General Properties of Sedative and Hypnotics Agents (3)
- Sedative (anxiolytic) agents: Reduce anxiety by exerting calming effects.
Sedative effects exist on a dose-dependent continuum with hypnosis, anesthesia, coma, and death. - Hypnotic agents: Produce drowsiness and encourage onset and maintenance of a sleep state
- Generally, CNS depression should be minimized compared to therapeutic benefit
Dose-Dependency and CNS Depression in Sedatives and Hypnotic Agents (3)
- Dose and degree of CNS depression vary between drug classes. Withdrawal symptoms can be severe among all classes, however.
- Barbiturates and alcohol have a positive linear relationship with worsening CNS depressive effects as their dosage increases
- Benzodiazepines and newer hypnotics have a hyperbolic curve (CNS effects taper off when a particular drug dosage is reached) and are considered safer agents
Indications for Sedative (anxiolytic) agents (5)
- GAD
- PTSD
- Acute stress disorder
- Panic disorder
- OCD
*Note: antidepressants are also often indicated for anxiety disorders
Indications for Hypnotic agents (1)
- Sleep-wake disorders
* Note: not all anxiolytics have sedative or hypnotic properties
General Neurochemical Theories of Anxiety (3)
- Anxiety disorders are a result of overactivity of the brain in response to threats, leading to avoidance, hypervigilance, and increased arousal
- Anxiety disorders exist on a spectrum:
A. Comorbidities are common
B. Treatment interventions are similar - SSRIs, benzodiazepines, exposure therapy, etc. - Variation between hyperreactors and hyporeactors
A. Highly anxious people respond less to startle stimuli in laboratory settings
Neural Control of Emotional Responses to External Stimuli (1)
- Neurotrophic contributions - animal studies have shown that BDNF is essential for the acquisition and extinction of anxiety
Specific Neurochemical Theories Models of Anxiety (3)
- Noradrenergic Model: ANS of highly anxious people is hypersensitive, caused by chronic overactivity of NE, which down-regulates autoreceptors, causing increased NE firing from the locus coeruleus. Increased glutamate release also causes subjective feelings of anxiety, which an precipitate panic attacks.
- GABA-Receptors Model: The GABAa receptor is the target for anxiety reduction and sedation promotion, because GABA signaling inhibits 5-HT, NE, and dopamine systems. Benzodiazepine allosterically enhance GABAa action. Specific role of GABA receptors in anxiety disorders has not been established.
- Serotonin Model: Greater 5-HT activity is thought to reduce NE activity in the locus coeruleus. SSRIs increase 5-HT levels, blocking manifestations of panic and anxiety. Partial agonists for 5-HT1A (which increase serotonin release, because 5-HT1A is an autoreceptor) are effective for GAD, but NOT panic disorder, which suggests reduced 5-HT signaling or stimulation of 5-HT pathways underlie GAD.
GABAergic Drugs - Varying Indications Depending on Drug Structure (2)
- Differences exist between benzodiazepines and their therapeutic effects, which primarily is determined by the different affinities for receptor subunits that each drug has
- Can produce sedation, muscle relaxation, anxiolytic-effects, and/or anticonvulsant effects
Benzodiazepines (Indications, MOA, Formulations, and PK)
Indications: Several anxiety disorders
MOA: Positive allosteric modulators of GABAa receptor. Increases endogenous GABA signaling
Formulations: Most drugs for treatment of anxiety are administered PO. *Note: there are IV/IM preparations for emergency situations like status epilepticus and seizure disorders
PK: Most metabolized by hepatic CYPs 3A4 and 2C19. Oxazepam is conjugated directly by phase 2 enzymes. Biotransformation increases duration of activity. Longer half-life reduces likelihood of withdrawal symptoms.
Benzodiazepines (Considerations and ADRs)
Considerations: If used longer than 2 weeks, drug should be tapered off. Switching a short half-life agent to a long half-life agents may ease likelihood of withdrawal symptoms. Patients treated for insomnia may experience rebound insomnia. *Triazolam is not often used due to effects on memory and respiratory complications.
ADRs: Drowsiness, confusion, ataxia (at high doses), and cognitive impairment (anterograde amnesia with high-potency agents). Overdose is rarely lethal, but sudden withdrawal can be fatal for dependent patients. Treat dependent patients with flumazenil, which is a GABAa receptor antagonist at the BZD site, BUT do this carefully because sudden withdrawal can cause SEIZURE and possibly death. BDZs have abuse liability as patients may develop dependence.
Benzodiazepines (Withdrawal Symptoms - 12)
- Anxiety
- Irritability
- Insomnia
- Hyperacusis
- Nausea
- Difficulty concentrating
- Tremor
- Depersonalization
- Hyperesthesia
- Myoclonus
- Deliruim
- Seizures
Barbiturates (General and MOA)
General: Risk of fatal overdose limits clinical use of barbiturates
MOA: Positive allosteric modulators of GABAa receptor at low doses. Increases GABA signaling. At high doses, drug becomes an agonist of GABAa receptors (has a synergistic effect on GABA signaling with its own allosteric binding site); enhances its own signaling AND endogenous GABA signaling.
Buspirone (Indications, MOA, ADRs, and PK)
Indications: GAD and anxiety in the elderly. Useful for chonic treatment of anxiety. Can be used as monotherapy in the absence of MDD.
MOA: 5-HT1A receptor antagonist; 5-HT1A is an autoreceptor that normally REDUCES serotonin release, antagonism or partial agonism of this receptor INCREASES serotonin release.
ADRs: Favorable profile. Non-sedating. No abuse liability.
PK: Hepatically metabolized by CYPs. Therapeutic effects may take 2-4 weeks to manifest.
General Properties of Other Sedative Drugs for Anxiety (6)
- General CNS depressants with little to no analgesia
- Effects on sleep architecture are similar to barbiturates
- Low therapeutic indices: acute intoxication produces respiratory depression and hypotension
- Chronic use can result in tolerance and physical dependence: withdrawal syndrome can be severe and life-threatening
- Pharmacodynamic interactions with other sedatives/CNS depressants
- Pharmacokinetic interactions with other CYP substrates
Other Sedative Agents for Anxiety (3)
- Chloral hydrate: May be used to treat patients with paradoxical reactions to benzodiazepines. Metabolized by hepatic alcohol dehydrogenase. Barbiturate-like effects on GABA receptor channels. Regulated as a schedule IV due to being a controlled substance.
- Meprobamate: Approved anxiolytic agent. May cause CNS depression in large doses; can cause severe respiratory depression, hypotension, shock, and heart failure. Mild analgesic effect, and enhances the analgesic effects and CNS depression of other drugs. Well-absorbed when administered orally. Undergoes phase II metabolism.
Withdrawal syndrome: anxiety, insomnia, tremors, hallucinations. 10% of cases have generalized seizures. - Carisoprodol: Skeletal muscle relaxant. Active metabolite is meprobamate. Also scheduled IV due to controlled substance.
Other agents used in the treatment of anxiety (3)
- Benzodiazepines and beta-blockers (aids with ANS effects of social anxiety) are the only agents with acute effectiveness.
- Others (SSRIs, SNRIs, buspirone) have delayed time to therapeutic effect. Similar to mechanisms of delay of antidepressant therapeutic effects.
- Bridge Therapy: Can administer benzodiazepines to overlap with SSRI treatment until SSRI reaches therapeutic levels, then benzodiazepine can be tapered off.
What are the types of insomnia? (3)
- Transient insomnia: less than 3 days. Due to brief environmental or situational stressor. Lowest dose of hypnotics recommended for 2-3 nights only. Avoid BZDs as they can impair performance prior to a significant life event.
- Short-term insomnia: 3 days - 3 weeks. Personal stressor such as illness, grief, or job problems. Hypnotics may be used adjunctively and intermittently for 7-10 nights.
- Long-term insomnia: longer than 3 weeks. Specific stressor that may not identifiable. Counsel on sleep hygiene, hypnotics, identification/treatment of underlying psychiatric condition
Management of Insomnia (6)
- Hypnotics reduce sleep latency, but disrupt sleep architecture: Dose-dependent decrease in REM and slow-wave sleep. Potency levels from high-to-low: Barbiturates > alcohol > benzodiazepines > “Z-drugs” and newer agents.
- Next-day effects: rebound anxiety, continued sedation (mental and motor depression), dysphoria, amnesia (generally with BDZs)
- Chronic use: rebound insomnia with cessation, dependence
- Cost-benefit analysis: hypnotic side effects vs. consequences of chronic insomnia
- Non-pharmacologic management: exercise, correcting identifiable causes, sleep hygiene, limit stimulant/alcohol intake, etc.
- Approved benzodiazepines: flurazepam, temazepam, quazepam, estazolam
“Z drugs” (Agents, General, Indications, MOA, Formulations, PK, and ADRs)
Agents: zolpidem, zaleplon
General: Rapid-acting, reduces sleep latency and awakenings, increases total sleep time.
Indications: Insomnia. Sedative only. Lacks anxiolytic, muscle relaxant, and anticonvulsant properties. Less disruptive of sleep architecture!
MOA: “Benzodiazepine receptor agonists” - Structurally unrelated to benzodiazepines. GABAa agonist.
Formulations: Available PO.
PK: Metabolized by CYPs.
ADRs: Relatively favorable profile. Less tolerance, withdrawal, or rebound insomnia compared to other hypnotic agents.
