Page 404 - Basic _ Clinical Pharmacology ( PDFDrive )

390 SECTION V Drugs That Act in the Central Nervous System

in withdrawal symptoms, though usually of less intensity than TABLE 22–2 Clinical uses of sedative-hypnotics.
those seen with benzodiazepines.
For relief of anxiety
For insomnia
BENZODIAZEPINE ANTAGONISTS: For sedation and amnesia before and during medical and surgical
FLUMAZENIL procedures
For treatment of epilepsy and seizure states
Flumazenil is one of several 1,4-benzodiazepine derivatives with a As a component of balanced anesthesia (intravenous administration)
high affinity for the benzodiazepine binding site on the GABA For control of ethanol or other sedative-hypnotic withdrawal states
A
receptor that act as competitive antagonists. It blocks many of For muscle relaxation in specific neuromuscular disorders
the actions of benzodiazepines, zolpidem, zaleplon, and eszopi- As diagnostic aids or for treatment in psychiatry
clone, but does not antagonize the CNS effects of other sedative-
hypnotics, ethanol, opioids, or general anesthetics. Flumazenil
is approved for use in reversing the CNS depressant effects of widely used for the management of acute anxiety states and for
benzodiazepine overdose and to hasten recovery following use of rapid control of panic attacks. They are also used, though less
these drugs in anesthetic and diagnostic procedures. Although the commonly, in the long-term management of GAD and panic
drug reverses the sedative effects of benzodiazepines, antagonism disorders. Anxiety symptoms may be relieved by many benzodiaz-
of benzodiazepine-induced respiratory depression is less predict- epines, but it is not always easy to demonstrate the superiority of
able. When given intravenously, flumazenil acts rapidly but has one drug over another. Alprazolam has been used in the treatment
a short half-life (0.7–1.3 hours) due to rapid hepatic clearance. of panic disorders and agoraphobia and appears to be more selec-
Because all benzodiazepines have a longer duration of action than tive in these conditions than other benzodiazepines. The choice of
flumazenil, sedation commonly recurs, requiring repeated admin- benzodiazepines for anxiety is based on several sound pharmaco-
istration of the antagonist. logic principles: (1) a rapid onset of action; (2) a relatively high
Adverse effects of flumazenil include agitation, confusion, therapeutic index (see drug B in Figure 22–1), plus availability of
dizziness, and nausea. Flumazenil may cause a severe precipitated flumazenil for treatment of overdose; (3) a low risk of drug inter-
abstinence syndrome in patients who have developed physiologic actions based on liver enzyme induction; and (4) minimal effects
benzodiazepine dependence. In patients who have ingested ben- on cardiovascular or autonomic functions.
zodiazepines with tricyclic antidepressants, seizures and cardiac Disadvantages of the benzodiazepines include the risk of depen-
arrhythmias may follow flumazenil administration. dence, depression of CNS functions, and amnestic effects. In
addition, the benzodiazepines exert additive CNS depression when
administered with other drugs, including ethanol. The patient should
■ CLINICAL PHARMACOLOGY OF be warned of this possibility to avoid impairment of performance of
SEDATIVE-HYPNOTICS any task requiring mental alertness and motor coordination. In the
treatment of generalized anxiety disorders and certain phobias, newer
TREATMENT OF ANXIETY STATES antidepressants, including selective serotonin reuptake inhibitors
(SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs),
are now considered by many authorities to be drugs of first choice (see
The psychological, behavioral, and physiologic responses that
characterize anxiety can take many forms. Typically, the psychic Chapter 30). However, these agents have a slow onset of action and
awareness of anxiety is accompanied by enhanced vigilance, motor thus minimal effectiveness in acute anxiety states.
tension, and autonomic hyperactivity. Anxiety is often secondary to
organic disease states—acute myocardial infarction, angina pectoris,
cancer, etc—which themselves require specific therapy. Another Orexin Receptor Antagonists:
class of secondary anxiety states (situational anxiety) results from Sleep-Enabling Drugs
circumstances that may have to be dealt with only once or a few
times, including anticipation of frightening medical or dental Orexin A and B are peptides found in specific hypothalamic
procedures and family illness or other stressful event. Even though neurons that are involved in the control of wakefulness and
situational anxiety tends to be self-limiting, the short-term use of that are silent during sleep. Orexin levels increase in the
sedative-hypnotics may be appropriate for the treatment of this and day and decrease at night. Loss of orexin neurons is associ-
certain disease-associated anxiety states. Similarly, the use of a seda- ated with narcolepsy, a disorder characterized by daytime
tive-hypnotic as premedication prior to surgery or some unpleasant sleepiness and cataplexy. Animal studies show that orexin
medical procedure is rational and proper (Table 22–2). receptor antagonists have sleep-enabling effects. This has
Excessive or unreasonable anxiety about life circumstances prompted the development of a new class of hypnotic drugs,
(generalized anxiety disorder, GAD), panic disorders, and agora- orexin antagonists, which include the drugs almorexant and
phobia are also amenable to drug therapy, sometimes in conjunc- suvorexant, the latter agent approved by the FDA.
tion with psychotherapy. The benzodiazepines continue to be