What are the BZDs that are used as Anxiolytics and Hypnotics
All except Temazepam and Triazolam are used as Anxiolytics
Temazepam and Triazolam are used as Hypnotics
Which BZDs have shortest and longest HL?
Longest: Diazepam (20–100 [36–200]) and Chlordiazepoxide (5–30 [36–200])
Shortest: Triazolam (2); Oxazepam (4-15 hours)
BZDs with HL of approximately 10-20 hours
HL of Clonazepam
Difference between long and short acting BZDs
Longer acting agents possess active metabolites and tend to produce a steady serum drug concentration and few rebound effects between doses, whereas shorter acting agents are prone to emergence of symptoms between doses.
Metabolism of BZDs
All benzodiazepines are metabolized by the liver, increasing the risk of sedation, confusion, and frank hepatic encephalopathy in patients with hepatic failure.
In patients with liver failure, lorazepam, temazepam, and oxazepam may be preferred because they undergo hepatic conjugation and renal excretion and have no active metabolites, whereas other benzodiazepines undergo hepatic microsomal metabolism and may have long-acting active metabolites.
What BZDs do not undergo hepatic metabolism?
All of them do undergo hepatic metabolism
Which BZDs undergo hepatic conjugation and have no active metabolite?
Oxazepam, Temazepam and Lorazepam
Adverse Effect of BZDs
Adverse effects of benzodiazepines are dose-dependent and include sedation, impaired cognitive function and judgment, amnesia, impaired motor performance, and disinhibition.
What happens with abrupt cessation of benzodiazepine use after long-term administration?
It may result in withdrawal symptoms including anxiety, agitation, tremor, autonomic hyperactivity, insomnia, nausea and vomiting, seizure, and delirium.
Treatment of BZD withdrawal
Benzodiazepine withdrawal is best managed by resumption of an intermediate- to long-acting benzodiazepine to stabilize the patient, followed by gradual taper under supervision.
Buspirone's mechanism of action
5-HT1A receptor partial agonist
No Effect on GABA or Cl channels
No abuse, tolerance potential
no BZD cross-reactivity
Indication for buspirone
Pharmacokinetic of buspirone
HL of 2 hours
Three divided doses
Works best for BZD naïve patients
Its metabolism is decreased by CYP3A4 inhibitors.
Buspirone's adverse effects
Nausea, headache, nervousness, and insomnia
Not lethal in overdose
Mechanism of action of Eszopiclone, zopiclone, zolpidem, and zaleplon
Selective agonists at the omega-1 modulatory site of the GABAA receptor complex, producing sedation
No anxiolytic, anticonvulsant or muscle relaxant side effects
Lower risk of dependence
What is Zolpidem useful for?
Inducing and maintaining sleep
Minimal Daytime sedation
What are the forms of Zolpidem?
Zolpidem is available in an extended-release form to assist with sleeping through the night, as well as a sublingual formulation for middle insomnia
What is the HL of Zolpidem and Zaleplon?
Side effects of Omega1 selective agonists
Daytime sedation, impaired cognitive performance, amnesia, and nocturnal activity such as wandering, eating, and driving that is not recalled the next day have been reported
Elderly patients are at increased risk for amnesia and falls with zolpidem.
FDA has recommended reducing by half the dose of products containing zolpidem, especially in women and the elderly
Ramelteon is a melatonin agonist FDA-approved for insomnia.
It has demonstrated efficacy for insomnia with no next-morning residual effects, similar adverse effects to placebo, and minimal withdrawal symptoms upon discontinuation
What is the most commonly prescribed medication in the US?
First BZD for Panic Disorder
BZDs approved for panic disorder
Facts about BZD use
One user in four uses the benzodiazepine for a year or longer.
Among those using it as a hypnotic, 14% reported long-term use.
Rates of use increase with age, from 2.6% among those 18–35 years to 8.7% among those 65–80 years.
In recent years, there has been a shift to the use of short-half-life benzodiazepines.
What is the shared property of BZD in structure?
Currently marketed benzodiazepines are similar in that they have the 1,4-benzodiazepine ring system
True or False:
The belief that one benzodiazepine is primarily anxiolytic while another is primarily hypnotic is not based on scientific evidence
True or False: Most BZDs are metabolized through oxidation
What BZDs are metabolized through glucuronidation
Which BZDs are metabolized through Reduction?
Nitrazepam and Flunitrazepam
What is the rate of absorption of BZDs?
Diazepam and clorazepate are rapidly absorbed and act quickly
Chlordiazepoxide and lorazepam have intermediate rates of absorption
and onset of action,
Prazepam is slowly absorbed and has a slower onset of action.
What is the difference between IM and oral Lorazepam and Chlordiazepoxide?
Chlordiazepoxide and lorazepam, when given orally, are absorbed at similar rates in the gastrointestinal tract.
When given intramuscularly, lorazepam is more reliably, rapidly, and completely absorbed than chlordiazepoxide
------------- of a benzodiazepine at physiological pH influences the rate at which it crosses the blood–brain barrier by passive diffusion from the circulation, and this, in turn, determines the rapidity of onset of action and intensity of effect
The lipid solubility (lipophilicity)
What is a key factor in the rapidity of onset of action and intensity of effect of BZDs?
The lipid solubility (lipophilicity) of a benzodiazepine at physiological pH influences the rate at which it crosses the blood–brain barrier by passive diffusion from the circulation
True or False: Diazepam has faster onset of action compared to lorazepam and chlordiazepoxide
True (due to higher lipophilicity)
With benzodiazepines, the duration of therapeutic action is determined mainly by ------------------------------
the rate and extent of drug distribution rather than by the rate of elimination.
Benzodiazepine distribution is largely determined by its ---------------
Diazepam, which has a longer half-life than lorazepam, has a shorter duration of clinical action after a single dose. What is the reason for this?
The reason for this is that diazepam, because of its greater lipid solubility, is more extensively distributed to peripheral sites, particularly to fat tissue.
Consequently, it is more rapidly moved out of the blood and brain into inactive storage sites, and its central nervous system (CNS) effects end more rapidly.
Conversely, less lipophilic benzodiazepines maintain their effective brain concentrations longer because they are less extensively distributed to the periphery
----------- lipophilic benzodiazepines maintain their effective brain concentrations longer because they are less extensively distributed to the periphery
What properties of BZDs are affected by rate of elimination?
The speed and extent of accumulation and the time to reach a steady state
The time for drug washout after termination of multiple doses
Accumulation of BZDs is slow and extensive when the half-life is -----
When the rate of ------ equals the rate of --------, the drug is said to have reached steady state.
A useful rule of thumb is that when treatment has been in progress for at least -------- times as long as the elimination half-life, then the accumulation process is more than 90% complete
Four to five
What is the concern with regards to sedation in relationship to HL of BZDS?
Because of greater drug accumulation with long-half-life benzodiazepines, frequent drowsiness and sedation are a theoretical concern.
Tolerance to sedation occurs with long-term use, even though the plasma drug level remains the same.
However, as a matter of caution, it is prudent to choose a benzodiazepine with a shorter or intermediate half-life for the elderly, individuals operating heavy machinery, and those engaging in high-level intellectual tasks.
What are some medications that magnify BZDs side effects by affecting hepatic oxidation?
cimetidine, estrogens, and the hydrazine monoamine oxidase inhibitors (MAOIs)
In the elderly and in individuals with liver disease, benzodiazepines that are ---- are safer than benzodiazepines that are metabolized by -----
are conjugated (e.g., temazepam, oxazepam, and lorazepam)/ oxidation (e.g., diazepam and alprazolam).
True or false:
Dosing schedules of benzodiazepines should be dictated by knowledge about the rate of distribution rather than by information about elimination half-life.
Dosing schedules of benzodiazepines should be dictated by knowledge about -----------------
the rate of distribution rather than by information about elimination half-life.
the sustained-release forms of alprazolam, clorazepate, diazepam, and adinazolam have a duration of therapeutic action of approximately ----- hours
Standard alprazolam has a duration of action of ------ hours, clonazepam has a duration of action of ---- hours, and other standard-formulation benzodiazepines are within this -------hour range.
What is the most abundant free amino acid in CNS?
Which GABA receptor controls Cl channels?
Four distinct pharmacological properties have been described for the benzodiazepine receptor:
anxiolytic, hypnotic, anticonvulsant, and muscle relaxation effects.
GABAA receptors with α2 (and/or α3) subunits mediate the -------effects, whereas GABAA receptors with an α1 subunit mediate the ----------- actions.
anxiolytic effects/sedative-hypnotic actions.
What is the effect of BZDs on GABA receptors?
when GABA occupies the GABAA receptor site, opening and closing of the chloride channel occur more frequently, and this effect is inhibitory
Although GABA works alone at the GABA receptor, the action of GABA is stronger in the presence of a benzodiazepine.
The benzodiazepine in the absence of GABA cannot influence the chloride channel by itself.
Which anxiety disorder has the most response to BZD?
What is the most acceptable Treatment for Panic attack
Combo of SSRI/SNRI with Benzos
Which anxiety disorder is not responsive to BZD?
True or false: BZD are effective in social phobia
What are the findings on the treatment of GAD with diazepam and imipramine?
Imipramine showed a trend of being significantly better on the primary outcome measure scale (the Hamilton Anxiety Scale [Ham-A]) and was statistically superior to diazepam on the Psychic Anxiety factor of the Ham-A.
Psychic anxiety includes the items of worry, anxious mood, tension, fears, and concentration problems.
Diazepam and imipramine had identical endpoint Ham-A Somatic Anxiety factor scores, suggesting that they are equally effective against the somatic anxiety symptoms in GAD.
This suggests that imipramine is a better “anti-worry” medication than the benzodiazepine. Patients taking diazepam had an earlier response than those taking imipramine.
What is the evidence for BZD in PTSD?
The strongest evidence for effective pharmacotherapy in posttraumatic stress disorder (PTSD) is with SSRIs.
A meta-analysis of medications in treating PTSD found effect sizes of 0.49 and 1.38 for benzodiazepines and SSRIs, respectively
What is the role of BZDs in management of agitation?
Intramuscular clonazepam has been compared with intramuscular haloperidol in the management of acute psychotic agitation.
Clonazepam use reduced agitation, but haloperidol use had a more rapid onset. Individuals with schizophrenia have high levels of anxiety and frequently experience panic attacks.
Overall, it appears that benzodiazepines have a role in the acute management of agitation, and their use can reduce the need for or the dose of antipsychotics used.
What is the side effect profile of BZDs based on half life and potency?
The first 1,4-benzodiazepines, such as diazepam and flurazepam, had slow rates of elimination and low receptor-binding affinities. Their main side effect was excessive daytime sleepiness.
The late 1970s saw the introduction of the 1,4-benzodiazepines flunitrazepam and lorazepam, which had shorter half-lives and were more potent. These drugs were associated with enhanced efficacy but also with more rapid development of tolerance and significant withdrawal problems.
The triazolobenzodiazepines were introduced in the 1980s and were even more potent and had even shorter half-lives. They also have been found to be associated with amnesia, daytime anxiety, early-morning insomnia, and withdrawal problems such as rebound insomnia, anxiety, and seizures
What are common side effects of BZDs?
Sedation and drowsiness are common, occurring in 4%–9% of patients taking benzodiazepines.
Ataxia occurs in up to 2%. The drowsiness tends to disappear with time or a reduction in dose
Benzodiazepines may impair psychomotor performance. Most benzodiazepines, shortly after administration at their peak concentration, cause anterograde amnesia. These effects are dependent on potency and route of administration.
Overall, this memory impairment does appear to be independent of the degree of sedation produced by the drug.
Benzodiazepine-treated subjects are often unaware of or underestimate the extent of their memory impairment
True or False: Memory impairment in BZDs is independent of degree of sedation
What are the hyperexcitability phenomena with BZDs?
Early-morning awakening and rebound anxiety and nervousness are more likely with the short-half-life, high-potency benzodiazepines such as triazolam, alprazolam, lorazepam, and brotizolam.
Treatment-emergent hostility may be seen in up to 10% of the patients receiving benzodiazepines. This is most likely to happen early in treatment, is unrelated to pretreatment impulsivity, and has been reported with all benzodiazepines with the exception of oxazepam.
Treatment-emergent mania has been reported with Alprazolam
Treatment-emergent mania has been reported with which BZD?
Treatment-emergent hostility is most likely to happen early in treatment, is unrelated to pretreatment impulsivity, and has been reported with all benzodiazepines with the exception of -------.
What are the features of BZD-induced amnesia?
Anterograde amnesia, even with oral dosing.
The deficit is one of disrupted consolidation and not impairment of memory retrieval.
The degree of amnesia can range from minimal inability to retain isolated pieces of information to total inability to recall any activities that occurred during a specific period.
What is the effect of BZDs on cognitive function?
Long-term benzodiazepine users have been compared with control subjects and found to have cognitive impairments that reversed on reexamination after taper
BZD in people with dementia
experienced geriatric clinicians often find that judicious use of low-dose, short half-life BZs reduces stress, promotes daytime functioning, and assists in sleep onset; elderly patients themselves report that they would gladly forgo short-term memory reduction in exchange for a calmer daytime and reliable sleep onset.
What is the result of the best-controlled study on the BZDs use in Alzheimer's?
The most recent, largest, best-controlled, and most prospectively designed study found no effect.
What is the most recent evidence on BZDs effects on AD?
The most recent BMJ study followed 3,434 adults ages 65 years and older for 7 years. None had dementia at study initiation; 23% developed dementia by the end of the study. Gray and colleagues used computerized pharmacy data to assess benzodiazepine use.
They found no link between the highest level of benzodiazepine use (on average, 1 year of daily use) and dementia or cognitive decline.
A small increased risk for dementia was seen in people with moderate (1–4 months) and low (up to 1 month) levels of benzodiazepine use but not in those using benzodiazepines for longer than 4 months.
The authors concluded that the pattern of findings “does not support the theory that cumulative benzodiazepine use at the levels observed in our population is causally related to an increased risk for dementia or cognitive decline”
What is the interaction between antacid and BZDs?
Antacids slow benzodiazepine absorption, because aluminum delays gastric emptying
How are BZDs metabolized?
In the liver, benzodiazepines are metabolized by oxidation, reduction, or conjugation.
Alprazolam, diazepam, clorazepate, prazepam, chlordiazepoxide, bromazepam, and halazepam are metabolized by oxidation;
nitrazepam by reduction;
lorazepam, oxazepam, and temazepam by conjugation.
What are important interactions between BZDs and other medications?
MAOIs, cimetidine, and oral contraceptives inhibit the oxidative system accentuating effects of BZDs that are metabolized through oxidation.
A decline in this system occurs with age or liver disease.
In the elderly, there is a 50% decrease in clearance, with a four- to ninefold increase in half-life and a two- to fourfold increase in the volume of distribution.
Heparinized patients should have partial thromboplastin time (PTT) monitored more closely, because PTT is prolonged by benzodiazepines.
Because antidepressants such as fluoxetine, paroxetine, and nefazodone and protease inhibitors such as indinavir sulfate inhibit the cytochrome P450 enzyme 3A4, they inhibit the metabolism of triazolobenzodiazepines such as midazolam, alprazolam, and triazolam.
What is the change in the kinetic of BZD in the elderly?
In the elderly, there is a 50% decrease in clearance, with a four- to ninefold increase in half-life and a two- to fourfold increase in the volume of distribution.
Which medications inhibit the metabolism of triazolobenzodiazepines such as midazolam, alprazolam, and triazolam?
Antidepressants such as fluoxetine, paroxetine, and nefazodone and protease inhibitors such as indinavir sulfate inhibit the cytochrome P450 enzyme 3A4.
True or false: Cross-tolerance between BZDs are good but not perfect
True or false: Tolerance is uncommon with BZDs
What is withdrawal syndrome?
A withdrawal syndrome is defined as a predictable constellation of signs and symptoms involving altered CNS activity (e.g., tremor, convulsions, or delirium) after the abrupt discontinuation of, or a rapid decrease in, dosing of the drug
When does the withdrawal symptoms of BZDs manifest usually?
Typically, a withdrawal syndrome from short-half-life benzodiazepines will intensify by the second day, will usually have peaked by day 5, and will begin to decrease and taper off by day 10. After 2 weeks, withdrawal symptoms usually have become minimal or are absent.
Drug factors associated with
withdrawal symptoms include length of use, dose, potency, and rate of discontinuation.
What are symptoms of BZD withdrawal?
The most common are anxiety, restlessness, irritability, insomnia, agitation, muscle tension, weakness, aches and pains, blurred vision, and racing heart, in that order.
Nausea, sweating, runny nose, hypersensitivity to stimuli, and tremor are less frequent.
Severe withdrawal symptoms, such as psychosis, seizures, hallucinations, paranoid delusions, and persistent tinnitus, are relatively rare and are more likely to occur in abrupt withdrawal from high doses of high-potency benzodiazepines and in the elderly
True or False: At the end of any course of treatment with therapeutic doses and of duration greater than 3–6 weeks, withdrawal of the benzodiazepine should be done as a very slow taper.
What is the course of BZD taper?
In a 3-year follow-up of patients who tapered successfully in a benzodiazepine taper program, 73% remained benzodiazepine free. Among those who were able to reduce intake by 50%, only 39% were benzodiazepine free at the end of 3 years. In the group that could not tolerate taper at all, only 14% were benzodiazepine free
True or False:
In reality, frequency of dosing is a function of the duration of therapeutic action of the drug rather than of any innate addiction potential of the drug.
True or False: At this time, no large epidemiological studies have used substance use disorder in relation to benzodiazepines.
What are the definition of substance dependence, addiction, and physical dependence?
Substance dependence is defined as a maladaptive pattern of substance use, leading to clinically significant impairment or distress
Addiction, by contrast, is defined as a chronic disorder associated with compulsive use of a drug, resulting in physical, psychological, or social harm to the user and continued use despite that harm
Addiction involves both intense drug-seeking behavior and difficulty in stopping the drug use. If these criteria are used, benzodiazepines are not addictive drugs.
Physical dependence is different from addiction and is defined as a physiological state of adaptation to a drug, with the development of tolerance to the drug’s effects and the emergence of a withdrawal syndrome during prolonged abstinence.
When used on a regular schedule, benzodiazepines are associated with physical dependence and have a withdrawal syndrome.
What is the definition of BZD abuse?
A benzodiazepine is being abused if it is used 1) to get high, 2) to promote psychological regression, 3) at doses higher than prescribed, and 4) after the medical indication has passed.
On the basis of this definition, the data suggest that the incidence of benzodiazepine abuse in clinical practice is low.
What is the prevalence of BZD dependence?
Although the data suggest that the prevalence of benzodiazepine abuse or dependence is generally low, this is not true among those who abuse alcohol and other drugs.
The principal reasons for benzodiazepine use among drug-addicted persons are self-treatment of withdrawal symptoms, relief from rebound dysphoria, or potentiation of alcohol or street drug effects
Benzodiazepines were the primary drug of abuse in one-third of polydrug abusers
What is the role of BZD in cocaine use disorder?
Snorting of benzodiazepines by individuals addicted to cocaine has been reported, primarily as a means of blunting the anxiogenic effect of cocaine and allowing for a more pleasant and “less edgy” high from that drug.
What is the rationale behind the BZD being related to facial clefts?
Early concern over benzodiazepine exposure in pregnancy arose because benzodiazepines act on GABA receptors, and GABA is involved in palate shelf reorientation
What is the evidence regarding BZDs role in formation of facial clefts?
Early studies in humans, including retrospective and case–control studies, reported an increased risk of oral clefts associated with diazepam.
These results, however, have been criticized on methodological grounds and are contradicted by more recent prospective studies, case–control studies, and meta-analyses that show no increased risk of oral clefts related to benzodiazepine use in pregnancy
True or false: Diazepam and desmethyldiazepam cross the placental barrier easily, and concentrations are higher in fetal blood than in maternal blood
What are the main concerns associated with BZD in last trimester and during labor?
CNS depression and a withdrawal syndrome (symptoms may occur weeks later).
There have been numerous reports of -------------- in babies born to women taking diazepam long term during pregnancy
“floppy infant syndrome”
True or false: Diazepam in isolated doses is safe during labor
What are the safety issues regarding BZD use during breast feeding
Neonates have only limited capacity to metabolize diazepam.
Benzodiazepines are excreted in breast milk
Because of the neonate’s limited capacity to metabolize these drugs, they can potentially accumulate and cause sedation, lethargy, and loss of weight in the nursing infant.
Although the extent to which benzodiazepines actually accumulate in the serum of breast-feeding infants is a matter of debate and three decades of studies support a low incidence of toxicity and adverse effects, caution taking benzodiazepines while breast feeding is advised.
True or False: benzodiazepine users were more likely to experience at least one episode of accident-related health care and a greater number of accident-related inpatient days and also utilized significantly more non-accident-related health care services than did nonusers.
True or false: Accident-related utilization of health care was more likely in the first month after the BZD was prescribed
True or false: BZD increase the risk of MVA and falls
Where does the notion of anxiety disorders being related to serotonin come from?
The notion of a role for serotonin in the treatment of anxiety arose from the finding that benzodiazepines reduce brain 5-HT turnover and that para-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, mimics the effects of benzodiazepines in behavioral models of anxiety
both benzodiazepines and buspirone --------5-HT impulse flow
What is the downstream of 5HT1A
It couples negatively to adenylyl cyclase
Where in the brain there is a high density of 5HT1A receptors
midbrain, hippocampus, and limbic areas of the brain
Mice lacking the 5-HT1A receptor gene exhibit manifestations of -----------
Brain regions with high densities of 5-HT1A receptors control -----------
thermoregulation, endocrine function, appetite, aggressive and sexual behavior, and mood
What is the role of 5HT1A receptors on 5-HT neurons in midbrain raphe regions?
They modulate release of 5-HT at synapses in forebrain.
These somatodendritic autoreceptors control synthesis and impulse flow and release of neurotransmitter from ascending 5-HT–containing neurons
What has been found in relation of 5HT1A receptors and victims of suicide?
Enhanced binding of the ligand to inhibitory 5-HT1A autoreceptors in the dorsal raphe of suicide victims, in support of the hypothesis that these individuals had diminished 5-HT neuronal activity
True or False: diminished function (reduced binding potential) of serotonin 5-HT1A receptors in the brains of both suicide victims and patients with major depressive disorder (MDD) compared with matched controls
What are the findings of 5HT1A in depression
Enhanced binding of ligand to inhibitory 5HT1A autoreceptors in the dorsal raphe
Diminished function (reduced binding potential) of serotonin 5HT1A receptors in the brain of both suicide victims and MDD
Blunted 5-HT1A receptor–mediated response to corticosteroids is present in patients with MDD
Which 5HT1A partial agonist has antidepressant effects?
What were the effects of buspirone on In the frontal cortex of freely moving rats?
buspirone produces dose-dependent decreases in dialysate levels of 5-HT and increases in levels of dopamine and norepinephrine, findings indicative of multiple mechanisms by which buspirone may modify monoaminergic neurotransmission
What is the mechanism of action of Buspirone in decreasing anxiety?
The antianxiety properties of buspirone reflect its actions at both pre- and postsynaptic 5-HT1A receptors.
At presynaptic 5-HT1A receptors in the dorsal raphe, buspirone acts as a full agonist, inhibiting neuronal 5-HT synthesis and firing, whereas at postsynaptic receptors in hippocampus and cortex, it functions as a partial agonist.
It is postulated that the anxiolytic effect of buspirone is mediated by serotonergic actions in the presence of a pre-existing deficiency of this neurotransmitter.
What is the difference between BZD and Buspirone ?
Buspirone differs from benzodiazepines in that it does not inhibit motor coordination or spontaneous motor activity but can produce serotonin syndrome in rats
Unlike benzodiazepines, buspirone lacks abuse potential and does not impair psychomotor performance alone or in combination with ethanol
The behavioral effects of buspirone and benzodiazepines differ somewhat in animal models of anxiety in that buspirone does not uniformly increase punished or conflict responding in rats and monkeys. In pigeons, by contrast, buspirone enhances punished response equivalently to benzodiazepines, a characteristic of 5-HT1A receptor agonists such as 8-OH-DPAT, whereas TCAs, SSRIs, opioids, antipsychotics, and psychomotor stimulants do not.
Buspirone enhances exploratory and social interaction behavior in rodents, similar to benzodiazepines.
True or false: Unlike benzodiazepines, buspirone lacks abuse potential and does not impair psychomotor performance alone or in combination with ethanol
What is the mechanism of antidepressant action of Buspirone?
5-HT1A agonists produce an antidepressant response through postsynaptic effects on 5-HT1A receptors
What is the pharmacokinetic of buspirone
Undergoes extensive first-pass metabolism with CYP3A4 with a mean elimination half-life of 3–4 hours
Food, hepatic and renal impairment increases elimination half-life
true or false: there is no difference in kinetic of buspirone between younger and older people
What is the major metabolic pathway to hepatically clear buspirone?
Conversion of buspirone to 6-OH-Bu is the major metabolic pathway in the hepatic clearance of buspirone
What are the effects of 1-PP?
Noradrenergic properties of 1-PP may induce unwanted side effects in patients who have panic attacks or are undergoing benzodiazepine withdrawal
What is the significance of 6-OH-BU?
bioavailability of 6-OH-Bu is greater than that of the parent drug (19% vs. 1.4% for buspirone), significantly contributing to buspirone’s therapeutic activity
In vitro, 6-OH-Bu exhibits high affinity (25 nM) and partial agonist activity for the 5-HT1A receptor
How are anxiolytic effects of Buspirone mediated?
by its actions on 5-HT receptors in the limbic system
What are the hormonal effects of Buspirone?
Acts as a D2 partial agonist on ant pituitary, regulating prolactin levels
5-HT1A receptors regulate the neuroendocrine hormones, including growth hormone, adrenocorticotropic hormone, corticosterone, and oxytocin
Buspirone produces dose-dependent increases in rat plasma prolactin levels
All azapirones decrease body temperature
True or false:
Pindolol, a 5-HT1A antagonist, does not block the buspirone-induced increase in prolactin
What are the two major approved indications for buspirone?
Anxiety and depression
What is the difference between BZD and Buspirone in treatment of anxiety?
Buspirone has a slower onset of therapeutic effect relative to the benzodiazepines
This slower onset is attributable to differences between buspirone and benzodiazepines in relief of somatic anxiety, whereas the two drugs are similar in rate of alleviation of psychic anxiety.Lack of sedation with buspirone also contributes to the perception of a more gradual onset of anxiolysis
True or False: With buspirone, relief of somatic anxiety (particularly insomnia) occurs only after psychic anxiety symptoms abate
What are the results of comparing Buspirone and Clorazepate in GAD?
Onset quicker for BZD
Efficacy similar after 4 weeks
No therapeutic tolerance with either drug
after 6 months several patients who stopped BZD experience anxiety but no one experience anxiety in the Buspirone group
Long-term follow-up at 40 months of patients revealed that none of the buspirone-treated patients needed anxiolytic medication, whereas more than 50% of the patients treated with clorazepate required continuation anxiolytic therapy
True or false: buspirone lacks physical dependence liability and does not impair cognition or acquisition of coping skills
True or False: Buspirone is effective in treating BZD withdrawal
What is the evidence for Buspirone in the elderly
Both safe and effective
No cognitive side effects or excess sedation
What is the evidence of Buspirone in panic attacks?
Why is Buspirone not effective in panic attacks?
buspirone increases firing rates in the locus coeruleus and causes noradrenergic hyperactivity both manifestations of panic disorder.
What is the evidence for Buspirone in depression?
Efficacious in subsyndromal, comorbid anxiety and depression as well as an augmentation
What are the nonapproved use of Buspar?
Facilitates smoking cessation
Efficacious in alcohol use disorder
Efficacious in opioid withdrawal
Not so efficacious in cocaine or cannabis use disorder
Probably not efficacious in schizophrenia
Might be useful in irritability in autism
Modest efficacy in premenstrual syndrome
Maybe AD and aggressive behavior in ADHD
What is the recommended dose of Buspirone in GAD and MDD with anxiety?
GAD: 15–20 mg/day initially, prescribed in divided doses, with increases to 30 mg/day if indicated and a maximum dosage of 60 mg/day
Higher buspirone dosages than those prescribed for anxiety disorders may be required in the treatment of MDD, either as monotherapy or as augmentation of an SSRI.
What is the difference in therapeutic response to buspirone between anxious patients naïve to benzodiazepine treatment compared with patients recently treated with a benzodiazepine
GAD patients with either no prior benzodiazepine treatment or temporally remote benzodiazepine treatment (> 6 months previously) experienced greater improvement with buspirone therapy than did patients who either were currently receiving or had recently completed treatment with a benzodiazepine.
What does the diminished therapeutic response with Buspirone in a patient with BZD use reflect?
It may reflect a subclinical benzodiazepine withdrawal syndrome (possibly exacerbated by buspirone’s 1-PP metabolite).
True or False: Directly switching from SSRI treatment to buspirone is not problematic.