Anxiolytics and Hypnotics Flashcards
What is the general mechanism of majority of anxiety and insomnia agents?
- increase GABAergic activity
- major use is to alleviate anxiety (anxiolytic)
- a higher doses they have hypnotic effects
- GABA agonists are also used to achieve general anesthesia
How does GABA act on its receptor
- all neurons have GABA channels - can have different amounts of GABA receptors so they have different sensitivity
- GABA is the major inhibitory NT in the brain
- it binds to an ionotropic receptor (GABAa) or the metabotropic receptor (GABAb)
- when GABA binds to GABAa it opens Cl channels to allow it into the cell
- this makes the neuron hyperpolarized and less likely to fire
Why are there no medicines blocking GABAa?
- blocking GABAa receptor induces seizures
What is the effect of increasing benzodiazepine dose?
- relief from anxiety (anxiolytics)
- sedation (sedatives)
- drowsiness, calm/somnolescence - hypnosis (hypnotic)
- sleep
- confusion, delerium, ataxia (stumbling gait) - surgical anesthesia
- depression of respiratory and vasomotor center (due to depression in medulla)
- coma
- death
Why are depressants addictive?
- depressants at low doses disinhibit dopamine neurons in the VTA
- normally, inhibitory neurons keep dopamine from burst firing but depressants remove this inhibition so dopamine neurons can burst fire
- burst firing causes a large surge of dopamine
- mimics natural reward –> surge of DA that makes us like it
What is the role of dopamine neurons in survival?
- set of neurons project to the basal ganglia: connection between VTA and gasal ganglia involved in reward system
- when something new happens dopamine neurons fire
- when the new thing has a good outcome (pleasure), they fire more (keeping warm, eating, being around people - good for survival)
- when the new thing has a bad outcome (pain) they fire less (tells us what to avoid)
- the next time we encounter the cue we remember whether it was pleasurable or painful
Explain how expectation affects dopamine firing rate
Exceeding low expectations
Before: regular dopamine firing rate and DA released, low expectation
After: high dopamine firing rate, large amount of dopamine released, elation
Satisfying high expectations
Before: high firing rate, high dopamine level, anticipation
After: dopamine firing rate and levels are steady, satisfaction
Dissapointing high expectations
Before: high dopamine firing rate and dopamine levels, anticipation
After: dopamine firing rate drops and momentary no firing, levels drop close to none, dissapointment
How does dopamine affect movement?
low dopamine = low movement
high dopamine = more movement
- when we are excited we move more than when we are disapointed
What occurs to the dopamine responses when rats are conditioned to expect a reward?
- intially rats are given a sweet reward with no CS and there is neuron firing
- training sessions with a light CS occurs one second before reward is given
- dopamine neurons fire right after the CS in anticipation even before receiving the reward and dopamine is stable when they actually receive it
- when the reward doesn’t occur there is firing right after the CS and then the neurons stop firing when the reward isnt given and the rat learns that the light doesnt always predict a reward
How do drugs of abuse hijack the reward system?
- when alcohol is consumed the inhiibtory neurons that hold dopamine neurosn quiet are depressed and fire less causing a surge in dopamine release
- this reinforces the activity
- it is difficult to unlearn any behaviour that consistently causes a dopamine release
What is role of compulsion in addiction?
addiction: compulsive drug use despite adverse consequences
- feeling compelled to take the drug even if intellectually you don’t want to do it because of the consequences but there is another system compelling you to do so
- this drive is stronger than normal insticts to eat and drink
What is MOA of barbiturates?
- positive allosteric modulators
- bind at the interface of y2 and b2
- increase the length of time that chloride channels stay open
- this increases the efficacy of GABA –> larger maximal effect of GABA –> higher inhibition of neuron activity
What are the uses of barbiturates?
Anticonvulsant: phenobarbital, pentobarbital
rapid sedation/physician assisted suicide/capital punishment by lethal injection: thiopental
Why are barbiturates no longer used for anxiety?
- very small therapeutic window
- potential for lethal overdose
- chronic use associated with tolerance, physical dependence and addiction
- it crosses the placenta - babies can be born slugging and with depressed respiration, and it can be passed through breast milk
What is the difference between tolerance, physical dependence, addition and withdrawal?
Tolerance: GABA system wants to return to RMP (downregulation of GABA R or upregulating opposing R)
Dependence: drug needed for regular physiology, if not taken can result in withdrawal
Addiction: DA system
Withdrawal: in absence of drugs the body cannot function normally physiologically
What are the effects of barbiturates with alcohol, benzodiazepines?
- additive effects with alcohol (acts as barbiturate)
- superadditive effects with benzodiazepines because it increases affinity of BZD to GABAa
What are the 3 possible effects of drugs tat bind to the benzodiazepine modulatory site?
- agonism (partial or full)
- inverse agonism (Ro-15-143 - produced anxiety and seizures, was tested as counteracting ethanol intoxication but never left trial)
- antagonism (flumazenil - counteracts OD of BNZ)
What is the drug effect of anxiolytic and sedative hypnotic agents?
agonists - positive allosteric modulators
What is MOA of benzodiazepines?
- binding increases affinity of GABA binding site on chloride channel for GABA
- this increases the potency of GABA
- less GABA is needed to open the channel
- in parts of the brain where there is not enough GABA (in anxiety) - with BNZ less GABA is required for the same effect as if there was enough GABA
How is the maximum effect of GABA changed with BRB and BNZ?
BRB: larger maximal effect of GABA with constant dose of BRB is increased because it holds the channel open –> efficacy
BNZ: the maximal effect of GABA is not changed with BNZ, but the curve shifts left because less GABA is needed to achieve the maximal effect
Describe the dose response effects of BNZs
- anxiolytics: 20-40% receptor activation
- hypnotics: 60-80% receptor activation
full agonists (what we use now) have a very narrow therapeutic window for anxiolytic effects and rapidly become hypnotics as dose increases
partial agonists are being experimented now in which the dose response stays within the anxiolytic receptor activation window even at full effect
Describe the pharmacokinetics of BNZs: metabolism, tissue distribution, action duration, half life and elimination
- hepatic metabolism
- rapid tissue distribution
- long acting (we have some that are short acting but they have a high abuse liability ex. xanax)
- long half life and elimination (from 10 to > 100 hours) –> problem because we only want to sleep for 8 hours during the night which leads to daytime drowsiness, but good for anxiety bc it’s long acting
Are the half lives of BNZ metabolites greater or less than the parent drug?
- the half lives of the metabolites are often greater than the parent drug
- the prototype drug diazepam has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t1/2=20 to 80 hours)
Benzodiazepine drug names
diazepam
lorazepam
alprazolam (xannax)
oxazepram
triazolam
Z class:
zolpidem
zopiclone
