pharmacology ch 19 - sedative hypnotic anxiolytic drugs

Diphenhydramine (Benadryl) Hydroxyzine (Atarax, Vistaril)

- May cross blood-brain barrier, produce sedation. - Sometimes used to treat mild insomnia and anxiety disorders; (ex. Diphenhydramine, hydroxyzine) - Doxepin recently approved for the treatment of insomnia has a high affinity for H1 receptors. - Sedative action of these drugs is caused by their ability to bind to H1 receptors and reduce acetylcholine released by neurons in the reticular nuclei (reticular activating system). - In contrast, caffeine and related methylxanthines can increase arousal by blocking presynaptic adenosine receptors, increasing cholinergic activity in the reticular nuclei. - Tolerance can occur during the long-term use of antihistamines, but these drugs are not associated with physical dependence or significant drug abuse.

Post-traumatic Stress Disorder (PTSD)

- May develop after exposure to a traumatic event, such as sexual assault or military combat. - SSRIs are used in the treatment of PTSD. - Other medications, such as benzodiazepines, may also be used to treat associated symptoms, such as an exaggerated startle response and flashbacks.

Acute Anxiety

- May develop in response to various factors, such as illness, separation from loved ones, or the anticipation of stressful events. - Often self-limiting and may resolve in a few weeks to a few months without drug treatment. - Benzodiazepines might provide short-term relief from more severe acute anxiety conditions.

Tasimelteon (Hetlioz)

- Melatonin agonist recently approved for the treatment of insomnia for non-24- hour sleep-wake disorder - Non-24 is a serious, chronic sleep disorder marked by disruption of the circadian rhythm - Non-24 affects up to 70% of people who are totally blind, whether blind from birth or acquired blindness

Neurologic Basis of Anxiety

- Neuronal pathways involved in anxiety disorders include: Sensory, Cognitive, Behavioral, Motor, Autonomic pathways - Sensory systems, cortical processing, and memory are involved in interpreting a stimulus to be dangerous and creating a state of heightened arousal. - Motor systems and autonomic processing participate in the exaggerated responses to an anxiety state.

Neurologic Basis of Sleep

- Neuronal systems involved in sleep include the basal forebrain nuclei and the reticular formation - Projecting from the basal forebrain to the cortex are cholinergic fibers that are believed to be involved in the induction of sleep - Basal forebrain is the only region of the brain active during slow-wave sleep and quiescent at other stages - The reticular formation facilitates the flow of sensory information from the thalamus to the cortex - When reticular nuclei are quiescent, the thalamus does not transfer information to the cortex, and this facilitates the onset of sleep

Ramelteon (Rozerem)

- New drug that acts selectively at melatonin receptors - Approved to treat sleep-onset insomnia - Does not produce dependence and has little potential for abuse - Compared with benzodiazepine drugs, there is no evidence for rebound insomnia after cessation of ramelteon - Should not be used with fluvoxamine, as this SSRI antidepressant is a strong CYP1A2 inhibitor, and concurrent use with ramelteon increases the peak plasma concentration of ramelteon 70-fold

Barbiturates - Pharmacokinetics

- Onset and duration of action are determined by their lipid solubility and rate of metabolicin activation - Highly lipid-soluble drugs (e.g., amobarbital, pentobarbital, and thiopental) - Well absorbed from the gut, rapidly redistributed from brain to peripheral tissues - Extensively metabolized to inactive compounds before they are excreted in urine - Phenobarbital, a more polar drug ,is slowly absorbed from the gut and more slowly redistributed from brain; this contributes to its longer duration of action - Phenobarbital is partly converted to inactive metabolites, but a significant fraction of the parent compound is excreted unchanged in the urine

Estazolam (Prosom) Flurazepam (Dalmane) Triazolam (Halcion)

- Have active metabolites with varying durations of action - Estazolam has a medium duration of action, whereas flurazepam has a long duration, and triazolam has a short duration of action - All three drugs are used to treat insomnia - A short-o rmedium-acting drug may be preferred for patients whose primary problem is getting to sleep. - Medium-or long-acting drug may be preferred for patients who report waking up too early - Short-acting triazolam is more likely to cause rebound insomnia when it is discontinued - Long-acting flurazepam is less likely to cause rebound insomnia but more likely to cause day time drowsiness. - Triazolam has been associated with a higher incidence of amnesia, confusion, and delirium, especially in elderly patients.

Benzodiazepines description

- Large group of drugs that have similar pharmacologic effects - Common chemical structure of a benzene ring (benzo) joined to a seven-member ring containing two nitrogen molecules (diazepine), give rise to the drug-class name, benzo—diazepine - The particular use of specific drugs is largely determined by their pharmacokinetic properties and route of administration - Some benzodiazepines were developed and approved to treat anxiety, whereas others are approved for the management of insomnia or for other purposes

Midazolam (Versed)

- used intravenously as an induction agent for patients undergoing surgery or to produce conscious sedation for endoscopy, minor outpatient surgery and other diagnostic procedures - benzodiazepine

Propranolol (Inderal)

- β-adrenoceptor antagonist (β-blocker) - Sometimes used to prevent the physiologic manifestations of: Stage fright, Acute situational anxiety, Performance anxiety - Prevents tachycardia and other signs and symptoms of acute anxiety caused by sympathetic stimulation

Nonsedating Anxiolytic Drugs

Buspirone (Buspar) Propranolol (Inderal)

Anti-histamines

Diphenhydramine (Benadryl), hydroxyzine (Atarax, Vistaril)

Anxiety Disorders

Anxiety is normally an adaptive response to the challenges of life, characterized by: Changes in mood (apprehension and fear), Sympathetic nervous system arousal, Hypervigilance - Chronic anxiety can: Impair a person's ability to perform activities of daily living, Lead to visceral organ dysfunction and unpleasant symptoms such as: Gastrointestinal (diarrhea), Cardiovascular (tachycardia, Neurologic problems (sweating, tremors, and dizziness) - Anxiety can contribute to heart disease and other disorders, including self-medication, leading to substance abuse

Sedative-Hypnotic Drugs

- Benzodiazepines - Barbiturates - Antihistamines - 'Z'-drugs, orexin receptor antagonists, and melatonin agonists (nonbenzodiazepine agents) - Because benzodiazepines have fewer adverse reactions and drug interactions and are safer in cases of overdose, they have largely replaced barbiturates and other older drugs - Barbiturates are still used when benzodiazepines are ineffective or contraindicated - The sedating antihistamines are occasionally used to treat mild insomnia and anxiety and have less potential for abuse than benzodiazepines and barbiturates - Many over-the-counter (OTC; nonprescription) sleep aids contain antihistamines as their effective ingredient

Zolpidem (Ambien) Zaleplon (Sonata) Eszopiclone (Lunesta)

" z drugs " - Largely replaced older benzodiazepines for the treatment of insomnia - Cause fewer adverse effects than older benzodiazepine agents—have relative lack of effect on REM or slow-wave sleep—and have less potential for tolerance and dependence - Their shorter duration of action and half life means less daytime sedation and hangover effects than benzos - Evidence of greater selectivity at targeting only GABAA receptors composed of α1 subunit combinations - Older benzodiazepines are less selective and bind to a more widespread distribution of receptor, producing a greater degree of adverse effects on sleep, cognitive performance, and memory - Zaleplon's elimination half-life is the shortest at approximately 1 hour - Zolpidem is available in a quick-acting sublingual tablet called Edluar

Benzodiazepines Pharmacokinetics

- Absorbed from the gut and distributed to the brain at rates proportional to their lipid solubility - As plasma concentration of a benzodiazepine declines, the drug is redistributed from the brain to the blood, and this mechanism contributes significantly to the termination of its effects on the CNS - All benzodiazepines are extensively metabolized in the liver - Most are converted to active metabolites in phase I oxidativ ereactions catalyzed by cytochrome P450 enzymes - Active metabolites of chlordiazepoxide, diazepam, and flurazepam are long acting and contribute to the long duration of action of these agents - Active metabolites of alprazolam, estazolam, midazolam, and triazolam are shorter acting - Each of these active metabolites is eventually conjugated with glucuronate to form an inactive polar metabolite excreted in the urine -Also undergo some degree of entero hepatic cycling that prolongs their duration of action

Thiopental (Pentothal)

- Administered intravenously to induce anesthesia - Also used in lethal injections - Extremely lipid soluble and has a very fast onset of action - The only barbiturate available that is classified as an ultra-short acting barbiturate - Rapidly redistributed from the brain to other tissues (muscle and fat), which accounts for its ultra-short duration of action

The Amygdala

- Almond-shaped structure in the temporal lobe - Plays a central role in mediating manifestations of anxiety, (conditioned avoidance reaction) - During the anticipatory period, those who are conditioned in this manner will exhibit signs of anxiety, such as autonomic and behavioral arousal. - Electrical stimulation of the amygdala induces signs of anxiety, whereas lesioning the amygdala or the administration of anxiolytic drugs prevents the behavioral and physiologic manifestations of anxiety during the anticipatory period. - It is believed that long-term potentiation in amygdala neurons establishes the memory of adverse events underlying anticipatory anxiety.

Melatonin and Related Drugs description

- Anti-insomnia Agents - A neuroendocrine hormone synthesized in the pineal gland - Interacts with specific receptors in the CNS and elsewhere - Believed to be the principal mediator of the biologic clock that determines circadian, seasonal, and reproductive rhythms in animal species; may accelerate the resetting of the biologic clock - In humans, released before the onset of sleep and produces drowsiness that facilitates sleep - Available without prescription; may be effective in the treatment of jet lag and insomnia in shift- change workers - May be effective in treating insomnia in elderly patients who make less melatonin - Appears to be effective in treating delayed sleep-phase syndrome and non-24-hour sleep-wake disorder

Barbiturates - interactions

- Barbiturates induce cytochrome P450 enzymes in the liver and thereby accelerate their own metabolism, as well as that of other drugs metabolized by these enzymes - Maximal enzyme induction is obtained by daily administration of phenobarbital, a long-acting agent - Barbiturates also induce the rate-limiting enzyme in porphyrin biosynthesis, α-aminolevulinate synthase - May exacerbate porphyria, a condition in which a hereditary defect causes excessive porphyrin synthesis and excretion, with attendant neurologic and cutaneous manifestations

Barbiturates - indications

- Barbiturates were extensively used to treat anxiety disorders and insomnia before the development of benzodiazepines but are seldom used for these purposes today. - Unlike benzodiazepines, barbiturates do not produce significant muscle relaxation and are not used in treating muscle spasm or spasticity disorders. - They are indicated for the treatment of seizure disorders and for the induction and maintenance of general anesthesia.

Benzodiazepines Adverse Effects

- Benzodiazepine scause CNS depression, motor incoordination, dizziness, and excessive drowsiness - May impair cognitive processing and can affect concentration, judgment, and planning - May also interfere with driving and other psychomotor skills - Longer-acting benzodiazepines (e.g.,diazepam) are used to treat insomnia, but drowsiness and a drug hangover can persist the next day -Intravenous (IV) administration of benzodiazepines produces greater CNS depression than oral administration, but incidences are rare

Benzodiazepines Mechanism of Action

- Benzodiazepines and barbiturates exert their effects on sleep and consciousness by facilitating the activity of the neurotransmitter gamma-aminobutyric acid (GABA) at various sites in the brain - GABA regulates the excitability of neurons in almost every neuronal tract - The GABAA receptor-chloride ion channel has binding sites for benzodiazepines and barbiturates, as well as alcohols, steroids, and inhalational anesthetics - Receptor-ion channel complex is made up of five subunits, with the major form of the complex containing alpha (α), beta (β), and gamma (γ) subunits - Benzodiazepine binding site is located at the interface between α and γ subunits at a site different from the binding site of GABA - Benzos binding to this site, increase the affinity of GABA for its binding site on the GABAA receptor- chloride ion channel complex

Benzodiazepines Mechanism of Action explained

- Benzodiazepines increase the frequency with which the channel opens, whereas barbiturates increase the length of time that the channel remains open - By increasing chloride conductance, these drugs cause neuronal membrane hyperpolarization; this in turn counteracts the depolarizing effect of excitatory neurotransmitters - Barbiturates increase chloride conductance independent of the presence of GABA, which is why they are capable of causing greater CNS depression and toxicity than the benzodiazepines - In addition to their effects on GABA, benzodiazepines also inhibit the neuronal reuptake of adenosine - This action increases the inhibitory effect of adenosine on neurons that release acetylcholine from the reticular formation, which is a brainstem structure mediating arousal - The effect of benzodiazepines on adenosine may also explain why these drugs dilate coronary arteries and decrease total peripheral resistance

Benzodiazepines Pharmacologic Effects

- Benzodiazepines produce a dose-dependent but limited depression of the CNS - Lower doses have a sedative and anxiolytic effect - Higher doses produce hypnosis (sleep) and moderate sedation, but not reaching the depth of general anesthesia needed for loss of reaction to painful stimulus - Relieves anxiety at doses that can produce relatively little sedation -In contrast to barbiturates, orally administered benzos do not produce significant respiratory depression, coma, or death unless they are administered with another CNS depressant (e.g., opioids or alcohol) - Benzodiazepines work only in the presence of GABA, the depth of CNS depression is limited - Benzodiazepines exhibit a ceiling effect

Barbiturates - Mechanism of Action

- Binds to an allosteric site on the GABAA receptor-chloride ion channel, distinct from the allosteric which benzodiazepines bind - Barbiturates increase the affinity of the receptor for GABA and the duration of time that the chloride channel remains open - In contrast to benzodiazepines, barbiturates also act to directly increase chloride influx in the absence of GABA - Barbiturates do not exhibit a ceiling effect: They have a linear dose-response curve with no ceiling effect - Higher doses of barbiturates increasingly depress the neuronal activity of the CNS, causing anesthesia, coma, and death from cardiorespiratory depression - This is why barbiturates exhibit greater toxicity and a smaller therapeutic index than benzodiazepines

Generalized Anxiety Disorder (GAD)

- Characterized by chronic worry and apprehension concerning future events. - Short-term therapy with benzodiazepines may relieve acute symptoms and provide bridge to psychotherapy. - Severity of disorder often fluctuates over time; benzodiazepines may be effective on intermittent basis. - Buspirone, a nonsedating anxiolytic, provides a useful alternative to benzodiazepines, produces little sedation, and is not associated with tolerance or dependence. - Must be taken for 3 or 4 weeks before its anxiolytic effects are felt. - Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, and the serotonin and norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine are also used in the treatment of GAD.

Obsessive-Compulsive Disorder (OCD)

- Characterized by obsessions, which are recurring or persistent: Thoughts, Impulses, Compulsions - Can be defined as repetitive behaviors in response to obsessions - OCD can be treated effectively with an antidepressant drug.

Phobic Disorders

- Defined as conditions which an individual is overly fearful about a particular situation or condition - Grouped into specific phobias: Social anxiety disorder (social phobia), Agoraphobia (Panic disorder can coexist with agoraphobia, an intense fear of being in a public place from which it might be difficult or embarrassing to cope with a panic attack - Phobic disorders are treated with a benzodiazepine or an antidepressant drug - Benzodiazepines: Provide acute relief of symptoms and enable patients to more easily benefit from psychotherapy - Antidepressants: Most effective long-term drug therapy for agoraphobia and social phobia. - Propranolol is useful in the prevention of stage fright, or acute situational or performance anxiety

- Oxazepam (Serax) - Temazepam (Restoril) - Clonazepam (Klonopin) - Lorazepam (Ativan)

- Do not form long-acting metabolites - Have short or medium durations of action - Are bio-transformed to inactive glucuronide compounds. - Maybe preferable in treatment of elderly patients because glucuronide conjugation does not decline significantly with aging - Lorazepam can be administered orally or intravenously and is used to treat anxiety and to control seizures - Oxazepam is a short-acting drug that is. administered to patients with anxiety - Temazepam is used primarily to treat. insomnia

Benzodiazepines Indications

- Effective in the treatment of anxiety disorders, insomnia, muscle spasm, seizure disorders, and spasticity - Also used for the treatment of alcohol withdrawal - Use of benzodiazepines should be limited to the short-term treatment of these conditions when possible - If long-term use is medically justified, the physician should carefully monitor drug use to prevent dosage escalation.

ceiling effect

- Greater doses do not produce significantly greater effects and do not depress the brain to the point of anesthesia and death. - Barbiturates do not exhibit ceiling effect; can produce severe respiratory depression and death after a large dose - Benzodiazepines exhibit ceiling effect

Classification and Treatment of Anxiety Disorders

- the appropriate management of anxiety disorders requires an accurate diagnosis, and treatment may involve the use of pharmacologic agents, psychotherapy, or both. - Acute Anxiety - Phobic Disorders - Obsessive-Compulsive Disorder (OCD) - Generalized Anxiety Disorder (GAD) - Post-traumatic Stress Disorder (PTSD)

Remimazolam (Byfavo)

- the newest benzodiazepine to join the sedative-hypnotic class - The structure of midazolam was modified with an ester linkage to make remimazolam - Given by IV injection and indicated for the induction and maintenance of conscious sedation for procedures lasting 30 minutes or less.

Suvorexant (Belsomra) Lemborexant (Dayvigo)

- Orexin is a neuropeptide produced in the hypothalamus and promotes wakefulness through interaction with orexin receptors. - A role for orexin in wakefulness was confirmed when it was discovered that some people with narcolepsy have a loss of orexin-producing neurons in the brain. - Suvorexant, first in class drug, is a competitive receptor antagonist at orexin receptors. - Suvorexant has good oral bioavailability and reaches maximum concentration in the blood after 2 hours. - Has a long elimination half-life of 12 hours after steady-state is reached in nightly users - Caution for next-day sleepiness is warranted. - More recently, a second orexin receptor antagonist was approved for the treatment of insomnia, called Lemborexant. - Lemborexant has similar bioavailability and time to peak absorption after oral administration as suvorexant but with a longer elimination half-life.

List of benzodiazepines

- Oxazepam (Serax) - Temazepam (Restoril) - Clonazepam (Klonopin) - Lorazepam (Ativan) - Estazolam (Prosom) - Flurazepam (Dalmane) - Triazolam (Halcion) - Midazolam (Versed) - Remimazolam (Byfavo)

Sedative

- Sedative: refers to the ability of these agents to calm or reduce anxiety, known as an anxiolytic effect. - Ethanol (alcohol) has sedative effects, but is not used therapeutically for these purposes.

Benzodiazepines - Interactions and Treatment of Adverse Effects

- Several drugs ,including flumazenil and β-carboline derivatives, interact with benzodiazepine receptors - Flumazenil (Romazicon): competitive benzodiazepine receptor antagonist

Sleep Disorders

- Sleep is a reversible state of reduced consciousness accompanied by characteristic changes in the electroencephalogram (EEG) - Five distinct patterns of brainwave activity occur during sleep, grouped into the four stages of nonrapid eye movement (NREM) sleep, and a pattern characterized by paralysis of voluntary muscles and quick, saccadic movement of the eye called rapid eye movement (REM) sleep - As an individual falls asleep, the high- frequency and low-amplitude activity of the alert state gradually diminishes during stages 1 and 2 and is replaced by the low-frequency and high-amplitude activity of slow-wave sleep (stages 3 and 4) - Over time, the individual returns to stage 1 and eventually to the REM stage - REM sleep is also known as paradoxical sleep because the EEG pattern is similar to that in the awake state - A normal adult cycles through the sleep stages about every 90 minutes - Sleep patterns change with age and are altered by sedative-hypnotic and other CNS drugs

Insomnia

- Some patients find it difficult to go to sleep or to stay asleep during the night - Others awaken too early in the morning - Management depends on the sleep disorder being physiologic, psychologic, or a medical condition - Occasional sleeplessness caused by acute stress or a minor illness is usually self-limiting - More severe insomnia caused by medical conditions is effectively treated with benzodiazepines or other sedative-hypnotic drugs, such as zolpidem and zaleplon - Insomnia related to psychological and psychiatric disturbances is best managed with a combination of psychotherapy and sedative-hypnotic drugs - Benzodiazepines and hypnotic drugs decrease sleep latency and increase sleep duration - Zolpidem, zaleplon, eszopiclone, suvorexant, lemborexant, ramelteon, and tasimelteon have become the drugs of choice to treat most types of insomnia due to fewer side effects

Buspirone (Buspar)

- Unique anxiolytic agent that does not share structural similarity with the other agents - Used in the treatment of chronic anxiety - Produces anxiolytic effect without causing marked sedation, amnesia, tolerance, dependence, or muscle relaxation - May cause headache, dizziness, and nervousness, but these side effects are usually mild and temporary - Partial agonist at serotonin 5-HT1A receptors and may exert its anxiolytic effect by activating feed- back inhibition of serotonin release. By this action, it can cause up-regulation of postsynaptic serotonin receptors - Effect takes time to develop and is consistent with the 3- to 4-week delay in the onset of the anxiolytic effect

Barbiturates - Pharmacologic effects

- Unlike anxiolytic effects of benzodiazepines, barbiturates are associated with considerable sedation. - When used to treat insomnia, barbiturates can cause hangover and day time sedation. - Suppress slow-wave and REM sleep. - Also cause tolerance and physical dependence during continuous use; withdrawal syndrome occurs if abruptly discontinued. - Short-acting barbiturates (e.g.,pentobarbital) have been extensively abused.

Clonazepam (Konopin)

- Used for the treatment of panic and anxiety disorders, as well as for the treatment of seizure disorders - benzodiazepine

Phenobarbital (Luminal)

- Used occasionally to treat seizure disorders - barbiturates

Pentobarbital (Nembutal) and amobarbital (Amytal)

- Used primarily to treat insomnia - barbiturates

Anti-insomnia Agents

- Zolpidem (Ambien), - Zaleplon (Sonata), - Eszopiclone (Lunesta) - Suvorexant (Belsomra), - Lemborexant (Dayvigo) - Ramelteon (Rozerem) - Tasimelteon (Hetlioz)

Orexin Receptor Antagonists

- anti-insomnia agents - Suvorexant (Belsomra), lemborexant (Dayvigo)

Hypnotic

- describes the ability of these agents to induce drowsiness and promote sleep caused by a greater depression of central nervous system (CNS) activity

Melatonin and Related Drugs:

Ramelteon (Rozerem) Tasimelteon (Hetlioz)