Sedative-hypnotics Flashcards
What are the general effects of sedative-hypnotics?
muscle relaxation calming effect anticonvulsant effects sleepiness sedation (decreased irritability) anterograde amnesia anesthesia **cardiac and respiratory depression (can cause death!)
As you increase the dose of sedative-hypnotics, was CNS effects occur?
lowest dose = anti-anxiety -> sedation -> hypnosis -> anesthesia -> coma/death
Why are benzodiazepines safer than barbiturates?
1) benzodiazepines have an antagonist (flumazenil) that will reverse an overdose 2) benzodiazepines require much higher doses than barbiturates to get the same CNS effect and generally will not have any effect greater than anesthesia
Why can you absolutely NOT drink any alcohol while on a sedative-hypnotic?
Because alcohol is also a sedative hypnotic and all these drugs have additive effects on CNS depression. Adding alcohol is like overdosing on your prescription
Where on the GABA-A receptor does GABA bind? Where do the benzodiazepines bind? What is the mechanism of action of benzodiazepines? Where do the newer, nonbenzodiazepine hypnotics bind?
GABA binds between the alpha and beta subunits
Benzodiazepines bind at a different site than GABA, between the alpha and gamma subunits. The mechanism of action of benzodiazepines is to enhance GABA’s ability to bind to the GABA-A receptor and increase the frequency of channel opening
The new, nonbenzodizepine hypnotics bind to the same site as benzodiazepines but are more selective than the benzos (only specific alpha subunits, alpha1, of the GABA receptors)
Where on the GABA-A receptor do barbituates bind? What is their mechanism of action?
Barbiturates bind at a different site than the benzodiazepines or GABA
Barbiturates increase the duration of Cl- channel opening
What CNS effects does the alpha1 subunit in GABA-A receptors influence? Alpha2 and alpha3? Alpha5?
alpha1 - sedation, ataxia, amnesia
alpha2/3 - anxiolytic, muscle relaxing
alpha5 - memory impairment(?)
What are the common barbiturates? What is their clincial use?
butalbital - one part of a cocktail for headache medicine
phenobarbital - seizures
thiopental - was used for inducing anesthesia and the death penalty but no longer in use in the US
Secobarbital - short term treatment of insomnia; sedative prior to anesthesia for surgery
What are the absorption properties of barbiturates? How are barbiturates metabolized? What can happen after long term use of barbiturates? How are barbiturates eliminated?
Absorption and distribution is extremely fast because the drug is very lipophilic
Barbiturates are metabolized to alcohols, ketones and acids slowly. Chronic use of barbiturates will induce the cytochrome P450 enzymes, leading to many drug interactions
Elimination is mostly renal
Alkalinizing urine will increase renal elimination
What drug is absolutely contraindicated when a patient has porphyria?
barbiturates
What are the benzodiazepine drugs? Are they short, intermediate or long acting?
short acting = midazolam
Intermediate = alparzolam (xanax) and lorazepam (ativan)
long acting = clonazepam (klonopin) and diazepam (valium)
What are the clinical uses of benzodiazepines?
status epilepticus
panic disorder, generalized anxiety disorder
specific phobias
insomnia
alcohol withdrawal
muscle spasms
parasomnias/sleep disorders
induction of anesthesia (midazolam)
acutely agitated patients
mania and catatonia
Which benzodiazepines do NOT have phase I metabolism by cytochrome P450 enzymes? Which benzodiazepines have phase I metabolism but very short half-lives of the active metabolites?
lorazepam, oxazepam, temazepam
These can be used in patients with liver disease (chronic alcoholics with liver failure that are going through withdrawal need these three drugs)
midazolam have a very short half life
Many benzos have very long half lives
What are the newer nonbenzodiazepines hypnotics?What are the clinically used for?
All used as hypnotics for insomnia and sleep disorders - NO anti-anxiety effects
zolpidem (ambien)
zaleplon (sonata)
eszopiclone (lunesta)
What are the absorption properties of the nonbenzodiazepine hypnotics? Metabolism properties? Elimination properties?
Rapid absorption, rapid metabolism, rapid elimination
Since these drugs help you fall asleep, you don’t want them to be long acting
What is the effect of benzos and barbs on the stages of the sleep cycle? What is the effect of the newer nonbenzodiazepine hypnotics on the stages of the sleep cycle?
benzos and barbs: decreased sleep latency, decreased time spent in REM and stage 3/4 sleep, increased time spent in stage 2 sleep
newer hypnotics: decreased sleep latency, does not effect the time in each stage of sleep as much as the benzos and barbs
What drugs are associated with abnormal noctural behaviors (sleepwalking, sleep-eating, having sex while asleep)?
newer nonbenzodiazepine hypnotics (zolpidem, zaleplon, eszopiclone)
What is the antidote for a benzodiazepine overdose? What are the adverse effects of this antidote? What is the antidote for a barbiturate overdose?
benzo overdose - flumazenil (but can’t use it in patients who are dependent on benzos or who have taken a tricyclic antidepressent because it can cause seizures and cardiac arrhythmias)
barbiturate - nothing
What are the sedative-hypnotics that act on GABA receptor? What are the sedative-hypnotics that act on other receptors? What are those receptors?
GABA: benzodiazepines and newer nonbenzodiazepine hypnotics, barbiturates, alcohol,
Non-GABA:
ramelteon - melatonin receptor agonist
buspiridone - 5HT1A receptor agonist
dexmedetomidine - alpha2 adrenergic agonist
What is clinical use of ramelteon?
used in patients who have trouble falling asleep
no effect on stages of sleep
WHat is the clincal use of buspirone?
anxiolytic
minimal abuse but effects may take a week to kick in
What is the mechanism of action of dexmedetomidine? What are its clinical uses? What is it’s major advantage?
mechanism of action - alpha2 adrenergic agonist (the autoreceptor on presynaptic neurons that shuts off NT release) reduces sympathetic activity and level of arousal
uses: non-intubated patients prior to surgery; intubated patients in the ICU
Does NOT cause respiratory depression!
What are the pathways of alcohol metabolism?
Ethanol -> acetylaldehyde -> acetate
First step can be accomplished by two mechanisms: alcohol dehydrogenase or the MEOS (microsomal ethanol oxidizing system) which consists of a couple of cytochrome P450 enzymes.
Second step is accomplished by aldehyde dehydrogenase
What drugs affect the alcohol metabolic pathway? What are they used for?
fomepizole inhibits alcohol dehydrogenase; used for methanol and ethylene glycol poisoning to inhibit these chemicals from being metabolized into toxic metabolites.
Disulfiram (antabuse) inhibits aldehyde dehydrogenase; used to treat alcohol dependence/abuse by causing build up of acetylaldehyde which causes nausea, vomiting, flushing, dizziness and headache.
To what receptors does ethanol bind? What is their effect on these receptors?
GABA receptors - enhances action of GABA at the GABA receptor
NMDA glutamate receptors - inhibits ability of glutamate to open these channels. Because of alcohol’s inhibitory effect, the body responds by upregulating the NMDA receptors. When a chronic alcoholic undergoes withdrawal, the patient can get seizures because of the excessive number of NMDA receptors that are now not being inhibited
What are the effects on the cardiovascular system of chronic alcohol abuse?
dilated cardiomyopathy leading to heart failure
arrythmias
What are the effects on the nervous system of chronic alcoholism?
symmetric peripheral nerve injuries
cerebellar damage leading to ataxia and gait disturbances
dementia
thiamine deficiency that leads to Wernicke-Korsakoff syndrome
optic nerve degeneration leading to decreased visual acuity
What are the effects on the liver and GI tract of chronic alcoholism?
alcoholic fatty liver (reversible) -> alcoholic hepatitis -> cirrhosis and liver failure
chronic pancreatitis
gastritis
anemia and malnutrition and malabsorption
What are the features of fetal alcohol syndrome?
small size and weight
microcephaly
poor coordination
short palpebral fissures
thin upper lip
smooth philtrum
mental retardation and congenital heart defects (severe FAS)
How should you manage an acute alcohol intoxication case?
correct electrolyte imbalances
treat hypoglycemia and ketoacidosis with glucose
give thiamine (banana bag) to prevent Wernicke-Korsakoff syndrome
correct dehydration
What drugs are used to treat alcohol dependence?
naltrexone (can’t use in liver disease), acamprosate (can use in liver disease but little efficacy), disulfiram
What are the adverse effects of Ramelteon? What are the indications of ramelteon? What is its mechanism of action?
Dizziness, fatigue, decreased testosterone production, increased prolactin production
Indicated for adults who have trouble falling asleep because it works quickly but does not affect sleep stages (won’t help the pt stay asleep)
melatonin receptor agonist
