Sedatives And Hypnotics Flashcards
What distinguishes a sedative from a hypnotic, and how can a single drug exhibit both properties?
A sedative reduces anxiety and exerts calming effects without necessarily inducing sleep, while a hypnotic induces and maintains sleep. Many CNS depressants (e.g., benzodiazepines) display dose-dependent effects—low doses act as sedatives, and higher doses function as hypnotics.
Which two major drug classes are considered sedative-hypnotics, and how do they differ in safety?
Barbiturates and benzodiazepines. Benzodiazepines have a wider therapeutic index, meaning a greater margin between effective and toxic doses, whereas barbiturates can cause severe CNS depression even with modest overdose.
How do sedative-hypnotics impact the level of arousal on the CNS depression spectrum?
They shift arousal along a continuum: wakefulness → sedation → sleep → anesthesia → coma → death, with barbiturates capable of covering the entire range, while benzodiazepines typically do not cause anesthesia or death at therapeutic doses.
Why are barbiturates more toxic in overdose compared to benzodiazepines?
Barbiturates are less selective, affect multiple CNS targets, can mimic GABA at high doses, and induce respiratory depression. Their steep dose-response curve contributes to a poor safety profile.
What is the mechanism of action common to both barbiturates and benzodiazepines at the GABAa receptor complex?
Both bind allosterically (at sites distinct from GABA) on the GABAa ionophore, enhancing chloride influx into neurons, which hyperpolarizes the membrane and inhibits neuronal firing.
How does benzodiazepine activity at GABAa differ from barbiturate activity?
Benzodiazepines increase the frequency of chloride channel opening, requiring GABA to be present. Barbiturates increase the duration of channel opening and can mimic GABA at high doses, making them more potent depressants.
What are the three classes of GABA receptors and their relevance?
GABAa: ionotropic, targets of most sedative-hypnotics; GABAb: metabotropic (GPCR), involved in muscle tone and anti-spastic effects; GABAc: less common, retinal distribution. Sedative-hypnotics like benzodiazepines act specifically on GABAa receptors.
What are the key ligands at benzodiazepine receptors and their effects?
Agonists (e.g., diazepam): sedative, anxiolytic; Antagonists (e.g., flumazenil): block BZD effects; used in overdose; Inverse agonists (e.g., beta-carbolines): provoke anxiety and seizures by decreasing GABA activity.
What is the clinical use of flumazenil and its major risk?
Flumazenil is used to reverse benzodiazepine sedation or overdose, but can precipitate withdrawal seizures in chronic users or mixed overdose (especially with tricyclic antidepressants).
Describe how benzodiazepines modulate GABA neurotransmission at the synaptic level.
They bind a site on the GABAa receptor complex, increase the frequency of Cl⁻ channel opening, enhance inhibitory postsynaptic potentials (IPSPs), and potentiate GABA’s natural calming effects without direct agonism.
What are the systemic effects of benzodiazepines at therapeutic doses?
Minimal effects on cardiovascular, GI, or respiratory systems. They do not cause significant respiratory depression unless combined with other depressants (e.g., alcohol).
What are potential side effects and risks of benzodiazepines?
Retrograde amnesia (especially midazolam); Ataxia, motor incoordination; Mild dependence/addiction risk; Less severe withdrawal than barbiturates.
How are benzodiazepines metabolized and what is the clinical significance?
Most are metabolized by hepatic microsomal enzymes, forming active metabolites. Some (like lorazepam) undergo glucuronidation and are safer in hepatic impairment.
Do benzodiazepines induce hepatic enzymes? Why does this matter?
No. Unlike barbiturates, benzodiazepines do not induce cytochrome P450, so they have fewer drug interactions and do not accelerate metabolism of other drugs.
What makes barbiturates more dangerous in overdose and drug interactions?
They induce hepatic microsomal enzymes, increasing metabolism of many drugs (e.g., anticoagulants, contraceptives). They also potentiate CNS depression when used with alcohol or antihistamines.
What is the detailed mechanism of action of barbiturates at the GABAa receptor?
Barbiturates bind to a separate site on the GABAa ionophore, increase the duration of Cl⁻ channel opening, prolong IPSPs, and at high concentrations, can directly activate the receptor even in the absence of GABA (GABA-mimetic effect).
Why do barbiturates pose a higher overdose risk compared to benzodiazepines?
Their ability to directly mimic GABA and prolong Cl⁻ influx without the presence of GABA increases risk for severe CNS depression, respiratory arrest, and death, especially when combined with other depressants.
What are the systemic effects of barbiturates in low vs. high doses?
Low dose: sedation, anxiolysis, mild CNS depression
High dose: anesthesia, coma, suppressed cardiac contractility, profound respiratory depression. They are less selective and depress excitatory pathways as well.
What makes barbiturates pharmacokinetically dangerous in polypharmacy situations?
They induce cytochrome P450 enzymes, accelerating the metabolism of many drugs (e.g., anticoagulants, oral contraceptives, corticosteroids), leading to therapeutic failure.
What CNS conditions may still warrant barbiturate use?
Status epilepticus (e.g., phenobarbital), short-acting anesthesia (e.g., thiopental for induction), occasionally for cerebral edema.
What are common therapeutic applications of benzodiazepines in dentistry and medicine?
Sedative-hypnotic (for anxiety or insomnia), anxiolytic (e.g., pre-op dental anxiety), anticonvulsant (e.g., status epilepticus), muscle relaxant, anesthetic adjunct (e.g., midazolam).
What are the benefits of benzodiazepines over barbiturates in dental anesthesia?
Wider safety margin, lower risk of CNS depression and death, less drug-drug interaction, less severe withdrawal, no enzyme induction.
What makes triazolam (Halcion) useful as a hypnotic?
Short half-life (2–4 hrs), rapid onset and clearance, less morning-after sedation, good for transient insomnia and elderly patients.
