Drugs for Insomnia Flashcards
Cell groups from the PPT and LDT that activate the thalamus use what neurotransmitter?
Ach
What is the role of orexin?
controls transition from sleep to awake states
What is the function of GABA in wakefulness?
GABA functions as a negative regulator of these ascending pathways and also functions as an inhibitor of the neuronal activity in the cortex.
What are the goals for treatment of insomnia?
improve nighttime and daytime symptoms
What are the only FDA approved drug classes for insomnia?
Benzodiazepines
Benzodiazepine receptor agonists
Melatonin receptor agonist
What is the MOA of benzodiazepines and benzodiazepine receptor agonists in the treatment of insomnia?
Endogenous GABA opens the channel and these drugs structurally reconfigure the open pore
What is the MOA of antidepressants in the off-label treatment of insomnia?
sedation due to anti-histaminergic effect centered in the tuberomammillary nucleus
What is the MOA of OTC 1st generation antihistamines in the treatment of insomnia?
sedation due to anti-histaminergic effect centered in the tuberomammillary nucleus
List the benzodiazepines used in the treatment of insomnia.
Estazolam Flurazepam Quazepam Temazepam Triazolam
Which benzodiazepine is known for its short half-life?
estazolam
True or false: all benzodiazepines bind to the GABA receptor at DISTINCT sites.
TRUE
Which alpha-subunits do benzodiazepines bind to on the GABA receptor?
BZ-1
BZ-2
BZ-3
What is the role of BZ-1 alpha subunit?
sedation
What is the role of BZ-2 alpha subunit?
anxiolysis
What is the role of BZ-3 alpha subunit?
myorelaxation and anticonvulsant
List the benzodiazepine receptor agonists used in the treatment of insomnia.
Zolpidem
Zaleplon
Eczopiclone
Which alpha subunits do benzodiazepine receptor agonists bind to?
BZ-1
What is interesting about the pharmacokinetic parameters of benzodiazepines and benzodiazepine receptor agonists?
Allosteric modulators, so left-shift in the dose response curve to endogenous GABA. Have a “ceiling effect”.
True or false: elimination half-life of benzodiazepines have a close relation to the time course of pharmacological effect.
FALSE: Formation of active metabolites makes it where the elimination half-life of a parent drug may have little relation to the time course of pharmacological effect
Which drugs are offered with a “quick release, slow release” co-formulation?
benzodiazepine receptor agonists
Which drug for insomnia has a rapid action with sublingual and oral spray?
zolpidem
Which drug for insomnia has sex-related differences in metabolism? (women slower than men)
zolpidem (REDUCE DOSE OF ZOLPIDEM in WOMEN due to increased risk of next-day impairment)
What is ramelteon?
melatonin receptor agonist
What receptors does ramelteon bind to?
MT1 and MT2 (GPCRs)
What does binding of ramelteon to MT1 do?
Binding to MT1 attenuates suprachiasmatic nucleus activity and induces sleep
What does binding of ramelteon to MT2 do?
MT2 binding maintains circadian rhythm.
How is ramelteon metabolized?
CYPS in the liver
List the antidepressants used to treat insomnia.
Doxepin
Mirtazapine
Trazodone
MOA: M block, NE reuptake block, 5-HT reuptake block. Primarily antihistamine at low doses
Doxepin
MOA: 5-HT reuptake block
trazodone
MOA: Significant alpha-2 antagonism reinforcing NE and 5-HT release
mirtazapine
List the 1st generation antihistamines used in the treatment of insomnia.
Diphenhydramine
Doxylamine
MOA of 1st generation antihistamines in treatment of insomnia.
H1 antagonism and anticholinergic effects
What is Suvorexant?
it was an orexin receptor antagonist (that gave problems with next-day sedation so it was rejected by the FDA)
What are the major FDA concerns with drugs to treat insomnia?
- Persistent CNS-debilitating effects the day after consuming the drug
- Unrecognized physical activity at night
- Suicidal Ideation
- Narcolepsy-associated events
List the benzodiazepine that is NOT CYP metabolized.
Temazepam
List the benzodiazepines that are CYP3A4 metabolized.
Estazolam
Flurazepam
Triazolam
List the benzodiazepine that is CYP 2B6>3A4.
Quazepam
What drug should be used with caution in Asians due to some CYP ethnic variabilities?
Zaleplon
What is the most widely prescribed hypnotic in USA and the only drug approved for middle-of the night awakening?
Zolpidem
What drug class is absolutely contraindicated in pregnancy (CAT X)?
Benzodiazepines
What benzodiazepines do you have to worry about accumulation with?
Flurazepam
Quazepam
Which benzodiazepine undergoes rapid inactivation?
Triazolam
What drugs should be used with caution in hepatic disease, COPD, depression, driving, and closed angle glaucoma?
Benzodiazepines
Benzodiazepine receptor agonists
What drug types do Benzodiazepines and Benzodiazepine receptor agonists have reactions with?
CNS drugs
CYP-metabolized drugs
TOXICITY: sedation, cognitive impairment, rebound insomnia (especially with short/intermediate-acting dugs) and can lead to physical dependence and withdrawal (with severe ventilatory impairment*)
Benzodiazepines
Benzodiazepine receptor agonists
What is the CYP specificity of Ramelteon
metabolized by 1A2>2C9 and 3A4
TOXICITY: SEDATION major; suicidal ideation; psychotic episodes
Antidepressants
TOXICITY: Few AEs (HA, somnolence, nausea, insomnia, and nasopharyngitis and URTI with long-term use)
ramelteon
True or false: remelteon is not a scheduled drug, so there is NO abuse potential or respiratory depression.
TRUE
What are some side effects seen with 1st generation antihistamines?
Sedation and xerostomia, blurred vision, urinary retention, increased intraocular pressure.
What is the only way in which benzodiazepines can be lethal?
Only lethal when consumed with quantities of alcohol
Which drug class should be used with caution in the elderly and those with narrow-angle glaucoma?
1st generation antihistamines
Which drug class should be used with caution in those with pre-existing suicidal thoughts or psychotic disorders?
antidepressants
In which drug class does rapid tolerance develop?
1st generation antihistamines
Which drug is used to reverse the effect of BNZ and BzRAs?
Flumazenil (GABA inhibitor)
What are the potential side effects of flumazenil?
seizures and symptoms of withdrawal as well as dysphoria, agitation, and possible increased adverse effects due to the abrupt awakening
