Anxiolytics, Sedatives And Hypnotics

Question 1

Benzodiazepines

Answer 1

Aprazolam
Chlordiazepoxide
Clonazepam
Diazepam
Lorazepam
Midazolam
Temazepam
Oxazepam

Question 2

BZD antagonists

Answer 2

Flumazenil

Question 3

Azapirones

Answer 3

Buspirone

Question 4

Miscellaneous insomnia medications

Answer 4

Zolpidem
Zaleplon
Eczopiclone
Suvorexant

Question 5

Melatonin receptor agonist

Answer 5

Remelteon

Question 6

General effects of CNS depressants as a function of dose

Answer 6

Anxiolysis 
Sedation
Hypnosis
General anesthesia
Death- depression of medulla with resp. Suppression

*effects predominantly driven by dose

Question 7

GABA cycling

Answer 7

Following neuronal release of GABA, it is transported to the nerve terminal by GAT-1 or transported to Astro Yates
Intracellularly, GABA is metabolized to glutamine and succinate by GABA aminotransferase in the astrocyte

Question 8

Site of drug action

Answer 8

Complex, distinct binding to GABA-A receptor domain

Question 9

Agonist activities at BZD receptor

Answer 9

Anxiolytic, sedative/hypnotic, muscle relaxant, anticonvulsant, amnestic dependency

Question 10

Partial agonist activity at BZD receptor

Answer 10

Anxiolytic only

Question 11

Partial inverse agonist

Answer 11

Promnestic (memory) enhancing

anxiogenic

Question 12

Inverse agonist activity at BZD receptor

Answer 12

Promnestic
Anxiogenic
Pro-convulsants

*affects receptors that have constitutive activity and decrease the baseline level of activity. Receptor will still bind to an agonist or antagonist, but just modulates its baseline activity.

Question 13

Clinical uses of benzodiazepine

Answer 13

Anxiety disorders
Insomnia
Seizure disorders
Agitation or anxiety association with other psychiatric disorders
Pre-operative amnestic
Alcohol withdrawal
Spastic disorders 
Involuntary movement disorders
Sedation- pre procedural, during mechanical ventilation in critically ill patients

Question 14

BZD are cross tolerant with

Answer 14

Alcohol

Question 15

BZD and anxiety - adv/disadv

Answer 15

Selection is not driven by efficacy- all same efficacy in both acute and chronic anxiety. Driven by pharmacokinetics- side effect profiles

Adv- rapid onset, relatively safe, good tolerability- no activation, useful for breakthrough symptoms, may enhance adherences to Tx and alleviate activation Sx of SRRIs (worse anxiety when first start SSRI)
Disadv- no reliable antidepressant efficacy, limited spectrum of efficacy, BID/TID dosing, initial sedation, possibility of physiologic dependence, risk of w/d sx upon discontinuation, concern regarding abuse potential (polysubstance abusers, lower probability in anxious patients without substance abuse)

Question 16

BZD structure

Answer 16

Structure activity relationships- all have 1,4-benzodiazepine ring system. Modification of the ring system results in differential electron-attracting ability of the attachment at the R1 position and increases potency
Tolerability comes into play here

Question 17

BZD absorption

Answer 17

Rapidly absorbed BZD enter the circulation quickly

GI absorption is dictated by intrinsic properties of the BZD

Question 18

Liposolubility and BZD

Answer 18

Lipophilicity, at physiologic pH influences the rate at which it crosses the BBB by passive diffusion and this in turn influences the speed of onset of action and intensity of effect
Highly lipophilic BZD enter the brain more quickly, ‘turning on’ the effect promptly, but ‘turning off’ the effect more quickly as they disappear into the fat
Less lipophilic compounds like lorazepam produce clinical effects more slowly but may provide more sustained relief, in spite of a shorter half life

Question 19

BZD duration of action

Answer 19

Determined by rate and extent of distribution rather than by the rate of elimination
Less lipophilic agents maintain their effective CNS concentrations longer because they are less extensively distributed to the periphery

Question 20

BZD biotransformation

Answer 20

BZD are metabolized hepatically by microsomal oxidation or glucuronide conjugation
Oxidative pathway is influenced by hepatic disease, age, several illnesses and the presence of other drugs that affect ox capacity- magnify the side effects of BZD
BZD that are conjugated are safer than those that are metabolized by oxidation in the elderly and hepatic diseases (*midazolam will accumulate in those with hepatic diseases, specifically)

Question 21

3 BZD that are not oxidatively metabolized

Answer 21

No active metabolites and are just conjugated- shorter half life

Lorazepam, oxazepam, temazepam

Question 22

Metabolism of BZD- age

Answer 22

Age related decline in phase 1 metabolism- oxidative
Decreased clearance and increased half life for some medications (diazepam, piroxicam)
Phase 2 metabolism is unaffected by age- glucuronide conjugation
Decreased liver mass in elderly

Question 23

BZD drug interactions

Answer 23

CNS depressants- potentiate BZD-associated sedation
Cimetidine- inhibits metabolism of longer acting BZD
Fluoxetine- decreases clearance of diazepam
CYP3A4 inhibitors (fluoxetine, fluvoxamine, grapefruit juice, ketoconazole)- decreased clearance of alprazolam and midazolam as well as triazolam

Question 24

BZD tapering and symptoms of withdrawal

Answer 24

10% recommended reduction rate, gradually over a period of several weeks, withdrawal rate is often determined by a person’s capacity to tolerate symptoms
Same as symptoms for alcohol and barbiturate withdrawal- increased anxiety, nervousness, sleep disorders, inner restlessness, depressive symptoms, irritability, psychosis-like conditions, delirium, depersonalization/derealization, confusion
Autonomic symptoms- trembling, sweating, nausea, dyspnea, motor agitation, increased HR/BP, headache, muscle tension
Seizures are the defining component of delirium tremens phase
Neurological- cognitive impairments, hyperacusis, photophobia, hypersomnia, muscle twitching

Question 25

Factors that increase complications and difficulty associated with withdrawal

Answer 25

Pharmacological factors- higher daily dose, shorter half life, longer duration of prior BZD therapy, more rapid taper Clinical factors- panic disorder, higher pre-taper levels of anxiety or depression, more personality psychopathology, concomitant substance abuse/use

Question 26

Treatment of BZD and alcohol withdrawal

Answer 26

Load with long-acting BZD Monitor vital signs serially (HR, resp.) Monitor alcohol withdrawal symptoms serially (tremulousness, mental status, diaphoresis) BZD admin- scheduled and PRN BZD (when necessary) or continuous when delirium begins (usually lorazepam)

Question 27

BZD: sedation

Answer 27

Decreases pre-surgical anxiety: diazepam | Continuous infusion therapy for sedation- lorazepam and midazolam (only available IV, anterograde amnesia)

Question 28

BZD muscle relaxants

Answer 28

Decrease muscle spasms and pain associated with injury or trauma Act at spinal and supraspinal levels, not at NMJ Decreases spasticity Required doses often result in excessive sedation Clonazepam may be BZD of choice because of less sedation

Question 29

Flumazenal

Answer 29

Able to reverse a full agonist BZD acting at the BZD site of the GABAa receptor complex This may be helpful in reversing the sedative effects of the BZD when administered for anesthetic purposes or when taken in overdose by a patient. Do not give to patients who are chronically treated with BZD- seizure risk

Question 30

Non-benzo anxiety Tx

Answer 30

Buspirone- 5HT1A agonist, does not act at GABAA/BZD receptor complex Does not exhibit cross tolerance with BZDs Fewer and less severe CNS effects Little dependence liability Slow onset of action 1/4 as effective as BZD, 2/3 as effective as SSRI Good adjuvant therapy with SSRI

Question 31

Insomnia drugs

Answer 31

Eszopliclone Zolpidem Zaleplon

Question 32

Zaleplon

Answer 32

Acts selectively at omega-1 BZD receptor site, involved in sedation Not omega-2BZD site (concentrated in areas of brain regulating cognition, memory, motor function, etc.) Rapid onset and half life is about 1 hour Ideal for jet lag and for those who require complete wash out before morning Some evidence of dependence Class IV like other Z drugs Low incidence of side effects- headache, constipation, difficulty with concentration, ataxia, dry mouth

Question 33

Zolpidem

Answer 33

Rapidly absorbed, quick onset of action 2.5 elimination half life Weak anxiolytic properties No incidence of AM hangover Little amnestic response Class IV Multiple formulations with varying release properties Low incidence of side effects- daytime drowsiness, dizziness/vertigo, ataxia, diarrhea *reduced dosing in women secondary to decreased clearance

Question 34

Eszopiclone

Answer 34

Presumed moa results from an interaction with GABA receptor complexes at binding domains located close to or allosterically coupled to BZD receptors Non-BZD hypnotic that is pyrrolopyrazine derivative of the cyclopurrolone class with a chemical structural unrelated to pyrazolopyrimidines, imidazopyridines, BZDs, barbiturates, or other hypnotics. Unique in that safety and efficacy data exist at 6 months Alcohol and drugs with sedating effects should not be used with eczopiclone since their sedating effects are additive Sedation, dizziness, risk of dependence are SEs

Question 35

Suvorexant

Answer 35

Novel dual orexin receptor antagonist (orexin in lateral hypothalamus and goes to diffuse NT systems for arousal and vigilance, levels are low in narcolepsy) Prevents arousal and promotes sleep Approved for tx of insomnia Improved sleep latency, wake after sleep onset, total sleep time Contraindicated in patients with narcolepsy In obese women, increase Cmax and AUC- side effects will be longer, use lower dose

Question 36

Neuropsychopharmacology of insomnia in pediatric population

Answer 36

Alpha 2 agonists- guanfacine, clonidine (decrease presynaptic calcium entry and decrease noradrenergic and DA NT release in prefrontal)= sedative effects

Question 37

Barbiturates

Answer 37

Phenobarbital Because of dependency and withdrawal symptoms and a lack of favorable safety profile, especially with other drugs, they fell out of favor Variability of action and duration Many active and inactive metabolites that are hard to predict Lethal in overdose Used in some refractory epilepsy