The document summarizes information about various sedative-hypnotic drugs including barbiturates, benzodiazepines, and other related compounds. It describes their mechanisms of action, pharmacokinetics, therapeutic uses, precautions, and adverse effects. Specifically, it notes that while barbiturates were widely used in the 20th century, their use has been replaced by benzodiazepines and other drugs due to the barbiturates' high abuse potential and narrow therapeutic window.

1. MARIA FE SALVADOR NAVARRETE MD
BIOLOGICALTHERAPIES

2. Barbiturates and Similarly Acting
Drugs
 used as sedative-hypnotic agents in 20th century
 high abuse and addiction potential,
 a narrow therapeutic range with low therapeutic index,
 and unfavorable side effects.
 The use of barbiturates and similar compounds such as
meprobamate (Miltown) has been practically eliminated by
the benzodiazepines,
 buspirone (BuSpar), and hypnotics such as zolpidem
(Ambien) and zaleplon (Sonata), which have a lower abuse
potential and a higher therapeutic index than the
barbiturates.
 the barbiturates and similarly acting drugs still have a role
in the treatment of certain mental disorders.

3. Pharmacologic Actions
 well absorbed after oral administration.
 The binding of barbiturates to plasma proteins is high, but
lipid solubility varies.
 metabolized by the liver and excreted by the kidneys.
 The half-lives of specific barbiturates range from 1 to 120
hours (Table 36.8-1).
 Barbiturates may also induce hepatic enzymes (cytochrome
P450), thereby reducing the levels of both the barbiturate
and any other concurrently administered drugs
metabolized by the liver.
 The mechanism of action of barbiturates involves the γ-
aminobutyric acid (GABA) receptor–benzodiazepine
receptor–chloride ion channel complex.

4. Therapeutic Indications:
Electroconvulsive Therapy
 Methohexital (Brevital) is commonly used as an
anesthetic agent for electroconvulsive therapy
(ECT).
 It has lower cardiac risks
 Used intravenously, methohexital produces rapid
unconsciousness and, because of rapid
redistribution, it has a brief duration of action (5
to 7 minutes)
 Typical dosing for ECT is 0.7 to 1.2 mg/kg.
Methohexital can also be used to abort
prolonged seizures in ECT or to limit postictal
agitation.

5. Seizures
 Phenobarbital (Solfoton, Luminal), the most
commonly used barbiturate for treatment of
seizures, has indications for the treatment of
generalized tonic-clonic and simple partial
seizures.
 Parenteral barbiturates are used in the
emergency management of seizures
independent of cause. Intravenous (IV)
phenobarbital should be administered slowly,
10 to 20 mg/kg for status epilepticus.

6. Narcoanalysis
 Amobarbital (Amytal) has been used
historically as a diagnostic aid in a number of
clinical conditions,
 including conversion reactions,
 catatonia,
 hysterical stupor,
 and unexplained muteness,
 and to differentiate stupor of depression,
 schizophrenia, and structural brain lesions.

7. SLEEP
 The barbiturates reduce sleep latency and the
number of awakenings during sleep, although
tolerance to these effects generally develops
within 2 weeks.
 Discontinuation of barbiturates often leads
to rebound increases on
electroencephalogram (EEG) measures of
sleep and a worsening of the insomnia.

8. Withdrawal from Sedative-
Hypnotics
 used to determine the extent of tolerance to barbiturates or other
hypnotics to guide detoxification.
 a test dose of pentobarbital (200 mg) is given orally.
 An hour later the patient is examined.
 Tolerance and dose requirements are determined by the degree to
which the patient is affected
 If the patient is not sedated, another 100 mg of pentobarbital can be
administered every 2 hours, up to three times (maximum, 500 mg over 6
hours).
 The amount needed for mild intoxication corresponds to the
approximate daily dose of barbiturate used.
 Phenobarbital (30 mg) may then be substituted for each 100 mg of
pentobarbital.
 daily dose requirement can be administered in divided doses and
gradually tapered by 10 percent a day, with adjustments made
according to withdrawal signs (Table 36.8-2).

9. Precautions and Adverse
Reactions
 paradoxical dysphoria,
 hyperactivity,
 and cognitive disorganization.
 Rare adverse effects associated with
barbiturate use include the development of
Stevens-Johnson syndrome,
 megaloblastic anemia, and neutropenia.

10.  A major difference between the barbiturates
and the benzodiazepines is the low
therapeutic index of the barbiturates. An
overdose of barbiturates can easily prove
fatal

11.  Barbiturate intoxication is manifested by
confusion, drowsiness, irritability,
hyporeflexia or areflexia, ataxia, and
nystagmus.

12.  Because of some evidence of teratogenicity,
barbiturates should not be used by pregnant
women or women who are breast-feeding.
 Barbiturates should be used with caution by
patients with a history of substance abuse,
depression, diabetes, hepatic impairment,
renal disease, severe anemia, pain,
hyperthyroidism, or hypoadrenalism

13. Drug Interactions
 The primary area for concern about drug
interactions is the potentially additive effects
of respiratory depression.
 Barbiturates should be used with great
caution with other prescribed central nervous
system (CNS) drugs (including antipsychotic
and antidepressant drugs) and nonprescribed
CNS agents (e.g., alcohol)

14. Paraldehyde
 Paraldehyde is a cyclic ether, first used in
1882 as a hypnotic. It has also been used to
treat epilepsy, alcohol withdrawal symptoms,
and delirium tremens. Because of its low
therapeutic index, it has been supplanted by
the benzodiazepines and other
anticonvulsants

15.  Precautions and Adverse Reactions
 Paraldehyde frequently causes foul breath
because of expired unmetabolized drug. It
can inflame pulmonary capillaries and cause
coughing. It can also cause local
thrombophlebitis with IV use. Patients may
experience nausea and vomiting with oral
use. Overdose leads to metabolic acidosis
and decreased renal output.There is risk of
abuse among drug addicts.

16. Drug Interactions
 Disulfiram (Antabuse) inhibits acetaldehyde
dehydrogenase and reduces metabolism of
paraldehyde, leading to possible toxic
concentration of paraldehyde. Paraldehyde
has addictive sedating effects in combination
with other CNS depressants such as alcohol
or benzodiazepines.

17. Meprobamate
 Meprobamate, a carbamate, was introduced
shortly before the benzodiazepines,
specifically to treat anxiety. It is also used for
muscle relaxant effects.

18.  Chloral Hydrate
 Chloral hydrate is a hypnotic agent rarely
used in psychiatry because numerous safer
options, such as benzodiazepines, are
available.

19. Benzodiazepines and Drugs Acting on
Benzodiazepine Receptors
 modulate γ-aminobutyric acid (GABA) activity.
 Nonbenzodiazepine agonists, such zolpidem
(Ambien), zaleplon (Sonata), and eszopiclone
(Lunesta)—the so-called “Z drugs―—
interactions with GABA-receptor complexes at
binding domains located close to or coupled to
benzodiazepine receptors.
 Flumazenil (Romazicon), a benzodiazepine
receptor antagonist used to reverse
benzodiazepine-induced sedation and in
emergency care of benzodiazepine overdosage

20.  With the exception of clorazepate (Tranxene),
all the benzodiazepines are completely
absorbed unchanged from the
gastrointestinal (GI) tract.
 The absorption, the attainment of peak
concentrations, and the onset of action are
quickest for diazepam (Valium), lorazepam
(Ativan), alprazolam (Xanax), triazolam
(Halcion), and estazolam (ProSom).

21.  rapid anxiolytic sedative effect, they are most
commonly used for immediate treatment of
insomnia, acute anxiety, and agitation or anxiety
associated with any psychiatric disorder.
 used as anesthetics, anticonvulsants, and
muscle relaxants.
 Because of the risk of psychological and physical
dependence, long-term use of benzodiazepines
should be in conjunction with psychotherapy and
in cases where alternative agents have been
tried and proved ineffective or poorly tolerated.

22.  Diazepam, chlordiazepoxide, clonazepam
(Klonopin), clorazepate, flurazepam
(Dalmane), prazepam (Centrax), quazepam
(Doral), and halazepam (Paxipam) have
plasma half-lives of 30 to more than 100
hours and, therefore, are the longest-acting
benzodiazepines

23.  Gaboxatal
 This is a new hypnotic agent which works on
the α-4 GABA receptor subtype rather than
on the α-1 GABA subtype which the other
benzodiazepines effect. α-4 GABA is
expressed at high levels in the thalmus.

24. Therapeutic Indications
Insomnia
 Because insomnia can be a symptom of a
physical or psychiatric disorder, hypnotics
should not be used for more than 7 to 10
consecutive days without a thorough
investigation of the cause of the insomnia.

25.  Anxiety Disorders
 Generalized Anxiety Disorder
 Benzodiazepines are highly effective for the
relief of anxiety associated with generalized
anxiety disorder.
 Because generalized anxiety disorder is a
chronic disorder with a high rate of recurrence,
some persons with generalized anxiety disorder
may warrant long-term maintenance treatment
with benzodiazepines.

26.  Panic Disorder
 Alprazolam and clonazepam, both high-potency
benzodiazepines, are commonly used
medications for panic disorder, with or without
agoraphobia.
 Although the selective serotonin reuptake
inhibitors (SSRIs) are also indicated for
treatment of panic disorder, benzodiazepines
have the advantage of working quickly and of
not causing significant sexual dysfunction and
weight gain.

27.  Social Phobia
 Clonazepam has been shown to be an
effective treatment for social phobia. In
addition, several other benzodiazepines (e.g.,
diazepam) have been used as adjunctive
medications for treatment of social phobia.

28.  OtherAnxiety Disorders
 Benzodiazepines are used adjunctively for
treatment of adjustment disorder with
anxiety, pathological anxiety associated with
life events (e.g., after an accident), OCD, and
posttraumatic stress disorder.

29.  Mixed Anxiety–Depressive Disorder
 Alprazolam is indicated for the treatment of
anxiety associated with depression.

30.  Bipolar I Disorder
 Clonazepam, lorazepam, and alprazolam are
effective in the management of acute manic
episodes and as an adjuvant to maintenance
therapy in lieu of antipsychotics. As an
adjuvant to lithium (Eskalith) or lamotrigine
(Lamictal), clonazepam may result in an
increased time between cycles and fewer
depressive episodes.

31.  Akathisia
 The first-line drug for akathisia is most
commonly a β-adrenergic receptor
antagonist. Benzodiazepines are also
effective in treating some patients with
akathisia

32.  Parkinson's Disease
 A few persons with idiopathic Parkinson's
disease will respond to long-term use of
zolpidem with reduced bradykinesia and
rigidity. Zolpidem dosages of 10 mg four
times daily may be tolerated without
sedation for several years.

33.  Precautions and Adverse Reactions
 The most common adverse effect of
benzodiazepines is drowsiness, which occurs
in about 10 percent of all persons.

34. Signs and Symptoms of
Benzodiazepine Withdrawal
 Anxiety
 Tremor
 Irritability
 Depersonalization
 Insomnia
 Hyperesthesia
 Hyperacusis
 Myoclonus
 Nausea
 Delirium Difficulty concentrating Seizures

35. Drug Interactions
 The most common and potentially serious
benzodiazepine receptor agonist interaction
results in excessive sedation and respiratory
depression occurring when benzodiazepines,
zolpidem, or zaleplon are administered
concomitantly with other CNS depressants,
such as alcohol, barbiturates, tricyclic and
tetracyclic drugs, dopamine receptor
antagonists (DRAs), opioids, and
antihistamines.

36. RAMELTEON
 Ramelteon (Rozerem), a new treatment for
insomnia, was approved by the US Food and
DrugAdministration (FDA) in 2005.

37. Pharmacologic Actions
 Unlike the other hypnotic agents discussed in
this section, ramelteon does not act on the
benzodiazepine or GABA system.
 It specifically targets the melatonin MT1 and
MT2 receptors in the brain's suprachiasmatic
nucleus (SCN).The SCN regulates 24-hour, or
circadian, rhythms including the
sleep–wake cycle.

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