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Pharm Exam 2 > Kapatos: Sedative-Hypnotic Drugs > Flashcards

Kapatos: Sedative-Hypnotic Drugs Flashcards

(61 cards)

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1
Q

Definitions
Sedatives:
Hypnotics:

A

Sedatives: produce calming or drowsiness

Hypnotics: facilitate onset and maintenance of sleep

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2
Q

Classification (Sedative or Hypnotic):

A

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

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3
Q

Classification (Sedative or Hypnotic):

Benzodiazepines vs. Barbituates

A

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

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4
Q

Effects:

A

Effects: dose-dependent CNS depressant effects

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5
Q

Subgroups (2)

A

Subgroups:

  • Benzodiazepines: most important subgroup
  • Barbituates
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6
Q

Miscellaneous Agents: (7)

A 
o	Meprobamate (carbamate)
o	Chloral hydrate (alcohol)
o	Buspirone
o	Zolpidem
o	Zaleplon
o	Eszopiclone
o	Ramelteon
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7
Q

Non-Prescription Hypnotics: (3)

A

Antihistamines

Serotonin Precursor

Product of Serotonin Biosynthetic Pathway

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8
Q

Antihistamines: (2)

A

Antihistamines:
o Diphenyhydramine
o Doxylamine

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9
Q

Serotonin Precursor:

A

Serotonin Precursor: L-tryptophan

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10
Q

Product of Serotonin Biosynthetic Pathway:

A

Product of Serotonin Biosynthetic Pathway: melatonin (synthesized and secreted by pineal gland in a circadian rhythm controlled by SS nervous system)

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11
Q

Absorption and Distribution

Highly Lipid Soluble:

A

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

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12
Q

Absorption and Distribution

Important Point:

A

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)

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13
Q

Benzodiazepine Metabolism

Phase I Reactions:

A

Phase I Reactions: many (but not all) undergo hepatic microsomal oxidation by P450 enzymes (CYP3A4/2C19)

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14
Q

Benzodiazepine Metabolism

Phase II Reactions:

A

Phase II Reactions: all are eventually conjugated to form glucuronides that are excreted in the urine

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15
Q

CYP3A4 Interactions: (5)

A

Inhibition: increases blood levels of benzodiazepines
o Erythromycin and clarithromycin (macrolides)
o Itraconazole and ketoconazole (antifungals)
o Nefazodone
o Grapefruit juice
o Cimetidine

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16
Q

Active Metabolites:

What agents accumulate after continuous dosing? (2)

A

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
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17
Q

Continuous Dosing

Accumulation may occur in :
Less of an issue with:
What do not undergo hepatic microsomal activation and are conjugated directly?

A

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)

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18
Q

Zolpidem/Zaleplon/Eszopiclone

A

Short Duration of Action: due to rapid metabolism by liver enzymes

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19
Q

Overall Duration of Action

Can be only a few hours: (5)

A 
Eszopiclone
Zaleplon
Zolpidem
Triazolam
Chloral hydrate
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20
Q

Overall Duration of Action

Can be as long as >30 hours: (4)

A

Chlordiazepoxide
Clorazepate
Diazepam
Phenobarbital

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21
Q

Mechanism of Action

General:

A

No single MOA has been identified, and different subgroups may have different actions

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22
Q

Benzodiazepines

Receptors:

A

Located in many areas of the brain (thalamus, limbic structures, cerebral cortex)

Form part of the GABAA receptor-chloride ion channel macromolecule complex

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23
Q

Benzodiazepines

Receptor Binding:

A

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

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24
Q

Benzodiazepines

Receptor Antagonist:

A

Receptor Antagonist: Flumazenil (reverses CNS effects of benzos)

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25
Barbituates | Receptor:
Receptor: do not compete for BZ or GABA binding; appear to interact with other sites on GABAA receptor chloride ion channel
26
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
27
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
28
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
29
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
30
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
31
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
32
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
33
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
34
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)
35
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)
36
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
37
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
38
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
39
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
40
Psychologic Dependence
Occurs frequently with most sedative-hypnotics Manifested by compulsive use to reduce anxiety
41
Physiological Dependence:
Constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when drug is discontinued
42
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
43
Clinical Use Anxiety States Preferred Agents:
Preferred Agents: benzodiazepines with intermediate or long durations of action (ie. diazepam)
44
Clinical Use | Panic and Phobic Disorders: (2)
Alprazolam (Xanax) | Clonazepam
45
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
46
Clinical Use Sleep Disorders Benzodiazepines: (2)
Benzodiazepines: widely used for primary insomnia and other sleep disorders - Flurazepam - Triazolam
47
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)
48
Clinical Use Anesthesia Induction: Components of Protocol:
Induction: thiopental Components of Protocol: diazepam and midazolam
49
Clinical Use | Seizure Disorders: (2)
Clonazepam | Phenobarbital
50
Clinical Use | Spasticity: (1)
Diazepam
51
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
52
Toxicity Psychomotor Dysfunction Includes:
Includes: cognitive impairment, decreased psychomotor skills, unwanted daytime sedation
53
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”
54
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
55
Toxicity Additive CNS Depression DDIs: (5)
- Alcoholic beverages - Antihistamines - Antipsychotics - Opioid analgesics - TCAs
56
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
57
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
58
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
59
Induction of the formation of liver microsomal enzymes that increase drug metabolism: (2)
Barbituates and carbamates only
60
Precipitation of acute intermittent porphyria:
Barbiturates (in susceptible patients)
61
Displacement of coumarins from plasma protein binding sites:
Chloral hydrate (increase anticoagulant effects)

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