Anxiolytics, Sedatives And Hypnotics Flashcards
Benzodiazepines
Aprazolam Chlordiazepoxide Clonazepam Diazepam Lorazepam Midazolam Temazepam Oxazepam
BZD antagonists
Flumazenil
Azapirones
Buspirone
Miscellaneous insomnia medications
Zolpidem
Zaleplon
Eczopiclone
Suvorexant
Melatonin receptor agonist
Remelteon
General effects of CNS depressants as a function of dose
Anxiolysis Sedation Hypnosis General anesthesia Death- depression of medulla with resp. Suppression
*effects predominantly driven by dose
GABA cycling
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
Site of drug action
Complex, distinct binding to GABA-A receptor domain
Agonist activities at BZD receptor
Anxiolytic, sedative/hypnotic, muscle relaxant, anticonvulsant, amnestic dependency
Partial agonist activity at BZD receptor
Anxiolytic only
Partial inverse agonist
Promnestic (memory) enhancing
anxiogenic
Inverse agonist activity at BZD receptor
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.
Clinical uses of benzodiazepine
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
BZD are cross tolerant with
Alcohol
BZD and anxiety - adv/disadv
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)
BZD structure
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
BZD absorption
Rapidly absorbed BZD enter the circulation quickly
GI absorption is dictated by intrinsic properties of the BZD
Liposolubility and BZD
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
BZD duration of action
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
BZD biotransformation
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)
3 BZD that are not oxidatively metabolized
No active metabolites and are just conjugated- shorter half life
Lorazepam, oxazepam, temazepam
Metabolism of BZD- age
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
BZD drug interactions
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
BZD tapering and symptoms of withdrawal
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
Factors that increase complications and difficulty associated with withdrawal
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
Treatment of BZD and alcohol withdrawal
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)
BZD: sedation
Decreases pre-surgical anxiety: diazepam
Continuous infusion therapy for sedation- lorazepam and midazolam (only available IV, anterograde amnesia)
BZD muscle relaxants
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
Flumazenal
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
Non-benzo anxiety Tx
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
Insomnia drugs
Eszopliclone
Zolpidem
Zaleplon
Zaleplon
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
Zolpidem
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
Eszopiclone
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
Suvorexant
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
Neuropsychopharmacology of insomnia in pediatric population
Alpha 2 agonists- guanfacine, clonidine (decrease presynaptic calcium entry and decrease noradrenergic and DA NT release in prefrontal)= sedative effects
Barbiturates
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
