Anxiolytics Flashcards
Which benzodiazepine is used primarily for preoperative sedation?
midazolam [short-acting]
Which benzodiazepines are used as anxiolytics?
- alprazolam [intermediate]
- lorazepam [intermediate]
- diazepam [long-acting]
What is the main feature that distinguishes benzodiazepines from each other?
What is the margin of safety?
When are they lethal?
Do they cause dependence? addiction?
Benzos are indistinguishable except for their metabolic half-life.
The margin of safety is 100-fold so it is nearly impossible to commit suicide with them EXCEPT if they are mixed with another CNS depressant or alcohol.
They cause physical dependence WITHOUT addiction
What is the order of effects when taking an anxiolytic/sedative/hypnotic?
- anxiolytic
- sedation
- hyponotic
- anesthesia
- coma
What is the MOA of benzodiazepines?
They bind to a different site on the GABA-A receptor as GABA and act as a positive allosteric regulator.
GABA binds at a/b interface and benzo binds at a/g interface. In the presence of GABA, benzodiazepines increased Cl- flux through the channel by increasing FREQUENCY of channel opening
What 3 drugs/substances have binding sites of GABA-A receptor and exert anxiolytic/sedative effects?
- benzodiazepines [have a ceiling]
- barbituates [no ceiling]
- alcohol [no ceiling]
How are benzodiazepines metabolized?
Which is metabolized into long-lasting active metabolites?
Which are metabolized to shorter duration active metabolites?
Which is metabolized by glucuronidation and bypasses P450 [making it safer for the elderly]?
In the liver
Long-acting = diazepam
Intermediate = alprazolam
Short-acting = midazolam
Bypass P450 = lorazepam
You want to select a benzodiazepine for preoperative sedation. What do you select?
midazolam - anterograde amnesia
What benzodiazepine is prescribed for:
- anxiety
- agorophobia
- panic disorder
- hyponosis
alprazolam
Which benzodiazepine is prescribed for:
- anxiety
- seizures [esp. epilepticus]
lorazepam
Which benzodiazepine is prescribed for:
- anxiety
- muscle spasm
- seizure disorders
- alcohol detox
diazepam
When do benzodiazepines pose the greatest risk for adverse effects?
What delivery method of benzos has the narrowest safety margin?
When they are taken with other depressants [most often alcohol]
IV has a narrower safety margin
What is the typical response when benzodiazepines are withdrawn after long-term use? Why?
How do you avoid these symptoms?
Benzodiazepines cause physical dependence so the body functions normally in the presence of the drug. When it is withdrawn it causes:
- rebound insomnia
- excitement
- anxiety
- seizures [sometimes]
These symptoms can be avoided with a drug taper rather than abrupt stop of administration
Which benzodiazepines are most difficult to withdraw from?
Why?
Intermediate acting like lorazepam and alprazolam are notoriously difficult because they act long enough for the body to get dependence, but are short-acting enough that they don’t “self-taper” like the long-acting diazepam
What special consideration is given when dosing the elderly with benzodiazepines?
Lower dose, less frequently because they have reduced P450 in the liver so the drug can’t be detoxed as easily.
Also, the elderly already have lower levels of alertness, attention and memory
What are the 6 main therapeutic uses of benzodiazepines?
- anxiety
- insomnia
- epilepsy
- muscle relaxation
- anesthetic
- alcohol detox
Many of the specific anxiety disorders like OCD, panic disorders, PTSD, and social phobias are treated with _________________. More generalized and less specific anxiety is treated with ________________.
Specific = antidepressants generalized = benzodiazepines
Tolerance to the __________effects of benzodiazepines is not developed.
anxiolytic
What part of the brain and what receptors do benzodiazepines work on the decrease anxiety?
They work on GABA receptors in the amygdala
Benzos can be effective at treating insomnia but their long term effects can do what?
How do you alleviate these effects?
Long term effects:
- alter normal sleep cycle
- exacerbate sleep disorders
Alleviate by:
- prescribe for short time [days->wks]
- only prescribe after behavior changes were attempted
When do you use short-acting benzos for insomnia?
Jet-lag and or stressful situations
Use should be limited to several nights.
What are the negative effects of short-acting benzos on insomnia?
They suppress REM sleep so upon termination, there is REM rebound where they have nightmares and daytime anxiety
What is long term insomnia usually a sign of?
What should be done in terms of treatment?
It is a sign of underlying condition like depression, respiratory problems, drug abuse.
- treat underlying problem
- if fails–> month trial of hypnotic
- if fails–> sleep disorder clinic
What benzo should be used if a patient has trouble:
- getting to sleep
- getting to and staying asleep
- wake in the middle of the night
- rapid acting, short half life
- rapid acting, long half life
- intermediate acting, intermediate T1/2
What 2 benzodiazepines are used in the treatment of status epilepticus?
diazepam, lorazepam
What are the muscle relaxant effects of benzos due to?
GABA receptor ligation in the brainstem, cerebellum and spinal cord
What drug is used to reduce the likelihood of death from co-ingestion of benzos and alcohol and to reverse midazolam anesthesia?
flumazenil - competitive antagonist for benzos on GABA-A
*short half life of 30 minutes so you need to re-administer
What receptor is bound by zolpidem and what is the effect?
It binds GABA-A and is STRICTLY hypnotic with:
- short half-life
- moderate effect on REM
What drug decreases latency of sleep onset and increases total sleep time by increasing stage 2 non-REM sleep?
Eszopiclone
[extends, sleep =ESzopiclone]
Which 2 drugs target GABA-A, are involved in sleep but not anxiety, and have fewer tolerance and withdraw problems than benzos?
- eszopiclone
2. zolpidem
What receptors and in what area of the brain does ramelteon operate on? Is it an agonist or antagonist?
What is the intended effect?
What are the adverse effects?
Ramelteon is an agonist for MT1 and MT2 melatonin receptors in suprachiasmatic nucleus.
The effect is reducing sleep latency .
Adverse effects are dizziness and fatigue, but NOT rebound insomnia
Which drug is used to reduce sleep latency but does NOT have the rebound insomnia seen with benzos?
ramelteon
What drugs have replaced benzos as first-line drugs for acute and long-term management of GAD?
Anti-depressants
- duloxetine
- escitalopram
- fluoxetine
- sertraline
- venlafaxine
What is the current view on how ethanol interacts with neuronal receptors?
- inhibits NMDA [decreasing frequency of Na channel opening]
- enhancing Cl- through GABA-A channels
What are the pharmacokinetics of ethanol?
Where is it absorbed?
Where does it distribute?
It is absorbed from the upper intestine due to large surface area.
Drinking on a full stomach slows absorption because gastric emptying into the intestine is delayed.
once absorbed, it distributes to all tissues and fluids, crossing the BBB rapidly
What enzyme metabolizes 95% of ethanol?
Where?
What are the kinetics?
95% is metabolized by ADH and the remainder is excreted in the lungs.
85% is metabolized in the liver
15% in the stomach lining
Women have lower levels of gastric ADH which is why they get drunker faster
Zero-order kinetics meaning that the enzyme can get saturated
Cellularly, where is ADH located?
in the cytoplasm NOT microsomal system
What drug inhibits aldehyde dehydrogenase causing acetaldehyde to build up giving side effects that motive alcoholics to stop drinking?
Disulfiram [Antabuse]
What is the MOA of disulfiram?
It blocks aldehyde dehydrogenase which converts acetaldehyde to acetyl CoA.
Acetaldehyde in high concentrations has numerous side effects that encourage stopping of drinking
What 2 drugs are mainly used for the treatment of alcohol dependence?
How do they differ in terms of effect?
- disulfiram- increases neg. side effects when the patient drinks
- naltrexone- opiate receptor antagonist that withdraws the pleasurable effects of drinking
What drug blocks opiate receptors to reduce the pleasurable effects of alcohol, and hence, reduce craving?
naltrexone
What happens when ADH is overwhelmed in a non-alcoholic drinking alcohol?
Some of the alcohol gets metabolized by P450 decreasing its ability to metabolize other drugs
What happens to metabolism when an alcoholic is drinking alcohol?
What happens when they stop drinking?
the microsomal system is up-regulated due to its chronic metabolism of alcohol. Therefore, metabolism of other drugs is increased due to the induction.
When they stop drinking, microsomal system is still upregulated and they will further break down drugs
What are the 5 most adverse effects of alcohol?
- acute intoxication
- liver damage
- Korsakoff’s syndrome- dementia
- additional disorders- pancreatitis, gastritis, ulcers, risk of cancer
- FAS
Why does alcohol cause FAS?
It stimulates GABA receptors and inhibits NMDA receptors in developing nerves when they are undergoing synaptogenesis and the neurons become apoptotic.
What are the 2 therapeutic uses of alcohol?
- inject for irreversible nerve block and to destroy the axon
- compete with methanol for ADH to prevent toxicity
How does methanol intoxication cause blindness and acidosis?
ADH converts it to formaldehyde which is converted by aldehyde dehydrogenase to formic acid which causes blindness and acidosis
How is methanol ingestion treated?
- treat the acidosis
- minimize conversion to formaldehyde by using ethanol to overwhelm ADH
- Dialysis
- Fomepizole - ADH inhibitor
What is the MOA of fomepizole?
inhibit ADH to prevent methanol intoxication and ethylene glycol intoxication
