Hypnotics

Question 1

Neurochemicals associated with sleep state

Answer 1

GABA
Adenosine (caffeine promotes wakefulness via antagonism of adenosine presynaptic receptors- increase cholinergic activity in reticular nuclei)
Serotonin
Opiate peptides (enkephalins, endorphin)

Question 2

Narcolepsy

Answer 2

Recurrent irresistible attacks of daytime sleepiness
Comes with or without cataplexy (sudden loss of muscle tone during sleep i.e. sleep paralysis)
Caused by low levels or deficiency of hypocretin (also called arexin)

Question 3

Insomnia + risk factors

Answer 3

Subjective difficulty falling asleep, or maintaining sleep
Risk factors: 
Older age
Female sex
Shift work
Lower SES
Marital status ( divorced or separated)
African-American
Family history
Genes- short allele on serotonin transporter gene

Question 4

Drugs used for treating Insomnia

Answer 4

GABAa receptor modulating:
Benzodiazepines- Flurazepam, Tamazepam, Triazolam
BZP receptor agonists- Zolpidem (Ambien), Eszopiclone (Lunesta), Zaleplon (Sonata)

Non-GABAa receptor modulating:
Buspirone
Ramelteon
Antihistamines

Question 5

Benzodiazepines pharmacological effects

Answer 5

Sedation (calming)
Hypnotic (sleep inducing)
Anxiolytic (anti-anxiety)
Anticonvulsant 
Skeletal muscle relaxant 

Relieves insomnia via:
Decrease sleep latency & increase total sleep time
Increase stage 2 sleep, but decrease REM, stage 3 & 4 sleep

Question 6

Benzodiazepine MOA

Answer 6

Bind to allosteric GABAa site to increase affinity of GABAa receptor for GABA- increase frequency of Cl- channel opening
Cl- influx- post synaptic hyper polarization- decrease sleep latency & increase total sleep time

Secondary mechanism:
decrease neuronal reuptake of adenosine thus enhancing inhibitory effect of ACh on reticular formation- decreases ACh release from pedunculo-pontine nucleus of RF- decrease arousal & increase sleep
BZPs also cause coronary vasodilation & decrease TPR

Question 7

Benzodiazepine administration & elimination

Answer 7

Orally or IV
Well absorbed & distributed to the brain in proportion to their lipid solubility profiles
Undergoes extensive hepatic metabolism- most are converted to active metabolites which are conjugated and secreted in urine

Question 8

Long acting BZPs

Answer 8

Flurazepam

Oxidized to long-acting metabolites

Question 9

Short or intermediate- acting BZPs

Answer 9

Estazolam

Short lived or inactive metabolites

Question 10

BZPs that undergo only phase 2 metabolism via conjugation

Answer 10

Lorazepam, Tamazepam
Safer in elderly patients- capacity for conjugation does not decrease with age unlike oxidative bio transformation & accumulation of these BZPs to toxic levels are less likely in the elderly

Question 11

Benzodiazepine adverse effects

Answer 11

General effects

• Sedation, light-headedness, ataxia, lethargy
• Anterograde amnesia (impaired memory/recall- use lowest effective dose to avoid)
• Paradoxical CNS stimulation- hyperactivity, irritability & aggressiveness
• Hangover- daytime sedation & performance impairment

Drug dependence liability

• Tolerance- develops 2-4 weeks of continuous use
• Physical dependence with autonomic withdrawal symptoms
• Rebound anxiety or insomnia- characterized by increased wakefulness (may last 1-2 nights after abrupt stoppage of BZPs with short or intermediate half-lives

Elderly

• Incidence of CNS side effects increase with age with increased half life/ drug accumulation- prolonged sedation, cognitive & psychomotor impairments are a concern
• Use BZP with long elimination is associated with falls & hip fractures in the elderly
• may be contraindicated in elderly with liver impairments

Pregnancy
- Teratogenic- increased risk of cleft lip or palate

Question 12

Benzodiazepine drug interactions

Answer 12

Potentiates CNS depressant effects of alcohol, antihistamines, antipsychotics, antidepressants and opioids
Elimination half life prolonged by CYP3A4 inhibitors

Question 13

Flumazenil MOA

Answer 13

Only clinically available benzodiazepine receptor antagonist
Binds with high affinity to specific sites on GABAa- receptor- competitive antagonism of BZPs allosteric effects

Question 14

Flumazenil administration

Answer 14

Given IV

Reverses effects of BZP overdose

Question 15

Barbiturates

Answer 15

Secobarbital

Phenobarbital

Question 16

Barbiturates MOA

Answer 16

Binds to GABAa receptor- increase duration of Cl- channel opening (as opposed to benzos which increase GABA affinity leading to increased frequency of Cl- channel opening)
Out of favor due to abuse liability, tolerance, respiratory depression

Question 17

Z- hypnotics

Answer 17

Benzodiazepine receptor agonists hypnotics 
Chemically unrelated to BZPs
Zaleplon 
Zolpidem
Eszopiclone

Question 18

Z-hypnotics MOA

Answer 18

Used to treat insomnia

• Bind to GABAa- potentiation of GABA at specific receptor subtypes (those composed of alpha-1 subunit) [BZPs potentiate all effects of GABA]
• Hypnotic effects devoid of significant anxiolytic, anticonvulsant or muscle relaxant effects
• Less potential danger for tolerance and dependence than BZPs
• Shorter duration of action thus devoid of hangover effects

Question 19

Zaleplon

Answer 19

Z-hypnotic
Quick onset & short duration of action
Sedative devoid of anticonvulsant, anxiolytic, or muscle relaxant effects

Question 20

Zolpidem

Answer 20

Z-hypnotic

Available as quick acting sublingual pills

Question 21

Z-hypnotic side effects

Answer 21

Zaleplon & Eszopiclone

• Headache & dizziness
• Chest pain & anti-cholinergic effects

Eszopiclone
- unpleasant taste
Relatively devoid of tolerance & withdrawal symptoms at normal doses

Question 22

Melatonin receptor agonists

Answer 22

Melatonin

Ramelteon

Question 23

Ramelteon MOA

Answer 23

Activates melatonin type 1/2 (MT1/2)- induction of sleep via decrease activity of supra-chiasmatic nucleus (circadian rhythm pacemaker)
-MT1/2 are G-protein coupled receptor
-Ligands- melatonin from pineal gland
Devoid of rebound insomnia, tolerance, or withdrawal symptoms seen with benzodiazepines

Question 24

Ramelteon adverse effects

Answer 24

Headache
Fatigue
Dizziness
Somnolence

Question 25

Ramelteon drug interaction

Answer 25

Concurrent use with fluvoxamine (SSRI antidepressant which inhibits CYP1A2) results in 70 fold increase in peak plasma concentration

Question 26

Neurochemicals associated with awake state

Answer 26

``` Acetylcholine Norepinephrine Histamine Dopamine Neuropeptides (Substance P, Corticotropin-releasing factor) ```

Question 27

Diazepam

Answer 27

Benzodiazepine that decreases mono synaptic reflex (without sedation)- other BZPs do so with CNS depression

Question 28

Histamine effect

Answer 28

Cause wakefulness via presynaptic facilitation ACh release in the reticular activating system

Question 29

Antihistamine drugs

Answer 29

Diphenhydramine; Hydroxyzine and Doxepin

Question 30

Diphenhydramine MOA

Answer 30

Lipid soluble drug that crosses the blood brain barrier blocking central histamine H1 receptors- decrease ACh release by neurons of reticular activating system Blockade of ACh in reticular formation results in drowsiness & sleep

Question 31

2nd Generation Antihistamines

Answer 31

Loratidine Do not cross BBB and only blocks H1 receptors peripherally Good allergic medications (same as 1st gen); do not hinder daily activities (not case with 1st gen)