ICL 5.1: Sedatives & Hypnotics Flashcards
what is chronic insomnia?
the persistence of symptoms at least 3 days a week for more than a month at a time
what conditions can cause secondary insomnia?
- depression
- pain
- restless leg syndrome
- obstructive sleep apnea
- prostate
- gastroesophogeal reflux disease
what things can cause sleep disorders?
- psychological factors
- sleep apnea (respiratory impairment)
- myoclonus
- idiopathic
what things are considered good sleep hygiene habits?
- minimize use of caffeine, cigarettes, stimulants and other medications
- recognize that alcohol may cause fragmentation of sleep – it stimulates GABA(A) and it’s an antagonist for NMDA
- maintain regular sleep schedule
- exercise regularly, not too close to bedtime
- avoid napping (after 2 p.m.)
which 6 neurotransmitters play a role in the neurochemistry of sleep?
- acetylcholine
- histamine
- adenosine
- norepinephrine
- serotonin
- melatonin
how does acetylcholine play a role in the neurochemistry of sleep?
midbrain nuclei (pedunculopontine and dorsolateral tegmental) release acetylcholine
acetylcholine enhances sleep (parasympathetic tone)
it may also help entrain circadian rhythm**
how does histamine play a role in the neurochemistry of sleep?
histamine is important for wakefulness!!
histamine neurons are located in the tuberomammillary nucleus (TMN)
the neuropeptide orexin A induces wakefulness through activation of histamine pathways – so they work together to keep you awake!
so drowsiness is associated with H1 antagonists aka anti-histamines! that’s why sometimes people with allergies taking medications can have a hard time sleeping
how does adenosine play a role in the neurochemistry of sleep?
adenosine promotes sleep through regulation of activity in midbrain cholinergic pathways
caffeine inhibits adenosine receptor activity (nonselective antagonist), promoting wakefulness
how does norepinephrine play a role in the neurochemistry of sleep?
locus coeruleus activation in the pons is associated with wakefulness
how does serotonin play a role in the neurochemistry of sleep?
raphe neurons (source of serotonin) can facilitate sleep
role of serotonin is complicated because of the involvement of multiple receptor subtypes
how does melatonin play a role in the neurochemistry of sleep?
melatonin promotes sleep and regulates sleep wake cycle
it’s chemically related to serotonin (5-HT).
melatonin receptors are located in the suprachiasmatic nucleus (SCN) of the hypothalamus.
what parts of the brain are involved in waking up?
cells in the locus coeruleus (norepinephrine) and raphe nucleus (serotonin) increase their activity in anticipation of awakening, increasing excitability of cortical neurons and suppressing brain rhythms
that’s why lesions of the brainstem can cause sleep and coma (“ascending reticular activating system”)
what parts of the brain are involved falling asleep/non-REM sleep?
decrease in firing of many brainstem neurons, increased firing in some cholinergic neurons
what parts of the brain are involved in REM sleep?
locus coeruleus (noradrenergic) and raphe nuclei (serotonergic) are silent, but cholinergic neurons in the pons are highly active
spinal motor neurons are inhibited!!
what are the various categories of sedative drugs that can be used?
- barbiturates
- non-barbiturate sedative-hypnotic: chloral hydrate
- benzodiazepines
- non-benzodiazepine
- other anxiolytics
benzodiazepines are just an anesthetic unless they are mixed with alcohol or other drugs then they can lead to medullary depression and coma
on the otherhand, barbiturates can cause medullary depression and coma all on their own if they are abused
what are the 5 therapeutic uses of benzodiazepines?
- sedation
- anxiolytic
- anesthesia
- anticonvulsants
- muscle relation
what are the anxiolytic effects of benzodiazepines?
benzodiazepines are approved to treat anxiety states however some older benzodiazepines may make it worse
anxiety states are generally treated with antidepressants like SSRIs (fluoxetine)
what is the MOA of benzodiazepines?
they facilitate GABA action at GABA(A) receptors
GABA(A) receptors are coupled to Cl- channels and there will be hyperpolarization due to Cl- influx
GABA(B) receptors are insensitive to benzodiazepines and barbiturates
what is the relationship between mechanisms of action for benzodiazepines and barbiturates?**
benzodiazepines are allosteric activators of GABA binding; they ↑ frequency of Cl- channel opening in response to GABA at GABA(A)
barbiturates are also allosteric activators at GABA(A) but instead they increase the open time of Cl- channels –> this means that barbiturates can stimulate GABA receptors directly in the absence of GABA while benzodiazepines can’t!
how are benzodiazepines metabolized in the body?
most long-acting drugs are dealkylated to active metabolites which have long half-lives
oxazepam (Serax®) and Lorazepam (Ativan®) are inactive metabolites because they are metabolized directly to glucuronides
dealkylation and hydroxylation is decreased in elderly, people with cirrhosis, and acute hepatitis; glucuronidation is unaffected –> so you shouldn’t prescribe drugs that get metabolized via dealkylation or hydroxylation in those patients
what are the adverse effects of benzodiazepines?
- extension of CNS depressant effects = drowsiness, dizziness, ataxia, paradoxical excitement in elderly
- CNS effects enhanced when taken with other drugs like ethanol, barbiturates, or antihistamines!!!
- can produce anterograde amnesia**
- rebound insomnia/anxiety
what are the withdrawal signs seen with benzodiazepines?
- rebound anxiety
- insomnia
- dizziness, headache, confusion, altered taste
- tinitus
- palpitations
- poor concentration, seizures, irritability
symptoms are more intense for benzodiazepines with short duration of action
what medications are used as benzodiazepine substitutions or during benzodiazepine detox?
- B-blockers
- antidepressants
- enhancing GABA activity with partial agonists or anticonvulsants
- flumazenil is a GABA(A) antagonist –> it reverses the effect of BDZ**
for detox, do the loading dose at 40% of the daily dose then decrease by 10% each day
what are benzodiazepine ligands?
agonists at the benzodiazepine binding site of GABA(A) receptors that display sedative/hypnotic and anxiolytic activity
ex. diazepam
ex. flurazepam
what is the MOA of flumazenil?**
it’s an antagonist at benzodiazepine binding sites
so it inhibits binding of benzodiazepine agonists like diazepam and flurazepam which have sedative activity
so this is what is used when people are overdosing on benzodiazepines!
however, it has NO direct effect on Cl- influx!
what is the MOA of a benzodiazepine inverse agonist?
it decreases chloride influx and blocks the effects of ethanol
it provides support for the effects of alcohol being mediated by enhancing GABAA receptor activity
ex. Ro-15-4513
what is the chemical effect of benzodiazepine agonists, antagonists, and inverse agonists?
agonists = increased Cl- influx
antagonists = no effect on Cl- influx, they just inhibit binding of benzodiazepine agonists
inverse agonists = decreased Cl- influx
what is the toxicity of benzodiazepines?
low toxicity
but in combination with other things, especially alcohol, they can be fatal
what drug can be used to block adverse effects of benzodiazepines?
flumazenil
flumazenil is a benzodiazepine antagonist that can be used to block adverse effects of benzodiazepines
like if someone goes in with a BDZ overdose, you can use flumazenil to treat since it’s an antagonist
what are the non-benzodiazepine sedatives?
- zolpidem (ambien)
- zaleplon (sonata)
- eszopiclone (lunesta)
these are all non-BDZ that bind to BDZ site on GABA receptors that are used to treat insomnia
what is zolpidem? what is the MOA of zolpidem?
aka Ambien!!
it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors
it’s used for insomnia, anti-convulsive, muscle relaxing
no withdrawal effects; minimal rebound insomnia
adverse effects = morning sedation
what is zaleplon? what is the MOA of zaleplon?
aka Sonata
it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors
fast onset, short duration when compared with zolpidem
it decreases the latency of sleep onset with little effect on total sleep time
what are the adverse effects of zaleplon?
- anterograde amesia**
- morning sedation
- transient visual illusions with higher dose
what is eszopiclone? what is the MOA of eszopiclone?
it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors
rapid onset action and it increases the total sleep time!
adverse effects = morning sedation
what is the MOA of ramelteon?
aka Rozerem
it’s a melatonin receptor agonists that binds and has action in the suprachiasmatic nucleus
what are the adverse effects of ramelteon?
- morning sedation
- elevates prolactin levels and should be avoided in patients with depression*
must use SSRIs instead
what is the MOA of barbiturates?
they facilitate GABA action on the GABA(A) receptors by increasing GABA affinity and prolonging duration of chloride (Cl-) channel opening
they have a DIRECT effect on GABA(A) receptors to open Cl- channels
barbiturates block glutamate receptor-mediated excitation at low doses and block K+ and Na+ channels at higher doses
what is the MOA of thiopental?
a barbiturate that also inhibits GABA transaminase which is the enzyme responsible for inactivation of GABA
since it’s a barbiturate it also
facilitates GABA action on the GABA(A) receptors by increasing GABA affinity and prolonging duration of chloride (Cl-) channel opening
what are the 3 therapeutic uses of barbiturates?
- anxiolytic
- hypnotic
- neurology
what are the anxiolytic uses of barbiturates?
used as a pre-anesthetic to reduce anxiety
usefulness is limited by low selectivity
there’s substantial drowsiness and ataxia
what are the neurological uses of barbiturates?
- useful in acute seizures arising from disease or poisoning
drowsiness, ataxia and respiratory depression still problematic
- decrease cerebral edema associated with surgery or head injury
what happens when there’s a barbiturate overdose?
the lethal dose of a barbiturate depends on the specific barbiturate pharmacokinetics but usually you will see:
- pupillary constriction or hypoxic paralytic dilatation
- coma, profound depression of respiration due to the effect of the drug and hypoxia on medullary centers
- pulmonary edema
- renal failure
how do you treat a barbiturate overdose?
- remove the drug from the stomach via lavage or apomorphine to induce vomiting
- artificial ventilation
- hemodialysis
do barbiturates cause dependence?
barbiturates produce both psychological and physiological dependence
chronic use induces GABAA receptor down-regulation
what are the effects of chloral hydrate on the body?
it’s a sedative that’s neither a benzodiazepine nor barbiturate
but it has general pharmacological features similar to barbiturates:
- produce CNS depression
- produce psychological and physical dependency
- effective as hypnotics for short periods of time
how is chloral hydrate metabolized in the body?
alcohol dehydrogenase
what is the toxicity of chloral hydrate?
low toxicity – relatively wide safety margin
irritating to the GI tract though
are barbiturates or chloral hydrate better at improving sleep?
chloral hydrate is superior to barbiturates with respect to modifying sleep patterns, REM rebound
when combined with ethanol, chloral hydrate rapidly and effectively promotes sleep
it slows ethanol metabolism thereby enhancing effects of ethanol
what are orexin-A and orexin-B?
they are neuropeptides produced in the lateral hypothalamus that:
1 stimulate tuberomammilary neurons
- elevate histamine levels
- promote wakefulness, regulate arousal
- play a role in regulating food intake
which neurotransmitters are related to narcolepsy?
orexin-A and orexin-B
hypocretin-1 and hypocretin-2 are critical in narcolepsy
narcolepsy patients have fewer orexin neurons and decreased levels of orexin-A
what is narcolepsy?
sleep/waking disturbance, often characterized by collapse into sleep state (REM-like) triggered by strong emotional expression
what is canine narcolepsy?
canine narcolepsy is caused by a genetic mutation in the hypocretin receptors
research shows that there’s few hypocretin-positive neurons in the hypothalamus or narcoleptic animals
what happens in mice when there’s no OX1 vs. OX2 receptors?
orexin peptide knockout mice have severe sleepiness
lack of OX1 receptor → normal
lack of OX2 receptor → sleepiness, no cataplexy (paralysis)
disruption of both receptors → marked sleepiness and cataplexy
what are OX1 and OX2 antagonists used to treat?
data suggest OX1 and OX2 antagonists might be useful in treating sleep disorders
orexin antagonists increase sleep in rodents
what is propranolol?
β1-adrenergic receptor antagonist
useful in the treatment of stage fright because it decreases symptoms like sweating, elevated heart rate and bP
what is hydroxyzine?
it’s an antihistamine used to help with insomnia
limited cognitive impairment but potentially adverse effects on fetus
what is the MOA of buspirone?
it’s a partial serotonin 5-HT1A agonist and a weak dopaminergic D2 mixed agonist/antagonist
it inhibits serotonin release via stimulation of serotonin autoreceptors
used for insomnia and also has anxiolytic activity
what are the side effects of buspirone?
CNS = dizziness, insomnia, headache
peripheral = nausea, tachycardia, myalgia, paresthesia, skin rash
Which of the following is most likely to result from treatment with moderate-high doses of diazepam?
A. alleviation of the symptoms of major depression
B. agitation and possible hyperreflexia with abrupt discontinuance after chronic use
C. improved performance on tests of psychomotor function
D. retrograde amnesia
A. alleviation of the symptoms of major depression
