Kapatos: Sedative-Hypnotic Drugs Flashcards
Definitions
Sedatives:
Hypnotics:
Sedatives: produce calming or drowsiness
Hypnotics: facilitate onset and maintenance of sleep
Classification (Sedative or Hypnotic):
Assignment indicates therapeutic use for sedation (relief of anxiety) or to encourage sleep (hypnosis)
Classification based on clinical use rather than structure due to chemical heterogeneity
Classification (Sedative or Hypnotic):
Benzodiazepines vs. Barbituates
Can also be classified based on duration of action
o Benzodiazepines can be short, intermediate or long acting
o Barbituates can be ultra-short, short or long acting
Effects:
Effects: dose-dependent CNS depressant effects
Subgroups (2)
Subgroups:
- Benzodiazepines: most important subgroup
- Barbituates
Miscellaneous Agents: (7)
o Meprobamate (carbamate) o Chloral hydrate (alcohol) o Buspirone o Zolpidem o Zaleplon o Eszopiclone o Ramelteon
Non-Prescription Hypnotics: (3)
Antihistamines
Serotonin Precursor
Product of Serotonin Biosynthetic Pathway
Antihistamines: (2)
Antihistamines:
o Diphenyhydramine
o Doxylamine
Serotonin Precursor:
Serotonin Precursor: L-tryptophan
Product of Serotonin Biosynthetic Pathway:
Product of Serotonin Biosynthetic Pathway: melatonin (synthesized and secreted by pineal gland in a circadian rhythm controlled by SS nervous system)
Absorption and Distribution
Highly Lipid Soluble:
Cross BBB after absorption from the GI tract
Lipophilic nature causes some benzos to be unreliable after IM injection
- For example, chlordiazepam and diazepam
Thiopental (barbiturate) has the highest lipid solubility and enters the CNS rapidly (used for induction of anesthesia)
- CNS effects rapidly terminated by redistribution of the drug to other tissues
Absorption and Distribution
Important Point:
Due to high lipid solubility, all sedative-hypnotics cross the placenta (depress normal neonatal vital functions)
Also detected in breast milk (depressive effects in nursing infants)
Benzodiazepine Metabolism
Phase I Reactions:
Phase I Reactions: many (but not all) undergo hepatic microsomal oxidation by P450 enzymes (CYP3A4/2C19)
Benzodiazepine Metabolism
Phase II Reactions:
Phase II Reactions: all are eventually conjugated to form glucuronides that are excreted in the urine
CYP3A4 Interactions: (5)
Inhibition: increases blood levels of benzodiazepines
o Erythromycin and clarithromycin (macrolides)
o Itraconazole and ketoconazole (antifungals)
o Nefazodone
o Grapefruit juice
o Cimetidine
Active Metabolites:
What agents accumulate after continuous dosing? (2)
Active Metabolites: many metabolites of benzodiazepines are biologically active (long half-lives)
- Accumulate after continuous dosing: occurs with some drugs, leading to excessive sedation
- Diazepam and flurazepam
Continuous Dosing
Accumulation may occur in :
Less of an issue with:
What do not undergo hepatic microsomal activation and are conjugated directly?
Accumulation may occur in drugs with long half-lives (see above)
Less of an issue with benzodiazepines with shorter half lives (no active metabolites)
Oxazepam and lorazepam (do not undergo hepatic microsomal activation and are conjugated directly)
Zolpidem/Zaleplon/Eszopiclone
Short Duration of Action: due to rapid metabolism by liver enzymes
Overall Duration of Action
Can be only a few hours: (5)
Eszopiclone Zaleplon Zolpidem Triazolam Chloral hydrate
Overall Duration of Action
Can be as long as >30 hours: (4)
Chlordiazepoxide
Clorazepate
Diazepam
Phenobarbital
Mechanism of Action
General:
No single MOA has been identified, and different subgroups may have different actions
Benzodiazepines
Receptors:
Located in many areas of the brain (thalamus, limbic structures, cerebral cortex)
Form part of the GABAA receptor-chloride ion channel macromolecule complex
Benzodiazepines
Receptor Binding:
Facilitates the inhibitory actions of GABA by increasing the chloride ion conductance and hyperpolarizing the membrane (therefore, you need to have GABA present for these to work)
Increase the FREQUENCY of GABA-mediated chloride channel opening
Benzodiazepines
Receptor Antagonist:
Receptor Antagonist: Flumazenil (reverses CNS effects of benzos)
Barbituates
Receptor:
Receptor: do not compete for BZ or GABA binding; appear to interact with other sites on GABAA receptor chloride ion channel
Barbituates
Receptor Binding:
Depresses:
Increases:
Depresses neuronal activity by PROLONGING the effects of the inhibitory effects of GABA and glycine (therefore, also need GABA to be present for these drugs to work)
Increase the DURATION of GABA-mediated chloride channel opening
Buspirone:
MOA:
Hypnotic, euphoric, muscle relaxant or anticonvulsant effects?
Cross-tolerance with benzos:
Buspirone: partial agonist at 5HT1A receptors AND agonist/antagonist at DA D2 receptor
Precise mechanism of anxiolytic effects unknown
No hypnotic, euphoric, muscle relaxant or anticonvulsant effects
No cross-tolerance with benzos
Buspirone
Potentiate effects of other sedative hypnotics?
Benzo withdrawal:
If you want to switch to buspirone:
Drug free interval:
Does not potentiate effects of other sedative hypnotics (including alcohol)
- Therefore, substitution of buspirone will NOT lessen/prevent benzo withdrawal
- If you want to switch to buspirone, need to first withdraw from benzo gradually
- Drug free interval between the 2 permits the physician to distinguish between withdrawal effects of benzos and failure of buspirone once employed
Eszopiclone/Zolpidem/Zaleplon
Eszopiclone/Zolpidem/Zaleplon: hypnotics that modulate GABAA receptor via interaction with BZ binding site (but these are NOT benzos)
Because of MOA, also antagonized by flumazenil
Ramelteon
Ramelteon: melatonin receptor agonist
Approved for sleep-onset insomonia (not for sleep maintenance)
No abuse potential and is not a controlled substance
Increased serum prolactin and decreased serum testosterone are possible side effects
Pharmacodynamics
General:
Depressant effects often:
Steepness of dose-response curve correlated with:
CNS effects of these drugs are highly dose-dependent (effects can range from sedation to coma, depending on the dose)
Depressant effects often ADDITIVE when two or more drugs given together
Steepness of dose-response curve correlated with safety
- Flatter curves (ie. benzos) safer
- Steeper curves (ie. barbiturates) less safe
Sedation
What occurs with ALL drugs in this class?
Usually accompanied by:
Both sedation and relief from anxiety occurs with ALL drugs in this class
Usually accompanied by:
- Impaired psychomotor functions
- Behavioral disinhibition
Hypnosis
High doses of benzodiazepines can lead to:
Withdrawal from chronic drug use can lead to:
Promote sleep onset and increase duration of sleep
- High doses of benzodiazepines can lead to decreased REM sleep
- Withdrawal from chronic drug use can lead to rebound increase in REM sleep
Anesthesia
Loss of consciousness:
Anterograde amnesia more common with:
Anesthesia can be produced by:
Loss of consciousness may occur at high doses (with amnesia and suppression of reflexes)
- Anterograde amnesia more common with benzos
- Anesthesia can be produced by most barbiturates and certain benzos (midazolam)
Anticonvulsant Actions
Seizures:
Anticonvulsant actions:
Status epilepticus:
Suppression of seizures occurs at high doses of most barbiturates and some benzos
- However, marked sedation is a problematic side effect
Selective anticonvulsant actions (ie. do not cause severe sedation) occurs only with a few drugs
- Phenobarbital
- Clonazepam
Treatment of status epilepticus
- High doses of IV diazepam, lorazepam or Phenobarbital (induce heavy sedation)
Muscle Relaxation
Skeletal muscle relaxation:
What is effective at SEDATIVE DOSES?
Meprobamate:
Skeletal muscle relaxation occurs at LOW DOSES
Use in specific spasticity states (ie. cerebral palsy)
- Diazepam is effective at SEDATIVE DOSES
Meprobamate has some SELECTIVITY as a muscle relaxant
Medullary Depression
High doses effects: (3)
High doses can cause depression of medullary neurons
- Respiratory arrest
- Hypotension
- CV collapse
These effects are the cause of death in OD
Tolerance:
Tolerance: decrease in responsiveness to the drug over time
Occurs when sedative-hypnotics used CHRONICALLY or in HIGH DOSES
Cross tolerance may occur across subgroups
Tolerance to Benzodiazepines
Associated with:
Rapid rebound in these receptors occurs when?
Associated with downregulation of BZ receptors (GABAA receptors)
Rapid rebound in these receptors occurs upon termination of benzo treatment
Psychologic Dependence
Occurs frequently with most sedative-hypnotics
Manifested by compulsive use to reduce anxiety
Physiological Dependence:
Constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when drug is discontinued
Physiological Dependence
Due to downregulation of BZ receptors, benzodiazepine withdrawal produces:
Occurs more commonly with:
Does not occur with:
Less of an issue with _____ than benzos
Due to downregulation of BZ receptors, benzodiazepine withdrawal produces neuronal hyperexctiability (anxiety, tremors, hyperrflexia, seizures)
Occurs more commonly with shorter-acting drugs (ie. pentobarbital or triazolam)
Does not occur with longer acting drugs (ie. diazepam) because they self-taper
Less of an issue with zopidem/zalepon/eszopiclone than benzos
Clinical Use
Anxiety States
Preferred Agents:
Preferred Agents: benzodiazepines with intermediate or long durations of action (ie. diazepam)
Clinical Use
Panic and Phobic Disorders: (2)
Alprazolam (Xanax)
Clonazepam
Buspirone
General Rule:
Use:
Buspirone: anxiolytic effects WITHOUT sedation of cognitive impairment; however, effects take a week or more to develop
General Rule:
- Put on a benzo first to immediately treat anxiety
- Then taper and use buspirone
Use: generalized anxiety disorder (GAD) in patients with a past history of substance abuse
Clinical Use
Sleep Disorders
Benzodiazepines: (2)
Benzodiazepines: widely used for primary insomnia and other sleep disorders
- Flurazepam
- Triazolam
Clinical Use
Sleep Disorders
Zolpidem/Eszopiclone/Zaleplon:
Cause less daytime impairment than most benzodiazepines
Minimal effects on sleep patterns (no rebound increase in REM sleep)
Clinical Use
Anesthesia
Induction:
Components of Protocol:
Induction: thiopental
Components of Protocol: diazepam and midazolam
Clinical Use
Seizure Disorders: (2)
Clonazepam
Phenobarbital
Clinical Use
Spasticity: (1)
Diazepam
Clinical Use
Management of Withdrawal:
Longer acting agents: (2)
Management of Withdrawal: in people physiologically dependent on EtOH or other sedative-hypnotics
Longer acting agents: chlordiazpoxide, diazepam
Toxicity
Psychomotor Dysfunction
Includes:
Includes: cognitive impairment, decreased psychomotor skills, unwanted daytime sedation
Toxicity
Psychomotor Dysfunction
More common with: (2)
Short acting hypnotics:
More common with benzodiazepines that have long-lived active metabolites
- Diazepam and flurazepam
Short acting hypnotics (esp. triazolam) may cause daytime anxiety and amnesia
Anterograde amnesia may also occur with high doses of benzos
- Basis for use in cases of “date rape”
Toxicity
Psychomotor Dysfunction
Caution:
Caution: dosage in elderly patients should be decreased by at least 50% to avoid daytime sedation
- Increases risks of falls and fractures
- Sedation in elderly due to CHANGE IN BRAIN FUNCTION, not change in liver metabolism
Toxicity
Additive CNS Depression
DDIs: (5)
- Alcoholic beverages
- Antihistamines
- Antipsychotics
- Opioid analgesics
- TCAs
Toxicity
Additive CNS Depression
Inhibition of Benzodiazepine Metabolism (CYP3A4 interactions):
Buspirone:
Inhibition of Benzodiazepine Metabolism (CYP3A4 interactions): see previous notes
Buspirone: additive CNS depression uncommon
Toxicity
Overdose
Respiratory and CV Depression:
Respiratory and CV Depression:
- More likely with alcohols, barbiturates and carbamates than with benzos
- More pronounced in people with respiratory depression, sleep apnea or CV disease
Toxicity
Overdose
Management:
______ can reverse CNS effects of benzos, zolpidem, zaleplon and eszopiclone:
Requires maintenance of patent airway and ventilatory support
Flumazenil can reverse CNS effects of benzos, zolpidem, zaleplon and eszopiclone ONLY
- Needs to be administered repeatedly due to short half-life
- Also important to take care with use in patients that have a history of seizures
Induction of the formation of liver microsomal enzymes that increase drug metabolism: (2)
Barbituates and carbamates only
Precipitation of acute intermittent porphyria:
Barbiturates (in susceptible patients)
Displacement of coumarins from plasma protein binding sites:
Chloral hydrate (increase anticoagulant effects)
