Page 407 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 22 Sedative-Hypnotic Drugs 393

of sedative-hypnotics. However, it should not be assumed that elimination. Cross-dependence, defined as the ability of one drug
the degree of tolerance achieved is identical for all pharmacologic to suppress abstinence symptoms from discontinuance of another
effects. There is evidence that the lethal dose range is not altered drug, is quite marked among sedative-hypnotics. This provides
significantly by the long-term use of sedative-hypnotics. Cross- the rationale for therapeutic regimens in the management of
tolerance between the different sedative-hypnotics, including withdrawal states: Longer-acting drugs such as chlordiazepoxide,
ethanol, can lead to an unsatisfactory therapeutic response when diazepam, and phenobarbital can be used to alleviate withdrawal
standard doses of a drug are used in a patient with a recent history symptoms of shorter-acting drugs, including ethanol.
of excessive use of these agents. However, there have been very few
reports of tolerance development when eszopiclone, zolpidem, or Drug Interactions
zaleplon was used for less than 4 weeks.
With the long-term use of sedative-hypnotics, especially if The most common drug interactions involving sedative-hypnotics
doses are increased, a state of physiologic dependence can occur. are interactions with other CNS depressant drugs, leading to addi-
This may develop to a degree unparalleled by any other drug tive effects. These interactions have some therapeutic usefulness
group, including the opioids. Withdrawal from a sedative-hypnotic when these drugs are used as adjuvants in anesthesia practice. How-
can have severe and life-threatening manifestations. Withdrawal ever, if not anticipated, such interactions can lead to serious conse-
symptoms range from restlessness, anxiety, weakness, and ortho- quences, including enhanced depression with concomitant use of
static hypotension to hyperactive reflexes and generalized seizures. many other drugs. Additive effects can be predicted with concomi-
Symptoms of withdrawal are usually more severe following discon- tant use of alcoholic beverages, opioid analgesics, anticonvulsants,
tinuance of sedative-hypnotics with shorter half-lives. However, and phenothiazines. Less obvious but just as important is enhanced
eszopiclone, zolpidem, and zaleplon appear to be exceptions to CNS depression with a variety of antihistamines, antihypertensive
this, because withdrawal symptoms are minimal following abrupt agents, and antidepressant drugs of the tricyclic class.
discontinuance of these newer short-acting agents. Symptoms Interactions involving changes in the activity of hepatic
are less pronounced with longer-acting drugs, which may partly drug-metabolizing enzyme systems have been discussed (see also
accomplish their own “tapered” withdrawal by virtue of their slow Chapters 4 and 66).

SUMMARY SEDATIVE-HYPNOTICS

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

BENZODIAZEPINES
• Alprazolam Bind to specific GABA A Dose-dependent depressant Acute anxiety states • panic Half-lives from 2–40 h (clorazepate longer)
• Chlordiazepoxide receptor subunits at effects on the CNS including attacks • generalized anxiety • oral activity • hepatic metabolism—some
• Clonazepam central nervous sedation and relief of anxiety disorder • insomnia and other active metabolites • Toxicity: Extensions of
• Clorazepate system (CNS) neuronal • amnesia • hypnosis sleep disorders • relaxation of CNS depressant effects • dependence
• Diazepam synapses facilitating • anesthesia • coma • and skeletal muscle • anesthesia liability • Interactions: Additive CNS
• Estazolam GABA-mediated respiratory depression (adjunctive) • seizure depression with ethanol and many other
• Flurazepam chloride ion channel disorders drugs
• Lorazepam opening frequency
• Midazolam • enhance membrane
• Oxazepam hyperpolarization
• Quazepam
• Temazepam
• Triazolam

BENZODIAZEPINE ANTAGONIST
• Flumazenil Antagonist at Blocks actions of Management of IV, short half-life • Toxicity: Agitation,
benzodiazepine- benzodiazepines and benzodiazepine overdose confusion • possible withdrawal symptoms
binding sites on the zolpidem but not other in benzodiazepine dependence
GABA A receptor sedative-hypnotic drugs
BARBITURATES
• Amobarbital Bind to specific GABA A Dose-dependent depressant Anesthesia (thiopental) Half-lives from 4–60 h (phenobarbital
• Butabarbital receptor subunits at effects on the CNS including • insomnia (secobarbital) longer) • oral activity • hepatic metabolism—
• Mephobarbital CNS neuronal sedation and relief of anxiety • seizure disorders phenobarbital 20% renal elimination
• Pentobarbital synapses facilitating • amnesia • hypnosis (phenobarbital) • Toxicity: Extensions of CNS depressant
• Phenobarbital GABA-mediated • anesthesia • coma and effects • dependence liability >
• Secobarbital chloride ion channel respiratory depression benzodiazepines • Interactions: Additive CNS
opening duration • steeper dose-response depression with ethanol and many other
• enhance membrane relationship than drugs • induction of hepatic drug-
hyperpolarization benzodiazepines metabolizing enzymes
(continued)