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PCL470 > Anxiolytics and Hypnotics > Flashcards

Anxiolytics and Hypnotics Flashcards

1
Q

What is the general mechanism of majority of anxiety and insomnia agents?

A
  • 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
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2
Q

How does GABA act on its receptor

A
  • 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
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3
Q

Why are there no medicines blocking GABAa?

A
  • blocking GABAa receptor induces seizures
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4
Q

What is the effect of increasing benzodiazepine dose?

A
  1. relief from anxiety (anxiolytics)
  2. sedation (sedatives)
    - drowsiness, calm/somnolescence
  3. hypnosis (hypnotic)
    - sleep
    - confusion, delerium, ataxia (stumbling gait)
  4. surgical anesthesia
  5. depression of respiratory and vasomotor center (due to depression in medulla)
  6. coma
  7. death
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5
Q

Why are depressants addictive?

A
  • 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
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6
Q

What is the role of dopamine neurons in survival?

A
  • 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
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7
Q

Explain how expectation affects dopamine firing rate

A

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

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8
Q

How does dopamine affect movement?

A

low dopamine = low movement
high dopamine = more movement
- when we are excited we move more than when we are disapointed

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9
Q

What occurs to the dopamine responses when rats are conditioned to expect a reward?

A
  • 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
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10
Q

How do drugs of abuse hijack the reward system?

A
  • 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
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11
Q

What is role of compulsion in addiction?

A

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

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12
Q

What is MOA of barbiturates?

A
  • 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
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13
Q

What are the uses of barbiturates?

A

Anticonvulsant: phenobarbital, pentobarbital
rapid sedation/physician assisted suicide/capital punishment by lethal injection: thiopental

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14
Q

Why are barbiturates no longer used for anxiety?

A
  • 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
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15
Q

What is the difference between tolerance, physical dependence, addition and withdrawal?

A

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

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16
Q

What are the effects of barbiturates with alcohol, benzodiazepines?

A
  • additive effects with alcohol (acts as barbiturate)
  • superadditive effects with benzodiazepines because it increases affinity of BZD to GABAa
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17
Q

What are the 3 possible effects of drugs tat bind to the benzodiazepine modulatory site?

A
  1. agonism (partial or full)
  2. inverse agonism (Ro-15-143 - produced anxiety and seizures, was tested as counteracting ethanol intoxication but never left trial)
  3. antagonism (flumazenil - counteracts OD of BNZ)
18
Q

What is the drug effect of anxiolytic and sedative hypnotic agents?

A

agonists - positive allosteric modulators

19
Q

What is MOA of benzodiazepines?

A
  • 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
20
Q

How is the maximum effect of GABA changed with BRB and BNZ?

A

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

21
Q

Describe the dose response effects of BNZs

A
  • 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

22
Q

Describe the pharmacokinetics of BNZs: metabolism, tissue distribution, action duration, half life and elimination

A
  • 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
23
Q

Are the half lives of BNZ metabolites greater or less than the parent drug?

A
  • 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)
24
Q

Benzodiazepine drug names

A

diazepam
lorazepam
alprazolam (xannax)
oxazepram
triazolam

Z class:
zolpidem
zopiclone

25
Q

Adverse effects of BNZs, BRBs, and alcohol?

A
  • somnolescence (sleepiness)
  • impairment of memory –> anterograde amnesia: loss of memory for events that occur after taking a drug
  • impaired cognition
  • motor function (falls, MVAs)
  • disinhibition of behaviours
26
Q

What are the names of newer hypnotics?

A

Zolpidem and zolpiclone (z class)

27
Q

Zolpidem MOA
(drug type, binding site, onset, metabolism in men vs women)

A
  • positive allosteric modulator of GABAa receptors
  • binds to different site than BNZs
  • only binds to alpha 1 containing GABAas receptors
  • rapid onset of 15 minutes –> good for intiating sleep but not maintaining it (controlled release formulation now available for this?)
  • women metabolize the drug much more slowly then men, possibly because of hormone regulation of CYP3A
  • in 2013 the FDA reduced recommended dose for women –> only need 1/4 dose of men
28
Q

Why is zolpidem used as a hypnotic and not an anxiolytic?

A
  • only binds to alpha 1 containing GABAa receptors which are not in the amygdala –> not anxiolytic
  • strong hypnotic
  • weak myorelaxant and convulsant
29
Q

What are the adverse effects of zolpidem?

A
  • similar to BNZ
  • also includes parasomnias - people can perform tasks and appear awake but they’re asleep
  • anterograde amnesia can occur so there’s no memory of them performing the activities
30
Q

Tolerance, relapse, rebound, dependence, withdrawal, and addiction with BNZs

A

Tolerance
- drug loses desired therapeutic effect
- GABA system downregulates to compensate for the upregulation seen with BNZs
- need a greater dose for the same effects
- not part of reward system
- issue for long term use for anxiety because dose escalation can increase the risk of addition
- relapse = return of original symptoms
- rebound = return of original symptoms at a greater intensity than before

Dependence
- body works best when drug is present, it is needed for normal physiology

Withdrawal
- when the body is dependent and the drug removed
- symptoms can be what was previously experienced
- this leads to repetitive use and risk for addiction

Addiction
- chronic use can lead to addiction - compulsion to take drug despite adverse consequences

31
Q

BNZ withdrawal symptoms

A
  • all sensory systems are enhanced becasue they were downregulated due to GABA
  • confusion
  • dysosmia
  • paresthesias
  • muscle cramps, twitches
  • blurred vision
  • diarrhea, decreased appetite, weight loss
  • hallucinations
  • psychotic symptoms
  • delerium
  • seizures –> dont always resolve because now there is down regulation of the break system after it was continuously amplified
32
Q

What neurotransmitted systems are affected by alcohol?

A

GABA
- major inhibitory NT in the brain
- alcohol facilitates the action of GABAa (acts as allosteric modulator)
- this creates enhanced inhibition

glutamate
- major excitatory NT
- alcohol inhibits NMDA glutamate receptors
- this diminishes excitatory action of glutamate which promotes inhibition system (keeps them hyperpolarized by preventing movement of Na and Ca)

dopamine
- reward process - responsible for rewarding aspects of alcohol consumption
- alcohol stimulates DA action by increasing firing of DA neurons

33
Q

How does the NMDA glutamate receptor work?

A
  • NMDAR is a Na and Ca channel
  • harder to open (not the one that is active all the time)
  • excitatory because it allows for the influx of Na+ leading to depolarization
  • inhibition leads to less excitation
  • drugs that activate it lead to seizures and cell death due to excitotoxicity
34
Q

How does alcohol act on the NMDA glutamate receptor?

A
  • ethanol acts as antagonist
  • this leads to less neuron excitation
  • blocking it prevents learning and memory –> this is why there are lapses in memory when you drink
  • PCP and ketamine also block the NMDAR –> don’t mix with alcohol
35
Q

How does alcohol depress neuron firing?

A
  • excitatory neurons produce ESPSs and inhibitory neurons produce IPSPs
  • alcohol blocks excitatory NMDA receptors and facilitates inhibitory GABA receptors
  • there are more IPSPs which counters EPSPs so the neuron integrating the information wont fire
36
Q

Acute effects of alcohol

A
  • euphoria, disinhibition, reduced anxety, impaired reaction time, balance, speech, vision, hearing and motor coordination
  • increased vasodilation (feeling flushed and warm) can lead to loss of body heat
  • increased gastric secretion (ulcers)
37
Q

What are the effects of alcohol poisoning and how is it treated?

A
  • vomiting, unconsciousness, coma, death from respiratory depression
  • there are no drugs to counteract it
  • stomach pumping doesnt really work because alcohol is absorbed quickly
  • keep them warm and give oxygen for the brain and hope their body breaks down the alcohol
38
Q

What disease states can arise from chronic alcohol use?

A
  • dependence: abrupt withdrawal can cause seizures and death
  • addiction
  • wernicke-korsakoff syndrome: amnesia and cognitive impairments due to thiamine deficiency due to less nutrients taken in, parts of the hippocampal learning system (mamillary bodies) degenerate
  • FASD: reduced testosterone and increased glucocorticoids
  • fatty liver, alcohol hepatitis and cirrhosis: alcohol converted to aldehyde which is reactive
  • hypertention, heart failure
  • liver cancer
39
Q

How does alcohol withdrawal lead to seizures and death?

A
  • NT levels are changed to compensate for alcohol
  • upregulation of NMDA and downregulation of GABA
  • can cause seizures and neuronal death due to excitotoxicity
40
Q

alcohol, BNZ, and barbiturates actions on GABA, NMDA, DA system, therapeutic effects, adverse effects

A

GABA
- all positive allosteric modulators
- bind at different sites
- alc and BRB open channel time
- BNZ increases frequency of channel

NMDA
- alcohol acts as + allosteric modulator and doesnt compete

DA
- al promote DA neurotransmission

therapeutics
- anxiety/sedation, hypnotic, anesthetic only BRB on its own but BNZ can be used as a part of it, anticonvulsant: BNZ and BRB: epilepsy, BRB: status elepticus

adverse effects
- somnolescence, addiciotn, tolerance, withdrawal, rebound, coma, death

PCL470 (14 decks)

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