Lennon/Sweatman - Sleep Flashcards
1
Q
What are the 2 ascending arousal pathways? How is GABA involved in these?
A
- CHOLINERGIC: cell groups in upper pons, pedunculo-pontine (PPT), and laterodorsal tegmental nuclei (LDT) activate the thalamus
- MONOAMINE: activates cerebral cortex to facilitate processing of inputs from thalamus –> arises from neurons in monoaminergic cell gps, incl. tuberomamillary nucleus (TMN) containing histamine, A10 cell gp (DA), dorsal and median raphe nuclei (serotonin, 5-HT), and locus ceruleus (noradrenaline)
1. Also receives contributions from peptiderfic neurons in lateral hypothalamus containing orexin or melanin P concentrating hormone and from basal forebrain neurons that contain γP aminobutyric acid (GABA) or ACh - GABA functions as a negative reulator of these ascending pathways, and is an INH of neuronal activity in the cortex itself
2
Q
What is the role of orexin in wakefulness?
A
- Orexin-containing neurons in areas of hypothalamus mediate very rapid transition b/t sleep & awake states
1. Link b/t limbic system, energy homeostasis, brain stem, and o/systems - Orexin neurons promote wakefulness via mono-aminergic nuclei that are wake-active
- Peripheral metabolic signals influence orexin neuronal activity to coordinate arousal and energy homeostasis
3
Q
What are the goals of the pharma tx of insomnia? Measurements?
A
- Improvement in nighttime and daytime symptoms
- Typical measures: sleep latency, awakenings, total sleep time, and residual “daytime” symptoms following drug use (incl. complaints, distress)
- NOTE: clinical trials focus on primary insomnia, and often ignore issues of comorbidities
4
Q
What are the 15 drugs used to tx insomnia (6 classes)?
A
- BENZODIAZEPINES: Estazolam, Flurazepam, Quazepam, Temazepam, Triazolam
- ANTIDEPRESSANTS: Doxepin, Mirtazapine, Trazodone
- BENZO RECEPTOR AGONISTS: Zolpidem, Zaleplon, Eszopiclone
- MELATONIN RECEPTOR AGONIST: Ramelteon
- 1st GEN ANTIHISTAMINES: Diphenhydramine, Doxylamine
- DUAL OREXIN RECEPTOR ANTAG: Suvorexant
5
Q
What are the general concerns regarding any drug used to tx insomnia (4)?
A
-
Daytime somnolence can be severe and occur suddenly: pts drive while impaired -> persistent CNS debilitating effects day after consuming drug
1. Continues to be a problem, even with the newer agents - Unconscious nighttime activity: can be as bizarre as driving while asleep, cooking/eating meals, and physical acts of aggression later blamed on drug activity
- Suicidial ideation (ask pts about mood status/changes)
- Other narcolepsy-assoc events: sleep paralysis, hypnagogic hallucinations (auditory, tactile, visual disturbances) during the wake to sleep transition, mild cataplexy
6
Q
What are the “key points” for the drugs to tx insomnia?
A
-
Most drugs are used “off-label,” at reduced doses (TCA’s and 1st-gen antihistamines like Diphenhydramine and Doxylamine, which are OTC; also Ramelteon)
1. Only a handful are APPROVED for insomnia: BNZ, BRA’s (Zolpidem) -
3/4 of Rx’s are for antidepressants: Trazodone, Amitryptiline, Mirtazepine
1. Anticonvulsants, i.e., Gabapentin
2. Antipsychotics, i.e., Quetiapine - Herbals: melatonin
7
Q
What are some of the interactions/add’l actions of orexin-containing neurons?
A
- Stimulation of DA centers by orexins modulates reward systems (VTA)
- Stimulation of neuropeptide Y neurons by orexin INC food intake
- Suprachiasmatic nucleus (SCN), the central body clock, sends input to orexin neurons via the dorsomedial hypothalamus (DMH)
- Input from limbic system (amygdala and bed nucleus of stria terminalis) might be important to regulate the activity of orexin neurons upon emotional stimuli to evoke emotional arousal or fear-related responses
8
Q
What 3 types of receptors should you think of when prompted about ligand-gated ion channels in pharm?
A
- GABA receptor complex, which gates for Cl-
- Nicotinic Ach system
- Serotonin 5HT-3 ion-gated channel for Na+
9
Q
How is Ramelteon distinct from the “approved” insomnia Rx’s?
A
- Acts on the melatonin receptor
- All of the remaining drugs (BNZ, BRA’s, barbiturates) act on GABA receptors in CNS
10
Q
Describe the structure of the GABA A receptor. What drugs act on this receptor? Do they do so at the same site?
A
- Multimeric, transmembrane-spanning protein complex that provides gating for Cl- entry into the cell
- In response to binding of endogenous GABA, several components of the channel structurally reconfigure to open ion pore
1. Barbiturates, benzos, BRA’s, and Flumazenil (antagonist) all bind to GABA receptor, but at distinct sites (see attached image) -> each class modifies response pattern of GABA receptor to endogenous ligand
2. At normal clinical doses, none of these drugs work in place of endogenous GABA in opening channel -> at very high barbiturate doses, there is some evidence to suggest that they are capable of themselves activating/opening channel
11
Q
How are the clinical effects of BNZ, BRA’s, and barbiturates on the GABA receptor different? Implications?
A
- Binding of barbiturates to receptor leads to much greater persistence in channel opening time -> since GABA is the major INH NT, barbiturates produce profound CNS depression, and are lethal at supra-pharmacological doses (function like GABA itself)
1. Could be used to tx insomnia, but use has been almost completely supplanted by safer BNZ/BRA - Binding of BNZ and BRA’s produces only allosteric modification, leading to leftward shift in dose response curve to endogenous GABA action -> inherently safer than barbiturates bc “ceiling effect” at very high doses
1. Only lethal when consumed with quantities of alcohol
12
Q
Why are the BNZ and BRA’s schedule IV drugs?
A
- Extended use can lead to physical dependence and withdrawal symptoms, incl.:
1. Anxiety, irritability, restlessness
2. Obstructive sleep apnea
3. Severe ventilatory impairment: specific antagonist available to mitigate this issue - Taper withdrawal: caution as doses decline
- NOTE: these drugs can also produce sedation, cognitive impairment, and rebound insomnia (esp. with short-acting and intermediate-acting drugs)
13
Q
What are the desired qualities of a drug to treat insomnia? Inherent dangers?
A
- Rapid onset time: rapid absorption of oral product or alternate delivery (like spray)
- Sufficient durability of action that pts arent awakened in middle of the night
1. Some newer BRA’s have quick release and slow release co-formulated product - DANGER of this is that drug effects will persist beyond intended 8-hour window of activity, leading to residual daytime effects
14
Q
What are the 3 distinct structural subgroups of the BNZ receptor site on the alpha subunit of the GABA receptor? Where do BRA’s act?
A
- Each structural gp appears to be responsible for distinct clinical aspects of overall pharmacology of benzos (which produce effects on all 3):
1. BZ-1: sedation/amnesia
2. BZ-2: anxiolysis
3. BZ-3: myorelaxation, anticonvulsant - Benzos tend to produce effects on all 3 receptor subgroups, but BRA’s only capable of sedative and amnesic actions via BZ-1 receptor complex at normal clinical doses
15
Q
With which benzos might you expect fewer cumulative and residual effects? Why?
A
- BNZ’s for which parent drug or active metabolites have long half-lives are predictably MORE LIKELY to cause cumulative effects with multiple doses (elim half-life of parent drug may have little relation to time course of pharma effects if active metabolites formed)
- Cumulative and residual effects (like excessive drowsiness) less of a problem with drugs like ESTAZOLAM, OXAZEPAM, and LORAZEPAM, which have relatively short half-lives and are metabolized directly to inactive glucuronides
- NOTE: BNZ’s a large family w/different durations of clinical activity, ranging from short (Midazolam) to very long (Diazepam)
16
Q
In regards to pharmacologic characteristics (i.e., metabolism, interactions), how are all of the benzos similar? In what way do they differ?
A
- IDENTICAL in virtually all aspects: all category X
2. Present problems with concurrent medical problems like: a) COPD, b) glaucoma, and c) cognitive function (may impair driving ability) - DIFFER in: involvement of CYP in their metabolism (Temazepam not metabolized by CYP; Quazepam metabolized by 2B6>3A4)
1. Potential for accumulation in pts with compromised metabolic function: Temazopam and Estazolam do NOT accumulate
17
Q
What are the pharma characteristics (i.e., metabolism, interactions) of the benzo receptor agonists? How do these differe from the benzos?
A
- All schedule IV drugs metabolized by CYP, and have potential for accumulation in predisposed ppl
- CATEGORY C relative to pregnancy (whereas benzos are contraindicated in this regard)
21
Q
How is melatonin involved in sleep regulation?
A
- 3 melatonin receptors, 2 of which are involved in sleep regulation in suprachiasmatic nucleus
- MT1 and MT2 G-protein coupled receptors widely distributed in CNS
- Binding MT1 attenuates SCN activity, and induces sleep
- MT2 binding maintains circadian rhythm
- MT3 receptors NOT involved in sleep regulation
23
Q
What anti-depressants are used to tx insomnia (3)? MOA? Which one is FDA-approved?
A
- Low-dose DOXEPIN (6mg) approved for insomnia
1. H1 antagonism: little antichol effect at this dose (see attached chart)
2. Residual effects next day
3. Not a controlled substance - Other drugs used “off label” at low doses
- Sedating “side effect” when used to tx depression has clinical utility here -> activity seems to be related to histaminergic signaling centered on the tubero-mammillary nucleus
28
Q
What are some drugs that can produce insomnia?
A
- Useful for doc to ascertain whether or not recent onset of insomnia coincides with initiation of drug use
- Insomnia may be “cured” by changing drug, or DEC dose before reaching for other drug to tx the drug-induced situation
- Avoidable polypharmacy issue
- NOTABLE: Felbamate (anti-convulsant), Levodopa, some AB’s and antivirals
