT, it also gets rapidly redistributed everywhere else
- The redistribution is associated with the loss in efficacy
What benzo has fast and reliable intramuscular absorption?
- Lorazepam
* Diazepam and chlordiazepoxide have poor IM bioavailability
Diazepam, chlordizepoxide and flurazepam can all end up causing an elderly person to be sedated in the daytime and other CNS effects. Why?
- The elderly have slower drug elimination routes/processes
- These drugs all have phase I metabolites that are still active, but have longer 1/2 lives.
- Thus, you can get a build up of this metabolite over time with repeated doses. Take this into account with elderly patients
What are the drug-drug interactions you need to think of with sedative-hypnotic drugs?
• Barbiturates are classic inducers of CYP450 enzymes
• Represent a major source of clinically significant drug interactions
○ One of the many reasons for declining use
• Drug interactions are possible whenever benzos are given with inducers or inhibitors of CYP450
○ Chronic benzo use DOES NOT induce CYP450
What are the three notable extension effects of benzodiazepines?
• Sedation and performance impairment
○ Excessive drowsiness, psychomotor incoordination, decreased concentration, cognitive deficits, impaired judgment
○ More likely to be seen with use of high doses or benzos with long or intermediate 1/2 lives
○ Shorter the 1/2 life, less the daytime sedation
○ These are more likely in older patients (impaired elimination)
• Drug-drug interactions
○ Safe to use alone but they have additive depressant effects if given with alcohol, opioids, antipsychotics, anticonvulsants, antihistamines, TCAs
• Anterograde amnesia
○ New memory is impaired
○ Happens through the enhancement of GABA function
○ Can use for uncomfortable procedures as they cooperate but don’t remember later
○ Criminal use in date rape
§ Flunitrazepam = roofies
What’s the black box warning of benzo’s?
- All drugs in this class have a black box warning relating to occurrence of strange sleep-related behavior and severe allergic reactions (anaphylaxis and facial swelling)
- Use of oral benzo’s alone is safe but it can make chronic pulmonary disease worse as well as symptomatic sleep apnea
If you use benzos during a surgical procedure and you want to hasten recovery, what benzo receptor antagonist can you use?
- Flumazenil is a benzo receptor antagonist
- Reverses sedative effects of benzos
- Doesn’t help at all in barbiturate or ethanol toxicity
What’s the drug regimen for Genarlized anxiety disorder?
- First line - Ssris, snris,
* Second line - Benzos, buspirone, TCAs
What’s the drug regimen for PTSD?
- First line - CBT (behavioral), SSRIs and SNRIs
* There is no second line here, the first line are super effective
What’s the drug regimen for Obsessive Compulsive disorder?
- First line - CBT (behavioral), SSRIs and SNRIs
* Second line - augment with atypical antipsychotics
What’s the drug regimen for Social Anxiety disorder?
- Generalized - Ssris, snris,
* performance - Beta Blockers (propanolol) or high potency BDZs (alprazolam, clonazepam)
What’s the drug regimen for Panic disorder?
• First line - high potency BDZs (alprazolam, clonazepam) for acute situation
○ Ssris for non-acute therapy
• Second line - Benzos, MAOIs, TCAs
The benzodiazepines given to us in the LO to memorize are what? (6)
- Diazepam (Designated)
- Alprazolam (aphrodesiac)
- Lorazepam (lotions)
- Flumazenil (facilitate)
- Oxazepam (overt)
- Midazolam (movements)
What are the two barbiturates French told us to memorize?
- Phenobarbital
* pentobarbital
