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pharm ch 38

Terms in this set (18)

our most widely used hypnotic, is approved only for short-term management of insomnia. However, although approval is limited to short-term use, many patients have taken the drug long term with no apparent tolerance or increase in adverse effects. All zolpidem formulations have a rapid onset, and hence can help people who have difficulty falling asleep. In addition, the extended-release formulation—Ambien CR—can help people who have difficulty maintaining sleep.
Although structurally unrelated to the benzodiazepines, zolpidem binds to the benzodiazepine receptor site on the GABA receptor-chloride channel complex and shares some properties of the benzodiazepines. Like the benzodiazepines, zolpidem can reduce sleep latency and awakenings and can prolong sleep duration. The drug does not significantly reduce time in rapid-eye-movement (REM) sleep and causes little or no rebound insomnia when therapy is discontinued. In contrast to the benzodiazepines, zolpidem lacks anxiolytic, muscle relaxant, and anticonvulsant actions. Why? Because zolpidem doesn't bind with all benzodiazepine receptors. Rather, binding is limited to the benzodiazepine1 subtype of benzodiazepine receptors.
Zolpidem is rapidly absorbed following oral administration. Plasma levels peak in 2 hours. The drug is widely distributed, although levels in the brain remain low. Zolpidem is extensively metabolized to inactive compounds that are excreted in the bile, urine, and feces. The elimination half-life is 2.4 hours.
Zolpidem has a side effect profile like that of the benzodiazepines. Daytime drowsiness and dizziness are most common, and these occur in only 1% to 2% of patients. Like the benzodiazepines, zolpidem has been associated with sleep driving and other sleep-related complex behaviors. At therapeutic doses, zolpidem causes little or no respiratory depression. Safety in pregnancy has not been established. According to the FDA, zolpidem may pose a small risk of anaphylaxis and angioedema.
Short-term treatment is not associated with significant tolerance or physical dependence. Withdrawal symptoms are minimal or absent. Similarly, the abuse liability of zolpidem is low. Accordingly, the drug is classified under Schedule IV of the Controlled Substances Act.
Like other sedative-hypnotics, zolpidem can intensify the effects of other CNS depressants. Accordingly, patients should be warned against combining zolpidem with alcohol and all other drugs that depress CNS function.
first representative of a new class of hypnotics, the pyrazolopyrimidines. The drug is approved only for short-term management of insomnia, but prolonged use does not appear to cause tolerance. Like zolpidem, zaleplon binds to the benzodiazepine1 receptor site on the GABA receptor-chloride channel complex, and thereby enhances the depressant actions of endogenous GABA. In contrast to zolpidem, zaleplon has a very rapid onset and short duration of action, and hence is good for helping patients fall asleep, but not for maintaining sleep.
Zaleplon is rapidly and completely absorbed from the GI tract. However, because of extensive first-pass metabolism, bioavailability is only 30%. A large or high-fat meal can delay absorption substantially. Plasma levels peak about 1 hour after administration and then rapidly decline, returning to baseline in 4 to 5 hours. Zaleplon is metabolized by hepatic aldehyde oxidase prior to excretion in the urine. Its half-life is just 1 hour.
Because of its kinetic profile, zaleplon is well suited for people who have trouble falling asleep, but not for people who can't maintain sleep. The drug can also help people who need a sedative in the middle of the night: Because of its short duration, zaleplon can be taken at 3:00 AM without causing hangover when the alarm goes off at 7:00 AM.
Zaleplon is well tolerated. The most common side effects are headache, nausea, drowsiness, dizziness, myalgia, and abdominal pain. Like the benzodiazepines, zaleplon has been associated with rare cases of sleep driving and other complex sleep-related behaviors. Respiratory depression has not been observed. Physical dependence is minimal, the only sign being mild rebound insomnia the first night after drug withdrawal. Next-day sedation and hangover have not been reported. Like the benzodiazepines, zaleplon has a low potential for abuse, and hence is classified as a Schedule IV drug.
Cimetidine (a drug for peptic ulcer disease) inhibits hepatic aldehyde oxidase, and can thereby greatly increase levels of zaleplon. Accordingly, dosage of zaleplon must be reduced if these drugs are used concurrently.
Like zaleplon and zolpidem, eszopiclone binds selectively with the benzodiazepine1 receptor on the GABA receptor-chloride channel complex, and thereby enhances the depressant actions of endogenous GABA.
Eszopiclone is approved for treating insomnia, with no limitation on how long it can be used. This contrasts with zaleplon and zolpidem, which are approved for short-term use only. Does this mean that eszopiclone is safer than the other two drugs, or less likely to promote tolerance? Not necessarily. It only means that the manufacturer of eszopiclone conducted a prolonged (6-month) study, whereas the manufacturers of the other two drugs did not. In that prolonged study, eszopiclone reduced sleep latency and nighttime awakening, increased total sleep time and sleep quality, had no significant effect on sleep architecture, and showed no indication of tolerance.
Eszopiclone is generally well tolerated. The most common adverse effect is a bitter aftertaste, reported by 17% of patients dosed with 2 mg and 34% of those dosed with 3 mg. Other common effects are headache, somnolence, dizziness, and dry mouth. Rebound insomnia may occur on the first night after discontinuing the drug. Like the benzodiazepines and the other benzodiazepine-like drugs, eszopiclone has been associated with cases of sleep driving and other sleep-related complex behaviors. Rarely, eszopiclone may cause anaphylaxis or angioedema. Eszopiclone has a low potential for abuse and hence is classified as a Schedule IV drug.
hen barbiturates are taken regularly, tolerance develops to many—but not all—of their CNS effects. Specifically, tolerance develops to sedative and hypnotic effects and to other effects that underlie barbiturate abuse. However, even with chronic use, very little tolerance develops to toxic effects.
In the tolerant user, doses must be increased to produce the same intensity of response that could formerly be achieved with smaller doses. Hence, individuals who take barbiturates for prolonged periods—be it for therapy or recreation—require steadily increasing doses to achieve the effects they desire.
It is important to note that very little tolerance develops to respiratory depression. Because tolerance to respiratory depression is minimal, and because tolerance does develop to therapeutic effects, with continued treatment, the lethal (respiratory-depressant) dose remains relatively constant while the therapeutic dose climbs higher and higher (Fig. 34-3). As tolerance to therapeutic effects increases, the therapeutic dose grows steadily closer to the lethal dose—a situation that is clearly hazardous.
As a rule, tolerance to one general CNS depressant bestows tolerance to all other general CNS depressants. Hence, there is cross-tolerance among barbiturates, alcohol, benzodiazepines, general anesthetics, chloral hydrate, and a number of other agents. Tolerance to barbiturates and the other general CNS depressants does not produce significant cross-tolerance with opioids (eg, morphine).
rolonged use of barbiturates results in physical dependence, a state in which continued use is required to avoid an abstinence syndrome. Physical dependence results from adaptive neurochemical changes that occur in response to chronic drug exposure.
Individuals who are physically dependent on barbiturates exhibit cross-dependence with other general CNS depressants. Because of cross-dependence, a person physically dependent on barbiturates can prevent withdrawal symptoms by taking any other general CNS depressant (eg, alcohol, benzodiazepines). As a rule, cross-dependence exists among all of the general CNS depressants. However, there is no significant cross-dependence with opioids.
The general CNS depressant abstinence syndrome can be severe. Contrary to popular understanding, abrupt withdrawal from general CNS depressants is more dangerous than withdrawal from opioids. Although withdrawal from opioids is certainly unpleasant, the risk of serious injury is low. In contrast, the abstinence syndrome associated with general CNS depressants can be fatal.
The following description illustrates how dangerous withdrawal from general CNS depressants can be. Early reactions include weakness, restlessness, insomnia, hyperthermia, orthostatic hypotension, confusion, and disorientation. By the third day, major convulsive episodes may develop. Approximately 75% of patients experience psychotic delirium (a state similar to alcoholic delirium tremens). In extreme cases, these symptoms may be followed by exhaustion, cardiovascular collapse, and death. The entire abstinence syndrome evolves over approximately 8 days. The intensity of symptoms can be greatly reduced by withdrawing general CNS depressants slowly.
A long-acting barbiturate (eg, phenobarbital) may be administered to facilitate the withdrawal process. Because of cross-dependence, phenobarbital can substitute for other CNS depressants, and can thereby suppress symptoms of withdrawal. Because phenobarbital leaves the body slowly, treatment permits a gradual transition from a drug-dependent state to a drug-free state. When phenobarbital is given to aid withdrawal, its dosage should be reduced gradually over 10 days to 3 weeks.
Respiratory Depression.
Barbiturates reduce ventilation by two mechanisms: (1) depression of brainstem neurogenic respiratory drive and (2) depression of chemoreceptive mechanisms that control respiratory drive. Doses only 3 times greater than those needed to induce sleep can cause complete suppression of the neurogenic respiratory drive. With severe overdose, barbiturates can cause apnea and death.
For most patients, the degree of respiratory depression produced at therapeutic doses is not significant. However, in elderly patients and those with respiratory disease, therapeutic doses can compromise respiration substantially. Combining a barbiturate with another CNS depressant intensifies respiratory depression.
Barbiturates have a low therapeutic index. Accordingly, overdose can readily cause death. Because of their toxicity, the barbiturates are frequently employed as vehicles for suicide, and hence should not be dispensed to patients with suicidal tendencies.
Barbiturates produce subjective effects that many individuals find desirable. As a result, they are popular drugs of abuse. The barbiturates that are most prone to abuse are those in the short to intermediate-acting group (eg, secobarbital). Individual barbiturates within the group are classified under Schedule II or III of the Controlled Substances Act, reflecting their high potential for abuse. Although barbiturates are frequently abused in nonmedical settings, they are rarely abused during medical use.
Use in Pregnancy.
Barbiturates readily cross the placenta and can injure the developing fetus. Women of child-bearing age should be informed about the potential for fetal harm and warned against becoming pregnant. Use of barbiturates during the third trimester may cause drug dependence in the infant.
Exacerbation of Intermittent Porphyria.
Barbiturates can intensify attacks of acute intermittent porphyria, a condition brought on by excessive synthesis of porphyrin. Symptoms include nausea, vomiting, abdominal colic, neuromuscular disturbances, and disturbed behavior. Barbiturates exacerbate porphyria by stimulating porphyrin synthesis (see Fig. 34-2). Because they intensify porphyria, barbiturates are absolutely contraindicated for individuals with a history of the disorder.
Barbiturates have long half-lives, and therefore can produce residual effects (hangover) when taken for insomnia. Hangover can manifest as sedation, impaired judgment, and reduced motor skills. Patients should be forewarned that their ability to perform complex tasks, both manual and intellectual, may be significantly decreased the day after taking a barbiturate to induce sleep.
Paradoxical Excitement.
In some patients, especially the elderly and debilitated, barbiturates may cause excitation. The mechanism of this paradoxical response is unknown.
Barbiturates can intensify sensitivity to pain. In addition, they may cause pain directly. These drugs have caused muscle pain, joint pain, and pain along nerves.
Acute intoxication with barbiturates is a medical emergency; left untreated, overdose can be fatal. Poisoning is often the result of attempted suicide, although it can also occur by accident (usually in children and drug abusers). Since acute toxicity from barbiturates and other general CNS depressants is very similar, the discussion below applies to all of these drugs.
Acute overdose produces a classic triad of symptoms: respiratory depression, coma, and pinpoint pupils. (Pupils may later dilate as hypoxia caused by respiratory depression sets in.) The three classic symptoms are frequently accompanied by hypotension and hypothermia. Death is likely to be the result of pulmonary complications and renal failure.
Proper management requires an intensive care unit. With vigorous treatment, most patients recover fully.
Treatment has two main objectives: (1) removal of barbiturate from the body and (2) maintenance of an adequate oxygen supply to the brain. Oxygenation can be maintained by keeping the airway patent and giving oxygen.
Several measures can promote barbiturate removal. Unabsorbed drug can be removed from the stomach (using gastric lavage) and from the intestine (using a saline cathartic). Drug that has already been absorbed can be removed with hemodialysis. For phenobarbital and other barbiturates that are excreted intact in the urine, forced diuresis and alkalinization of urine may facilitate their renal excretion.
Steps should be taken to prevent hypotension and loss of body heat. Blood pressure can be supported with fluid replacement and dopamine. Body heat can be maintained with blankets and warming devices.
Barbiturate poisoning has no specific antidote. CNS stimulants should definitely not be employed. Not only are stimulants ineffective, they are dangerous: Their use in barbiturate poisoning has been associated with a significant increase in mortality. Naloxone, a drug that can reverse poisoning by opioids, is not effective against poisoning by barbiturates.