Sedative-hypnotic agents

A 49-year-old woman has chronic problems with early morning waking. She reports anxiety due to problems in her personal life. Doctor prescribed diazepam. 1. hich one of the following is most likely to result from treatment with moderate doses of diazepam! "A# Alle$iation of the symptoms of ma%or depressi$e disorder "&# Agitation and possible hyperreflexia with abrupt discontinuance after chronic use "'# (ncreased porphyrin synthesis "D# (mpro$ed performance on tests of psychomotor function ")# *etrograde amnesia Answer 1. Diazepam has no more effecti$eness than placebo in the treatment of ma%or depressions+ but its use can cause a decrease in psychomotor function. &enzodiazepines do not increase acti$ity of li$er drug-metabolizing enzymes or of enzymes in$ol$ed in porphyrin synthesis "such barbiturates#. At high doses+ benzodiazepines may cause anterograde+ not retrograde+ amnesia. ith abrupt discontinuance following chronic use+ anxiety and agitation may occur+ sometimes with hyperreflexia and+ rarely+ seizures. ,he answer is "&#. 2. A -.-year-old man+ $ery o$erweight+ complains of not sleeping well and feeling tired during the day. /e tells his physician that his wife is the cause of the problem because she wakes him-up se$eral times during the night due to his loud snores. ,his appears to be a breathing-related sleep disorder+ so you will probably write a prescription for "A# 'lorazepate "&# 0lurazepam "'# Secobarbital "D# ,riazolam ")# 1one of the abo$e Answer 2. &enzodiazepines and barbiturates are contraindicated in breathing-related sleep disorders because they will further compromise $entilation. (n the obstructi$e sleep apnea syndrome "pick-wickian syndrome#+ obesity is a ma%or risk factor. ,he best prescription you can gi$e this patient is to lose weight. ,he answer is ")#. 2. hich one of the following statements concerning the barbiturates is accurate! "A# Symptoms of the abstinence syndrome are more se$ere during withdrawal from phenobarbital than from secobarbital "&# 'ompared with barbiturates+ the benzodiazepines exhibit a steeper dose-response relationship "'# &arbiturates may increase the half-li$es of drugs metabolized by the li$er "D# An increase in urinary p/ will accelerate the elimination of phenobarbital ")# *espiratory depression caused by barbiturate o$erdosage can be re$ersed by flumazenil Answer 2. ithdrawal symptoms from use of the shorter-acting barbiturate secobarbital are more se$ere than with phenobarbital. ,he dose-response cur$e for benzodiazepines is flatter than that

for barbiturates. (nduction of li$er drug-metabolizing enzymes occurs with barbiturates and may lead to decreases in half-life of other drugs. 0lumazenil is an antagonist at &3 receptors and is used to re$erse '1S depressant effects of benzodiazepines. As a weak acid "p4a 5 6#+ phenobarbital will exist mainly in the ionized "nonprotonated# form in the urine at alkaline p/ and will not be reabsorbed in the renal tubule. ,he answer is "D#. 4. 'oncerning the clinical uses of benzodiazepines and related drugs+ which one of the following statements is accurate! "A# Alprazolam is effecti$e in the management of obsessi$e-compulsi$e disorders "&# &romazepam and clonazepam has effecti$eness in patients who suffer from phobic anxiety states "'# Diazepam is used for chronic management of bipolar affecti$e disorder in patients who are unable to tolerate lithium "D# (ntra$enous buspirone is useful in status epilepticus ")# Symptoms of the alcohol withdrawal state may be alle$iated by treatment with zaleplon Answer 4. &enzodiazepines ha$e no significant therapeutic benefit in the management of obsessi$e-compulsi$e disorders. Drugs effecti$e for this condition increase the acti$ity of serotonergic systems in the brain. 'lonazepam has been used commonly as an anticon$ulsant and also has efficacy in anxiety states+ including agoraphobia. 'lonazepam "not diazepam# has also been used as a back-up drug in bipolar affecti$e disorder. ,he answer is "&#. -. ,he wife of a 74-year-old computer programmer considers him to be of a 8ner$ous disposition.8 /e is easily startled+ worries about inconse9uential matters+ and sometimes complains of stomach cramps. At night he grinds his teeth in his sleep. ,here is no current history of drug abuse. Assuming that the symptoms experienced by this young man are not related to a medical condition+ the most appropriate drug treatment would be the %udicious use of "A# &uspirone "&# :idazolam "'# ;henobarbital "D# ,riazolam ")# 3olpidem Answer -. ,he symptoms described suggest that this patient is suffering from a generalized anxiety disorder. &uspirone or longer-acting benzodiazepines are considered to be the drugs of choice for the management of such disorders. :idazolam and triazolam are short-acting benzodiazepines used in anesthesia protocols and for sleep disorders+ respecti$ely. ,he answer is "A#. .. *egarding the characteristic properties of the drug prescribed for this young man+ the physician should inform the patient to anticipate "A# Additi$e '1S depression with alcoholic be$erages "&# A significant effect on memory "'# ,hat the drug will take a week or so to begin working

"D# A need to gradually increase drug dosage because of tolerance ")# ,hat if he stops taking the drug abruptly he will experience withdrawal signs Answer .. &uspirone is a selecti$e anxiolytic with pharmacologic characteristics 9uite different from those of most other drugs used in anxiety states. &uspirone has rninimal effects on cognition or memory< it is not additi$e with ethanol in terms of '1S depression< tolerance is minimal< and it has no dependence liability. /owe$er+ buspirone is not effecti$e in acute anxiety because it has a slow onset of therapeutic action. ,he answer is "'#. 6 . hich one of the following statements best describes the mechanism of action of benzodiazepines! "A# &enzodiazepines acti$ate =A&A-& receptors in the spinal cord "&# ,heir inhibition of =A&A transarninase leads to increased le$els of =A&A "'# &enzodiazepines block glutamate receptors in hierarchical neuronal pathways in the brain "D# ,hey increase the fre9uency of opening of chloride ion channels that are coupled to =A&A-A receptors ")# ,hey are direct-acting =A&A receptor agonists in the '1S Answer 6. &enzodiazepines are thought to exert most of their '1S effects by increasing the inhibitory effects of =A&A. &enzodiazepines interact with specific receptors "&3 receptors# that are components of the =A&A-A receptor-chloride ion channel macromolecular complex to increase the fre9uency of chloride ion channel opening. &enzodiazepines are not =A&A receptor agonists because they do not interact directly with this component of the complex. ,he answer is "D#. >. An >7-year-old woman+ otherwise healthy for her age+ has difficulty sleeping. ,riazolam is prescribed for her at one-half of the con$entional adult dose. hich one of the following statements about the use of triazolam in this elderly patient is accurate! "A# Ambulatory dysfunction does not occur in elderly patients taking one-half of the con$entional adult dose "&# /ypertension is a common ad$erse effect of benzodiazepines in patients o$er 6? years of age "'# @$er-the-counter cold medications may antagonize the hypnotic effects of the drug "D# She may experience amnesia+ especially if she also drinks alcoholic be$erages ")# ,riazolam is distincti$e in that it does not cause rebound insomnia on abrupt discontinuance Answer >. (n elderly patients taking benzodiazepines+ hypotension is far more likely than increased blood pressure. ,he elderly are more prone to '1S depressant effects of hypnotics< e$en a dose reduction of -?A may still cause excessi$e sedation with possible ambulatory impairment. Additi$e '1S depression occurs commonly with drugs used in @,' cold medications+ and rebound insomnia occurs with the abrupt discontinuance of benzodiazepines used as sleeping pills. Amnestic effects of the benzodiazepines are enhanced by the concomitant use of alcoholic be$erages. ,he answer is "D#.

9. ,he most likely explanation for the increased sensiti$ity of elderly patients to a single dose of triazolam and other sedati$e-hypnotic drugs is "A# 'hanges in brain function that accompany the aging process "&# Decreased renal function "'# (ncreased cerebral blood flow "D# Decreased hepatic metabolism of lipid-soluble drugs ")# 'hanges in plasma protein binding Answer 9. Decreased blood flow to $ital organs+ including the li$er and kidney+ occurs during the aging process. ,hese changes may contribute to cumulati$e effects of sedati$e-hypnotic drugs. /owe$er+ this does not explain the enhanced sensiti$ity of the elderly patient to a single dose of a central depressant+ which appears to be due to changes in brain function that accompany aging. ,he answer is "A#. B?. A 7>-year-old woman has sporadic attacks of intense anxiety+ with marked physical symptoms including hyper$entilation+ tachycardia+ and sweating. (f she is diagnosed as suffering from a panic disorder+ the most appropriate drug to use is "A# Alprazolam "&# 'hloral hydrate "'# 0lurazepam "D# :eprobamate ")# ;ropranolol Answer B?. Alprazolam and clonazepam are the most effecti$e of the benzodiazepines for the treatment of panic disorders. ;ropranolol has sometimes been used to attenuate excessi$e sympathornimetic acti$ity in persons who suffer from performance anxiety "8stage fright8#. ,he answer is "A#. BB. hich one of the following drugs may increase anticoagulant effects by displacement of warfarin from plasma protein binding sites and is inacti$e until con$erted in the body to an acti$e metabolite! "A# &uspirone "&# 'hloral hydrate "'# 'lorazepate "D# Secobarbital ")# 3aleplon Answer BB. 'hloral hydrate is a prodrug and is metabolized to trichloroethanol+ the acti$e moiety. (t displaces certain drugs from plasma protein binding sites and may cause bleeding when administered to patients gi$en warfarin. ,he chronic use of chloral hydrate has been associated with an increased incidence of neoplastic disease. 'lorazepate is also a prodrug hydrolyzed to form nordiazepam+ the acti$e metabolite. ,he benzodiazepines do not displace other drugs from plasma protein binding sites. ,he answer is "&#.

B7. hich one of the following drugs has been used in the management of alcohol withdrawal states and in maintenance treatment of patients with tonic-clonic or partial seizure states! (ts chronic use may lead to an increased metabolism of warfarin and phenytoin. "A# 'hlordiazepoxide "&# :eprobamate "'# ;henobarbital "D# ,riazolam ")# 3olpidem Answer B7. 'hronic adrninistration of phenobarbital increases the acti$ity of hepatic drugmetabolizing enzymes+ including cytochrome ;4-? isozymes. ,his often increases the rate of metabolism of drugs administered concomitantly+ with decreases in the intensity and duration of their effects. ,he answer is "'#. B2. A 4?-year-old patient with li$er dysfunction is scheduled for a surgical procedure. Corazepam can be used for preanesthetic sedation in this patient without concern for excessi$e '1S depression because the drug is "A# A selecti$e anxiolytic like buspirone "&# Acti$ely secreted in the renal proximal tubule "'# 'on%ugated extrahepatically "D# )liminated $ia the lungs ")# *e$ersible by administration of naloxone Answer B2. ,he elimination of most benzodiazepines in$ol$es their metabolism by li$er enzymes+ including cytochrome ;4-? isozymes. (n a patient with li$er dysfunction+ lorazepam+ which is metabolized extrahepatically+ is less likely to cause excessi$e '1S depression. &enzodiazepines are not eliminated $ia the kidneys or lungs. 0lumazenil is used to re$erse excessi$e '1S depression caused by benzodiazepines. ,he answer is "'#. B4. ,his hypnotic drug facilitates the inhibitory actions of =A&A+ but it lacks anticon$ulsant or muscle relaxing properties and has minimal effect on sleep architecture. "A# &uspirone "&# Diazepam "'# 0lurazepam "D# ;henobarbital ")# 3aleplon Answer B4. 3aleplon and zolpidem are related hypnotics which+ though structurally different from benzodiazepines+ appear to ha$e a similar mechanism of action. /owe$er+ neither drug is effecti$e in the management of seizures nor in muscle spasticity states. 'ompared with benzodiazepines+ zaleplon and zolpidem are less likely to alter sleep pattern. *ememberbuspirone is not a hypnoticD ,he answer is ")#. B-. ,he most fre9uent type of drug interaction that occurs in patients using drugs of the sedati$ehypnotic classis "A# Additi$e '1S depression

"&# Antagonism of sedati$e or hypnotic actions "'# 'ompetition for plasma protein binding "D# (nduction of li$er drug-metabolizing enzymes ")# (nhibition of li$er drug-metabolizing enzymes Answer B-. hile drug interactions based on pharmacokinetics do occur with sedati$e-hypnotics+ the most common drug interaction is additi$e '1S depression. Additi$e effects can be predicted with concomitant use of alcoholic be$erages+ anticon$ulsants+ opioid analgesics and phenothiazines. Cess ob$ious but e9ually important is enhanced '1S depression with many antihistamines+ antihypertensi$es+ and antidepressants of the tricyclic class. ,he answer is "A#. Conclusion @f the currently marketed drugs+ drug of choice for insomnia are 2rd generation hypnotics E zolpidem+ zopiclone and zoleptone. (t is suggested that nightly use of sedati$e-hypnotics ought to be limited to F 2 weeks. /owe$er+ many patients seem to need and to benefit from continuous use o$er years. ,he need for continued use should be ree$aluated at regular inter$als.