CNS 3 Flashcards
- Were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep.
- Today, they are largely replaced by the benzodiazepines, primarily because it induce tolerance, drug-metabolizing enzymes, physical dependence, and are associated with very severe withdrawal symptoms. Foremost is their ability to cause coma in toxic doses.
- Certain drugs, such as the very short-acting thiopental, are still used to induce anesthesia.
Barbiturates
- Interaction with GABAA receptors → enhances ____ transmission
- The binding site is distinct from that of the _____.
- Potentiate GABA action on chloride entry into the neuron by prolonging the duration of the ____ channel openings.
- Can block excitatory ____ receptors
- Anesthetic concentrations of pentobarbital also block high-frequency ____ channels.
- All of these molecular actions lead to ____ neuronal activity
- GABAergic
- benzodiazepines
- chloride
- glutamate
- sodium
- decreased
– acts within seconds
– duration of action of about 30 minutes
– used in the intravenous induction of anesthesia
Thiopental
– duration of action greater than a day
– useful in the treatment of seizures
Phenobarbital
– short-acting barbiturates
– effective as sedative and hypnotic (but not antianxiety) agents
Pentobarbital, secobarbital, and amobarbital
Barbiturates suppress the hypoxic and chemoreceptor response to ___, and overdosage is followed by respiratory depression and death.
CO2
– Barbiturates induce ____ microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on this enzyme metabolism to reduce their concentration.
- P450
the ultrashort-acting barbiturates, such as ____, are used intravenously to induce anesthesia.
thiopental
When used as hypnotics, barbiturates suppress _____ more than other stages.
However, most have been replaced by the benzodiazepines.
REM sleep
Is used in long-term management of tonic-clonic seizures, status epilepticus, and eclampsia.
Phenobarbital
Has been regarded as the drug of choice for treatment of young children with
recurrent febrile seizures. However, it can depress cognitive performance in children, and the drug should be used cautiously.
Phenobarbital
– drowsiness, impaired concentration, and mental and physical sluggishness
– the CNS depressant effects of barbiturates synergize with those of ethanol
- drug hangover
- nausea and dizzeness occasionlly
barbiturates
– increase porphyrin synthesis → contraindicated in patients with acute intermittent porphyria.
– Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest.
– Withdrawal is much more severe than that associated with opiates and can result in death
- poisoning
barbiturates
- it acts on a subset of the benzodiazepine receptor family, BZ1.
- has no anticonvulsant or muscle-relaxing properties.
- It shows few withdrawal effects, and exhibits minimal rebound insomnia, and little or no tolerance occurs with prolonged use.
- is rapidly absorbed from the gastrointestinal tract, and it has a rapid onset of action and short elimination half-life (about 2 to 3 hours).
Zolpidem
Adverse effects of this include nightmares, agitation, headache, gastrointestinal upset,
dizziness, and daytime drowsiness
Zolpidem
- is very similar to zolpidem in its hypnotic actions, but it causes fewer residual effects on psychomotor and cognitive functions compared to zolpidem or the benzodiazepines.
- This may be due to its rapid elimination, with a half-life that approximately 1 hour.
Zaleplon
- is an oral nonbenzodiazepine hypnotic (also utilizing the BZ1 receptor similar to zolpidem and zaleplon)
- Also used for treating insomnia
- Effective for up to 6 months of use
- Rapidly absorbed (time to peak, 1 hour)
- Adverse events reported with eszopiclone include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste.
Eszopiclone
This novel hypnotic drug that activates melatonin receptors in the suprachiasmatic nuclei of the CNS decreases the latency of sleep onset with minimal rebound insomnia or withdrawal symptoms.
• has no direct effects on GABA-ergic neurotransmission in the CNS.
• Unlike conventional hypnotics, it appears to have minimal abuse liability, and it is not a controlled substance.
•The adverse effects of the drug include dizziness, fatigue, and endocrine changes including decreased testosterone and increased prolactin.
Ramelteon
Which one of the following is a short-acting hypnotic? A. Phenobarbital. B. Diazepam. C. Chlordiazepoxide. D. Triazolam. E. Flurazepam.
Triazolam.
A 45-year-old man who has been injured in a car accident is brought into the emergency room. His blood alcohol level on admission is 275 mg/dL. Hospital records show a prior hospitalization for alcohol-related seizures. His wife confirms that he has been drinking heavily for 3 weeks. What treatment should be provided to the patient if he goes into withdrawal?
Lorazepam
A 28-year-old woman has sporadic attacks of intense anxiety with marked physical
symptoms, including hyperventilation, tachycardia, and sweating. If she is diagnosed as suffering from a panic disorder, the most appropriate drug to use is
Clonazepam
Severe form of alcohol withdrawal whose main symptoms are sweating, tremor, confusion, and hallucinations
Delirium tremens (DTs)
A syndrome of craniofacial dysmorphia, heart defects, and mental retardation caused by the teratogenic effects of ethanol consumption during pregnancy
Fetal alcohol syndrome
A syndrome of ataxia, confusion, and paralysis of the extraocular muscles that is associated with chronic alcoholism and thiamine deficiency
Wernicke-Korsakoff syndrome
Alcohol is metabolized primarily (90 percent) in the
liver
Two enzyme systems metabolize ethanol to acetaldehyde:
- Alcohol dehydrogenase (ADH)
2. Microsomal ethanol-oxidizing system (MEOS)
- Cytosolic, NAD+ dependent enzymes found mainly in the liver and gut
- Accounts for the metabolism of low to moderate doses of ethanol
- Limited supply of the coenzyme NAD+ → reaction has zero-order kinetics →fixed capacity for ethanol metabolism of 7–10 g/h
- Gastrointestinal metabolism of ethanol is lower in women than in men.
- Genetic variation in this affects the rate of ethanol metabolism and vulnerability to alcohol-use disorders.
Alcohol dehydrogenase (ADH)
- At blood ethanol levels higher than 100 mg/dL, the liver system that catalyzes most phase I drug-metabolizing reactions contributes significantly to ethanol metabolism
- Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and this system activity → this is partially responsible for the development of tolerance to ethanol
Microsomal ethanol-oxidizing system (MEOS)
formed from the oxidation of ethanol by either ADH or MEOS is rapidly metabolized to acetate by aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues.
Acetaldehyde
Aldehyde dehydrogenase is inhibited by ___ and other drugs, including metronidazole, oral hypoglycemics, and some cephalosporins.
disulfiram
The major acute effects of ethanol on the CNS are
- sedation,
- loss of inhibition,
- impaired judgment,
- slurred speech,
- ataxia.
Occurs with concomitant ingestion of ethanol and a wide variety of CNS depressants, including sedative-hypnotics, opioid agonists, and many drugs that block muscarinic and H1 histamine receptors.
Additive CNS depression
Even at relatively low blood concentrations, significantly depresses the heart.
Ethanol,
Occurs mainly as a result of CNS adaptation and to a lesser extent by an increased rate of ethanol metabolism.
Tolerance
Is the most common medical complication of chronic alcohol abuse.
Liver disease
Is the most common neurologic abnormality in chronic alcohol abuse.
Peripheral neuropathy
More rarely, ____, along with alcohol abuse, leads to Wernicke-Korsakoff syndrome, which is characterized by ataxia, confusion, and paralysis of the extraocular muscles.
thiamine deficiency
Prompt treatment with parenteral thiamine is essential to prevent a permanent memory disorder known as
Korsakoff’s psychosis
Ethanol use in pregnancy is associated with ___ that include mental retardation (most common), growth deficiencies, microcephaly, and a characteristic underdevelopment of the midface region.
teratogenic effects
Is not a primary carcinogen, but its chronic use is associated with an increased incidence of neoplastic diseases in the gastrointestinal tract and a small increase in the risk of breast cancer.
Ethanol
Is used to protect against Wernicke-Korsakoff syndrome, and correction of electrolyte imbalance may be required
Thiamine administration
The withdrawal syndrome is managed by correction of electrolyte imbalance, and administration of ____ and____.
thiamine and a sedative-hypnotic
A long-acting ____ (eg, diazepam, chlordiazepoxide) is preferred unless the patient has compromised liver function, in which case a short-acting type of this drug with less complex metabolism (eg, lorazepam) is preferred.
benzodiazepine
The opioid receptor antagonist ____ has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain in treating alcoholism
naltrexone
An NMDA glutamate receptor antagonist, the aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs.
Acamprosate
If ethanol is consumed by a patient who has taken ____, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension.
disulfiram
