Slides 5 Flashcards
What is a common feature of sedative-hypnotic use ?
Tolerance
What occurs among the sedative-hypnotics and also with ethanol ?
Partial cross-tolerance
An increase in what may contribute to tolerance with barbiturates ?
Drug metabolism
With benzodiazepines, tolerance may be due to:
Down regulation of brain BDZ receptors
Tolerance can occur with extended use of?
Zolpidem, but much less so with zaleplon and eszopiclone.
What is the cause of the compulsive use of virtually all sedative-hypnotics?
The perceived relief of anxiety, euphoria, disinhibition, and promotion of sleep
The consequences of abuse can be both?
Psychologic and physiologic.
What happens when the pattern of sedative-hypnotic use becomes compulsive?
More serious complications develop, including tolerance and physiologic dependence.
What is Physiologic dependence?
An altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome.
Abstinence or withdrawal syndrome consists of?
1) Increased anxiety
2) Restlessness
3) Insomnia
4) CNS excitability that may progress to:
a) Convulsions
b) Weakness
c) Orthostatic hypotension
What is the difference between drugs with long half-life and short half-life in terms of withdrawals?
Drugs with long half-life are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms.
Drugs with short half-lives may show signs of withdrawal even between doses (triazolam).
True of False:
Withdrawal symptoms of zolpidem, zaleplon, or eszopiclone are more intense than that with BDZs
False; it is less intense
True of False:
Lethal dose range is not altered significantly by long-term use
True
True of False?
The degree of tolerance achieved is identical for all pharmacologic effects
False; it is not identical
What can cross-tolerance between different sedative-hypnotics, including ethanol, lead to?
Unsatisfactory therapeutic response when standard doses of a drug are used in a patient with a recent history of excessive use of another agent.
What is Flumazenil? What type of drug is it?
A benzodiazepine derivative with high affinity for BDZ binding sites on GABAA receptor; Competitive antagonist.
Flumazenil blocks many of the actions of ?
BDZs, zolpidem, zaleplon, and eszopiclone.
True of False ?
Flumazenil does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids or general
anesthetics.
True
Flumazenil is used for:
1) Reversing the CNS effects of BDZ overdose
2) Hastening recovery following use of BDZ in anesthesia and diagnostic procedures.
True of False:
Antagonism of BDZ-induced respiratory depression is more predictable.
False; it is less predictable
What is Flumazenil’s half-life?
It has a short half-life due to rapid hepatic clearance (0.7-1.3 hours)
What are the adverse effects of Flumazenil?
1) Agitation, confusion, dizziness, and nausea.
2) Severe abstinence syndrome in patients with physiologic dependence
3) Seizures and cardiac arrhythmias in patients who have ingested benzodiazepines with tricyclic antidepressants
What are the therapeutic effects of sedative-hypnotic drugs?
1) Relief of anxiety states (cause still needs to be treated)
2) Treatment of insomnia
3) Sedation and amnesia before and during medical and surgical procedures
4) Epilepsy and seizures (termination of an attack)
5) As a component of balanced anesthesia (IV)
6) For control of ethanol or other sedative-hypnotic withdrawal states
7) For muscle relaxation in specific neuromuscular disorders
8) Suppression of delirium tremens (alcohol withdrawal)
9. Drug-induced hyperexcitability states
Which sedative-hypnotic drug is used to relieve anxiety (panic disorders and agoraphobia)?
Alprazolam
Which drugs are preferred for insomnia?
Benzodiazepine and the newer agents over barbiturates
Which drug is used for sedation and amnesia before and during medical and surgical procedures?
Midazolam
Which drug is given for suppression of delirium tremens (alcohol withdrawal)?
Parenteral lorazepam
What are the adverse effects of sedative-hypnotic drugs?
1) Relatively low doses may lead to drowsiness,
impaired judgment, and diminished motor skills
2) BDZ may cause a significant dose-related anterograde amnesia
3) Confusional states (especially in the elderly)
4) Hangover effects
5) At higher doses, may produce lethargy or a
state of exhaustion, or symptoms equivalent to
ethanol intoxication
6) Exacerbation of breathing problems in patients
with chronic pulmonary disease and those
with symptomatic sleep apnea
7) Cardiovascular collapse
8) Extensive clinical use (triazolam) has caused
behavioral disinhibition, delirium, aggression,
and violence.
9) Hypersensitivity reactions.
10) Teratogenicity
What do many of the adverse effects of sedative-hypnotics result from?
CNS depression
What causes confusional states from sedative-hypnotic drugs?
Overuse of sedative-hypnotics
What do hangover effects include?
1) Drowsiness
2) Dysphoria
3) Mental or motor depression the following day
Which drugs most commonly cause hangover effects?
Drugs with long half-lives
Which patients are more sensitive to hangover effects from sedative-hypnotic drugs?
Elderly patients
Barbiturates are contraindicated in patients with:
A history of acute intermittent porphyria
Sedative-hypnotics have what kind of effect with CNS depressants, alcohol,
opioids, anticonvulsants, phenothiazines, antihistamines, and antidepressant drugs?
Additive effect
Where can drug interactions happen including sedative-hypnotics?
At the level of drug metabolizing enzymes (Barbiturates induce drug metabolism)
What is Ramelteon?
An agonist at melatonin receptors, MT1 and MT2, located in the suprachiasmatic nuclei of the brain.
Melatonin receptors are thought to be involved in:
Maintaining the circadian rhythms underlying the sleep-wake cycle.
Who is Ramelteon prescribed for?
Patients who have difficulty in falling asleep.
What effect does Ramelteon have on GABAergic neurotransmission in the CNS?
NONE
What effect does Ramelteon have on rebound insomnia or withdrawal symptoms?
NONE
What is the metabolism pathway of Ramelteon?
Rapidly absorbed after oral administration and
undergoes extensive first-pass metabolism (CYP1A2), forming an active metabolite with a longer half-life (2-5 hours). CYP2C9 contributes.
What induces metabolism of Ramelteon?
Rifampin
Ramelteon should not be used in combination with:
Inhibitors of CYP1A2 (ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (fluconazole).
What are the adverse effects of Ramelteon?
1) Dizziness, somnolence, fatigue.
2) Endocrine changes (decreases testosterone levels, and increases prolactin levels)
Ramelteon should be used with caution in patients with:
Liver dysfunction
What are some Orexin receptor antagonists?
1) Almorexant
2) Suvorexant
What are Orexin receptor antagonists involved in?
The control of wakefulness
and they are silent during sleep
What kind of drugs are Almorexant and Suvorexant?
Sleep-Enabling Drugs
What are Orexin A and B?
Peptides found in specific
hypothalamic neurons.
When do Orexin levels increase and decrease?
Increase in the day and decrease at night.
What is the loss of orexin neurons associated with?
Narcolepsy (a disorder characterized by daytime sleepiness) and Cataplexy (sudden loss of muscle tone while a person is awake).
What is a substrate of CYP3A4?
Suvorexant
How can we prolong the half-life of Suvorexant?
By inhibitors of the enzyme including azole antifungal drugs, clarithromycin, and verapamil.
What kind of effect does Buspirone have?
A selective anxiolytic effect
What does Buspirone do?
Relieves anxiety without causing marked sedation, hypnosis, or euphoria.
What effect does Buspirone have on anticonvulsant or muscle relaxant effects?
NONE
Does Buspirone interact with GABAergic systems?
NO
What causes Buspirone’s anxiolytic effect?
Partial agonist activity at brain 5-HT1A receptors.
What does Buspirone have affinity for?
Brain dopamine D2 receptors.
What happens if you abruptly discontinue Buspirone?
No rebound anxiety or withdrawal signs
Can Buspirone be used for withdrawal syndrome from
benzodiazepines or other sedative-hypnotics?
No, it’s not useful.
Buspirone has __ abuse liability.
Minimal
When does Buspirone’s anxiolytic effect take place?
3-4 weeks
Why is Buspirone unsuitable for acute anxiety states?
Because its anxiolytic effect takes 3-4 weeks to be
established.
What is Buspirone used for?
Generalized anxiety states but is less effective in panic disorders.
What is the metabolism of Buspirone?
Rapidly absorbed orally but undergoes extensive first-pass metabolism by CYP enzymes to form several active metabolites
One of Buspirone’s metabolites has:
An α2-adrenoceptor blocking action
What is the elimination half-life of Buspirone?
2-4 hours
The elimination of Buspirone is increased by __, and decreased by __.
Inhibitors (erythromycin,
grapefruit juice and ketoconazole) of CYP3A4; its inducers (rifampin).
What may slow Buspirone’s clearance?
Liver dysfunction
What causes less psychomotor impairment: Buspirone or BDZs?
Buspirone
Does buspirone affect driving skills?
NO
True or false:
Buspirone potentiates effects of conventional sedative-hypnotics, ethanol, tricyclic
antidepressants.
False; it does not.
True or false:
Elderly patients are not more sensitive to Buspirone’s actions.
True
What are the adverse effects of Buspirone?
1) Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, headache, tinnitus
2) Gastrointestinal distress
3) Paresthesias
4) Dose-dependent pupillary constriction
5) Blood pressure may be significantly elevated in
patients receiving monoamine oxidase (MAO)
inhibitors
