Psychopharmacology APA- Sedative/Hypnotics

• All except Temazepam and Triazolam are used as Anxiolytics
• Temazepam and Triazolam are used as Hypnotics

• Longest: Diazepam (20–100 [36–200]) and Chlordiazepoxide (5–30 [36–200])
• Shortest: Triazolam (2); Oxazepam (4-15 hours)

• Alprazolam
• Lorazepam
• Temazepam

18-50 hours

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.

• 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.

All of them do undergo hepatic metabolism

Oxazepam, Temazepam and Lorazepam

Adverse effects of benzodiazepines are dose-dependent and include sedation, impaired cognitive function and judgment, amnesia, impaired motor performance, and disinhibition.

It may result in withdrawal symptoms including anxiety, agitation, tremor, autonomic hyperactivity, insomnia, nausea and vomiting, seizure, and delirium.

Benzodiazepine withdrawal is best managed by resumption of an intermediate- to long-acting benzodiazepine to stabilize the patient, followed by gradual taper under supervision.

• 5-HT1A receptor partial agonist
• No Effect on GABA or Cl channels
• No abuse, tolerance potential
• no BZD cross-reactivity

GAD

• HL of 2 hours
• Three divided doses
• Discontinuation syndrome
• Works best for BZD naïve patients
• Its metabolism is decreased by CYP3A4 inhibitors.

• Nausea, headache, nervousness, and insomnia
• Not lethal in overdose

• 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

• Inducing and maintaining sleep
• Minimal Daytime sedation

Zolpidem is available in an extended-release form to assist with sleeping through the night, as well as a sublingual formulation for middle insomnia

• 1-5 Zolpidem
• 1.5-2 Zalpelon

• 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

Xanax

• Chlordiazepoxide
• Alprazolam

• Alprazolam
• Clonazepam

• 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.

Currently marketed benzodiazepines are similar in that they have the 1,4-benzodiazepine ring system

True

True

• Temazepam
• Lorazepam
• Oxazepam

Nitrazepam and Flunitrazepam

• 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.

• 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

The lipid solubility (lipophilicity)

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 (due to higher lipophilicity)

the rate and extent of drug distribution rather than by the rate of elimination.

lipophilicity.

• 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

Less

• The speed and extent of accumulation and the time to reach a steady state
• The time for drug washout after termination of multiple doses

Long

metabolic removal/ingestion

Four to five

• 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.

cimetidine, estrogens, and the hydrazine monoamine oxidase inhibitors (MAOIs)

are conjugated (e.g., temazepam, oxazepam, and lorazepam)/ oxidation (e.g., diazepam and alprazolam).

True

the rate of distribution rather than by information about elimination half-life.

12

4-6/7/4-7

glutamic acid

GABAA

anxiolytic, hypnotic, anticonvulsant, and muscle relaxation effects.

anxiolytic effects/sedative-hypnotic actions.

• 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.

Panic disorder

• SSRI/SNRI
• Combo of SSRI/SNRI with Benzos

OCD

True

• 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.

• 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

• 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.

• 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

• 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

• 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

Alprazolam

Oxazepam

• 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.

Long-term benzodiazepine users have been compared with control subjects and found to have cognitive impairments that reversed on reexamination after taper

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.

The most recent, largest, best-controlled, and most prospectively designed study found no effect.

• 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”

Antacids slow benzodiazepine absorption, because aluminum delays gastric emptying

• 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.

• 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.

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.

Antidepressants such as fluoxetine, paroxetine, and nefazodone and protease inhibitors such as indinavir sulfate inhibit the cytochrome P450 enzyme 3A4.

True

True

• Alprazolam 1
• Clonazepam 0.7
• Lorazepam 2
• Diazepam 10
• Chlordiazepoxide 25

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

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.

withdrawal symptoms include length of use, dose, potency, and rate of discontinuation.

• 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

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

True

• 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.

• 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.

• 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

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.

Early concern over benzodiazepine exposure in pregnancy arose because benzodiazepines act on GABA receptors, and GABA is involved in palate shelf reorientation

• 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

CNS depression and a withdrawal syndrome (symptoms may occur weeks later).

“floppy infant syndrome”

True

• 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

True

True

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

reduce

It couples negatively to adenylyl cyclase

midbrain, hippocampus, and limbic areas of the brain

anxious behavior

thermoregulation, endocrine function, appetite, aggressive and sexual behavior, and mood

• 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

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

• 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

Gepirone

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

• 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.

• 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

5-HT1A agonists produce an antidepressant response through postsynaptic effects on 5-HT1A receptors

• 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

Conversion of buspirone to 6-OH-Bu is the major metabolic pathway in the hepatic clearance of buspirone

Noradrenergic properties of 1-PP may induce unwanted side effects in patients who have panic attacks or are undergoing benzodiazepine withdrawal

• 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

by its actions on 5-HT receptors in the limbic system

• 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

• Anxiety
• Anxiety and depression

• 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

• 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

False

• Both safe and effective
• No cognitive side effects or excess sedation

Not effective

buspirone increases firing rates in the locus coeruleus and causes noradrenergic hyperactivity both manifestations of panic disorder.

Efficacious in subsyndromal, comorbid anxiety and depression as well as an augmentation

• 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

• 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.

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.

It may reflect a subclinical benzodiazepine withdrawal syndrome (possibly exacerbated by buspirone’s 1-PP metabolite).

True

dizziness (12%), drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), insomnia (3%), light-headedness (3%), dry mouth (3%), and excitement (2%)

• No abuse potential
• No inhibition of CYP
• No problem with complex motor skills or memory tasks

• modest elevations of haloperidol and cyclosporin A levels
• Serotonin syndrome with MAOI