Anxiolytics and Hypnotics Flashcards
GABA channels let
Chloride anions in
Mechanism of action for pharmacological agents treating acute anxiety and insomnia
For a majority of these drugs, action is to increase GABAergic energy
GABA agonists uses
Act to hyperpolarize cells (Cl- in)
- anxiolytics
- hypnotic (sleep)
- surgical anesthesia
GABA A vs GABA B receptor
- GABA A is an ion channel
- GABA B is a metabotropic receptor
What happens when you block GABA A
no medicine blocks GABA A, experiments have shown blocking this channel to cause seizures
What happens with increased GABAergic transmission between normal transmission and death
normal GABAergic transmission
> then relief from anxiety (anxiolytic)
> then sedation (sedatives): drowsiness, increase in reaction time
> then hypnosis (sleep)
> then confusion, delirium, ataxia (stumbling gait)
> then surgical anesthesia
> then depression of respiratory and vasomotor center
> then coma
> death
Why are depressants addictive?
- depressants at high doses will reduce activity of all neurons, but depressants at low doses will disinhibit dopamine neurons
- so, normally DA neurons are inhibited by inhib. interneurons. Removing the inhibition allows the DA-ergic neurons to burst fire
- burst-fire DA mimics natural reward
How to learn and survive (DA mechanism)
When something new happens, dopamine neurons fire
- if that new thing has a good outcome, they fire more
- if that new thing has a bad outcome, they fire less
(more firing = more DA)
next time we encounter that cue, we remember what happened last time and can predict whether it will be pleasurable or painful based on what happened last time
Eventually, with a conditioned stimulus and expectation of a reward, dopamine firing…
shifts to occur at the CS and not at the actual reward itself
It is very difficult to unlearn a behaviour that consistently…
causes a dopamine surge. Drugs of abuse take advantage of this and hijack the ‘reward’ system
Addiction
compulsive (drug use) despite adverse consequences (expanded to include gambling, sex, eating, shopping)
Ethanol action on reward system
disinhibits dopamine neurons by inhibiting inhibitory interneurons (more DA released)
Barbiturates
- increase the length of time that the channel stays open, which increases the efficacy of GABA (positive modulators of GABA) so that more Cl- comes in every time the channel opens
- Used for rapid sedation and anesthesia
- used in assisted-suicide and capital punishment
why aren’t barbiturates used for anxiety anymore
- can cause lethal overdose
- chronic use can cause tolerance (GABA related), physical dependence, and addiction (DA related)
Barbiturates and: babies, alcohol, BZDs
- barbiturates can cross the placenta and cause baby to be born sluggish and with respiratory depression (can also cross breastmilk)
- additive effects with alcohol
- superadditive effects with BZDs because BZDs increases affinity of GABA to GABA A
examples of barbiturates
phenobarbital, pentobarbital, thiopental
Actions at the Benzodiazepine Modulatory Site
(and examples of drugs)
- agonism (partial and full) - anxiolytic and sedative hypnotic agents are agonists
- inverse agonism - will cause anxiety and seizures but also counteract ethanol intoxication. ex. Ro15-143
- Antagonism - counteract OD of BZDs. ex. flumazenil (will compete with BZDs for binding site)
Ro15-143
was a drug that never left clinical trials
- on its own it produces anxiety and seizures
- can be used to counteract drunkenness but problem is people would drink more after waking up and then Ro15-143 would wear off and they would have even more alcohol in their system than before
Tolerance: good and bad scenarios
good: you adjust to SSRIs (no more gut probz, headaches, insomnia, etc)
bad: you adjust to barbituates and alcohol so with repeated use, efficacy goes down
tolerance is good when it gets rid of negative effects but bad when it reduces efficacy
Addiction does not equal tolerance
addiction is compulsion to take a drug despite negative consequences
WHILE
tolerance is your body has changed physiologically
Barbiturates vs BZDs
Barbiturates increase the amount of chloride that comes into the cell with each opening of a GABA channel (keeps it open longer)
WHILE
BZDs increase the affinity of the GABA A channel for GABA (GABA at a lower conc will bind the receptor and Cl- will come in)
Why would you want a partial GABA agonist?
You would get anxiolytic effects without the hypnotic effects (even with dose escalation)
BZD Pharmacokinetics
- hepatic metabolism
- rapid tissue distribution (long acting and long half-lives & elimination half-lives from 10-100+ hours which is an issue if you actually want to wake up in the morn however shorter-acting BZDs have greater abuse liability)
- may have active metabolites with half-lives greater than the parent drug
BZDs and babies
BZDs cross the placenta and are detectable in breast milk
- may exert depressant effects on the CNS of the lactating infant
prototype BZD
diazepam (valium)
- has active metabolites: desmethyl-diazepam and oxazepam
- long-acting: half-life of 20-80 hours
examples of BZDs
diazepam, lorazepam, alprazolam (xanax), oxazepam, triazolam
z-class of BZDs
for sleeping! Zzz
Zolpidem (Ambien)
Zopiclone
Zolpidem
- Sold under brand-name Ambien
- In z-class of of BZDs
- a positive allosteric modulator of GABA A receptors
- binds to a different site than BZDs and only binds to alpha-1 containing GABA A receptors so they’re a strong hypnotic but weak myorelaxant/ anticonvulsant
- rapid onset (good for initiating sleep but bad at maintaining)
- adverse fx similar to BZDs but can also include parasomnias
Why are women more sensitive to Zolpidem than men?
Not really known but thought to be maybe related to the hormonal-regulation of CYP3A
Parasomnias
Syndromes where people appear awake but can perform complex tasks like driving a car. Can also involve anterograde amnesia (person can’t form new memories) so person doesn’t have any memory of performing the activities
Adverse effects of BZDs
If you increase GABAergic transmission, all areas of the brain will be hit
- somnolence (sleepiness)
- impairment of memory (anterograde amnesia, no memory of events that occur after taking drug)
- impaired cognition
- motor function (falls, motor vehicle accidents)
- disinhibition of behaviours (don’t consider long-term consequences)
Contraindication
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient
Warnings for BZD usage
- alcohol/substance use is a relative contraindication (remember that alcohol has synergistic effects with GABA agonists)
- potential somnolence with anxiolytic use
- tolerance develops which can make long-term usage problematic
- withdrawal: symptoms may or may not have been previously experienced (original symptoms return = relapse, original symptoms at greater intensity = rebound)
- addiction, potentially
Withdrawal symptoms associated with coming off a drug that increases GABAergic transmission
BZDs, alcohol, barbiturates
- confusion
- clouded or heightened sensory perception
- dysosmia (abnormal taste/smell)
- paresthesias (tingling, numbness, burning)
- muscle cramps, twitches
- blurred vision
- diarrhea, decreased appetite, weight loss
- hallucinations and other psychotic symptoms
- delirium
- seizures
Why might withdrawal from BZDs/Barbiturates/Alcohol cause seizures and why are they different than epileptic seizures
Different from epileptic seizures that normally self resolve, these ones do not always resolve on their own
- As a compensatory response to BZD drugs, you’ve down-regulated the brake system in your brain
- with no BZD to act as the artificial brake and your natural system caput, your brain has no chance against the seizures
Why we study alcohol in PCL470
It has limited therapeutic applications, BUT
- so many people drink it
- drug-drug interactions between alcohol and other drugs are super important to learn because of the wide-spread usage of alc
- it is psychoactive and has abuse and addiction liability
Three neurotransmitter systems affected by alcohol
- GABA - alc facilitates action of the GABA A receptor (creates enhanced inhibitions)
- Glutamate - alc inhibits NMDA receptors whcih diminishes the excitatory capability of glutamate (also why anterograde amnesia occurs)
- dopamine - alc increases firing of DA neurons (prevents their inhibition by dampening inhibitory interneurons)
so alcohol depresses neuron firing through both 1 and 2 (increasing inhibition through GABA and decreasing excitation by blocking NMDARs)
NMDA and ethanol
- NMDARs are sodium and calcium channels that normally act to depolarize the membrane
- ethanol antagonizes NMDA receptors making it less likely a neuron will be excited
Why shouldn’t you mix alcohol and ketamine or PCP
PCP and Ket also block NMDARs as well as alc. additive effects
Blocking NMDARs is bad but on the flip side, activating them too much can…
induce seizures and cell death
- excitotoxicity from too much calcium
Central and peripheral effects of alcohol
acute effects:
- euphoria, disinhibition, reduced anxiety, impaired reaction time, balance, speech, vision, hearing, motor coordination (50-100 mg/dL)
- increased vasodilation (flushed, feeling of warmth), which can lead to loss of body heat
- increased gastric secretion (GI ulceration)
- vomiting, unconsciousness (200-300 mg/dL)
- coma (300 - 400 mg/dL)
- death from respiratory depression (> 500 mg/dL)
Disease-states from chronic alcohol consumption
- dependence (abrupt withdrawal can cause seizures and death)
- addiction
- wernicke-korsakoff syndrome
- fetal alcohol syndrome
- endocrine effects: reduced production of testosterone and increased glucocorticoids
- fatty liver, alcoholic hepatitis, and cirrhosis of the liver (fibrosis/scarring)
- hypertension and with that increased risk of heart failure
- liver cancer and increased risk of several cancers including breast and colon cancer
dependence and withdrawal…
go hand-in-hand
wernicke-korsakoff syndrome
Amnesia and cognitive impairment due to thiamine deficiency:
- people don’t get enough thiamine because they’re drinking more than eating
- mammillary bodies near the hippocampus are most vulnerable to thiamine deficiency and neuronal death will occur
Fetal alcohol syndrome
In utero exposure to alcohol causes craniofacial abnormalities, cognitive and behavioural deficits, stunted growth
Why does alcohol cause cirrhosis of the liver?
Alcohol changes the chemicals that breakdown scar tissue
- scar tissue builds up and replaces normal tissue and liver function is impaired
Why is medical supervision needed during alcohol detoxification?
(also list symptoms of withdrawal)
chronic use often leads to physical dependence
- upregulated NMDARs and downregulated GABARs to compensate for depressant actions of alcohol
Alcohol withdrawal can lead to fatal symptoms:
Delirium tremens (DTs) is the most severe form of ethanol withdrawal, manifested by altered mental status (global confusion) and sympathetic overdrive (autonomic hyperactivity), which can progress to cardiovascular collapse. Minor alcohol withdrawal is characterized by tremor, anxiety, nausea, vomiting, and insomnia. Major alcohol withdrawal signs and symptoms include visual hallucinations and auditory hallucinations, whole body tremor, vomiting, diaphoresis, and hypertension (high blood pressure).
similarities and differences of alcohol, BZDs, and barbiturates
similarities:
- All three are positive allosteric modulators of GABA receptor (alcohol just facilitates GABA action, barbit. increase channel open time, and BZDs increase channel affinity for GABA)
- all three promote DA firing
- have similar therapeutic effects (anxiolytic, sedation, hypnotic, etc) and adverse effects (somnolence, addiction, tolerance and withdrawal, rebound, coma, death)
differences:
- only alcohol acts on NMDARs (antagonizes)
- BZDs they have a wider therapeutic index, tolerance develops more slowly, and their liability for abuse is lower than that of the barbiturates.
