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1992 Update on Anxiolytics and Hypnotics Lynn Osako University of California, San Francisco

Mary Gutierrez Chapman University, [email protected]

Michael Z. Wincor University of Southern California

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Recommended Citation Osako L, Gutierrez MA, Wincor M. Update on anxiolytics and hypnotics. Calif Pharmacist. 1992:32-37.

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Comments This article was originally published in California Pharmacist in 1992.

Copyright California Pharmacists Association

This article is available at Chapman University Digital Commons: http://digitalcommons.chapman.edu/pharmacy_articles/488 "' JOURNAL CE------~

• Lynn Osako, Pharm.D, History Mary Gutierrez, Pharm.D. and Michael Wincor, Pharm.D. Agents to produce sleep, called hypnotics, have been around thousands of yeats. Evidence shows that poppy plants were used as the first hypnotics sorne two-thousand yeats ago. The old­ est hypnotic agent is chloral hydrate. Its popularity waned when the barbiturates came along but has become more popu­ lar in the last few decades. 1 It is less effective than flurazepam and tolerance toits effects develops rapidly.2

The bromides were introduced in the mid-1800s. Problems with these agents Update on include the ir extremely long half-life of about 12 days, their low therapeutic in­ dex and irritation to the Gl system.1

anxiolytics and Early in the 20th century, barbitu­ rates were introduced and quickly be­ came popular hypnotic agents. These hypnotics agents have numerous adverse reactions such as respiratory depression, nausea and vomiting, circulatory collapse and severe depression of the CNS. Barbitu­ rates have become associa red with abuse and overdose, and drug withdrawal can also be a serious problem. A chronic user of barbiturates, upon withdrawal, may Goal experience irritability, insomnia and, in serious cases, convulsions and death.1 The goal of this article is to educate pharmacists on the new er anxiolytic and hypnotic agents. Other nonbarbiturate-nonbenzo­ diazepines indude piperidinediones su ch Objectives as glutethimide and methyprylon, ethchlorvynol, methaqualone and mep­ After reading this article, the pharmacist shouid be able to: robamate. Ali of these agents have prob­ lems similar to those of the barbiturates, • Discuss the advantages of the new hypnotics and anxiolytics over specifically physical dependence and 1 3 previous agents. overdose potential. •

• Discuss possible adverse effects and drug interactions of the new Benzodiazepines were a major break­ hypnotics and anxiolytics. through in sedative-hypnotics and have become the most frequently prescribed • Recommend one of the newer agents as an alternative to more conven­ drugs in the U.S. Their main advantage tionai therapy when appropriate. over previous agents are their higher therapeutic index. T aken alone, these agents rarely cause death and produce 1 3 Provided by an educational grant from little respiratory depression. • Physical dependence has become their major problem, however. 1

Drug therapies of anxiety states are a

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fairly recent development. Although hypertensive crisis, which can occur epines in itschemical and pharmacologie anxiety states were recognized in the when the patient on an MAOI eats food properties. It was first introduced in 1985 19th cenrury, most therapy revolved rich in tyramine (aged cheese, red wine, in West Germany and is the first drug around psychotherapy.4 A variety of sherry, beer, smoked meats orfish, etc.) developed primarily as an anxiolytic.4 drugs in different pharmacological classes and uses sympathomimetics or stimu­ are now used to treat the anxiety disor­ lants. Another disadvantage is that it Pharmacology. Unlike the benzodi­ ders. Alcohol is commonly used to self­ takes weeks for a noticeable effect to azepines, buspirone actually increases rreat situational anxiety; however, it is occur.5 noradrenergic activity. Buspirone's never a treatment of choice, 5 and alco­ mechanism of action is not completely holism has become a complication of lmipramine is the tricyclic amide­ understood, but it apparently does not many anxiety disorders. z pressant (TCA) most commonly used involve action on the benzodiazepine­ for treating panic disorder, while other gamma aminobutyric acid-chloride ( BZ­ 1 When barbiturates came along, they TCAs su ch as desipramine are occasion­ GABA-Cl) ionophore camp lex. It binds were not only used as hypnotics, but also ally used.5 Like the MAOis, weeks of selectively ta 5-HT lA receptors, and this used to treat anxiety.2 Barbiturates are therapy are required before a response is most likely where the majority of its not, however, specifie anxiolytics and occurs. Their anticholinergic side ef­ have the disadvantages discussed ear­ fects are more pronounced than with the Her. MAOls and may cause psychotic reac­ 2 5 • tions, especially in the elderly. • TCAs Antihistamines are used occasionally can also cause orthostatic hypotension, The major and are especially good for patients with tachycardia and decreased cardiac con­ 5 6 2 5 a high propensity for drug abuse. • The duction. • T oxicity is another serious disadvantage for ali anticholinergic effects of these agents problem with these patients, and a few the hypnotics and for are their primary disadvantage, espe· week's supply can easily cause death. cîally in the elderly in whom central most of the anxiolytics effects such as confusion and hallucina­ Benzodiazepines, as mentioned car­ is their potential for tions may also occur.5 lier, are the most commonly prescribed drugs in the U.S. Anxiery syndromes physical dependence. Beta-adrenergic blocking agents are make up a large percentage of those For those anxiolytics used primarily to alleviate the physical prescriptions, and benzodiazepines can symptoms of stress. These agents are be used in ali different types of anxiety without addictive nonspecific and rarely are helpful in disorders. Their advantages and disad­ potential, the primary psychiatrie patients.4 Clonidine is also vantages are mentioned above in the used to treat anxiety; however, its side discussion on hypnotics. problems are adverse effects of hypotension, depression and effects and toxicity. fatigue have limited its use.5 The need for newer agents

Antipsychotics were used more fre­ Although the above-mentioned quently for anxiety attacks in the past. agents are effective against anxiety and They are less commonly used for thar insomnia, each has its own problems. anxiolytic activity is produced. 7 These purpose now because of their question­ The major disadvantage for all the receptors are localized in areas of the able efficacy and the ir high potential for hypnotics and for most of the anxiolytics CNS which may explain its more favor­ adverse effects su ch as tardive dyskinesia is their potential for physical depen­ able adverse effect profile versus the and extrapyramidal effects. 4•6 dence. For those anxiolytics without benzodiazepines. Buspirone does not addictive potential, the primary prob­ share the anticonvulsant and muscle Antidepressants, however, continue lems are adverse effects and toxicity. relaxant properties of the benzodiaz­ to be used and have shawn efficacy in Therefore, the search goes on for drugs epines and exhibits anxiolytic effects certain anxiety states. In the early 1960s with specifie actions, few side effects, a only.7 monamine oxidase inhibitors (MAOls) high therapeutic index and no addictive were found to be effective for panic potential. Pharmacokinetics. Buspirone is ab­ disorder.6 Phenelzine is most commonly sorbed rapidly and completely from the used, and studies have proven its effec­ Buspirone (Buspar®) 01 system. After undergoing first-pass tiveness in panic disorder.5 Side effects metabolism only 4% of the drug reaches include orthostatic hypotension, weight Buspirone is a relatively new drug the systemic circulation.5 The onset of gain, sexual dysfunction, edema and which is unique from the beruodiaz- action of buspirone is considerably de-

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layed and occurs sometime during the should be a 10-day washout after MA01 This is probably due to its long onset of first three weeks of therapy; therefore, it use before buspirone therapy is initi­ action and because buspirone does not cannat be used for short-term or as­ ated. 8 There have be en reports of eleva­ alleviate the withdrawal symptoms of needed treatment. The distribution of tions in ALT concentrations with con­ benzodiazepines. buspirone is not completely known. The comitant buspirone and trazodone use. apparent volume of distribution is about However, this remains unconfirmed in Dosing and administration. 5.3 L/kgJ It is 95% bound to plasma studies. As long as liver function tests Buspirone is only available orally. The proteins,5 mostly to albumin and a 1- are monitored, the manufacturer daims starting dose is 10-15 mg/cl in two or acid glycoprotein. The elimination half­ thar the two may be used together.8 three divided doses. lt can be given with life is about four hours in healthy pa­ When haloperidol and buspirone are or without food. Increases of 5 mg/day tients while it is prolonged with renal used together, elevations occur in every two to four days can be made after impairment and hepatic cirrhosis. haloperidol concentration. This prob­ one week of therapy at 15 mg/day. The Buspirone is metabolized in the liver, ably occurs through competition resulr­ usual maximum dose is 60 mg/day. Op­ primarily by oxidation, into several me­ ing in the inhibition of the metabolism timal effects may not occur for as long as tabolites. The major active metabolite is of haloperidol.8 lt is not recommended six weeks. 5 It has not been determined 1-pyrimidinyl-piperazine (1-PP). lt has that both be used concurrently until how to ad just doses in hepatic and renal about 20-25% of the anxiolytic activity more information is obtained on this impairment. Sorne have suggested a 25- ofbuspirone; 7 however, it is unclear how interaction. 8 Buspirone does not appear 50% reduction in patients thatare anurie. much it adds to buspirone's action. Both to interact with benzodiazepines; how­ buspirone and its metabolites are ex­ ever, it is still recommended that they The side effect profile ofbuspirone is creted primarily in the urine although not be given together.8 a defini te advantage over the benzodiaz­ less than 0.1% is excreted as unchanged epines. There îs little sedation, making drug.7 Indications. Indications for buspirone it an alternative for patients in whom include generalized anxiety disorders. the sedation and psychomotor impair­ Adverse effects. Adverse effects ment are intolerable. lt would also be which have been reported include gas­ indicated in patients who may have a trointestinal complaints (nausea and history of drug dependence. The disad­ vomi ting), dizziness and headache. Each • The side effect profile vantage is its long onset of action. ln of rhese si de effects were reported in less patients with symptoms requiring im­ than 10% of patients. Sedation is re­ of buspirone is a mediate alleviation, buspirone may not ported in 10% of patients, which is the definite advantage be ideaL same incidence as with placebo. There are slightly more reports of adverse ef­ overthe Clomipramine (Anafranil®) fects in the elderly.4 Also, there are few benzodiazepines. reports of psychomotor impairment. Clomipramine is a tricyclic antide­ Another unique feature of buspirone is There is little pressant used for more than 20 years in its inability to potentiate the effect of sedation, making it Europe and Canada which has more alcohol and lack of addiction potential. 4 recently been used for various anxiety an alternative for disorders. 9 lt is so far the only agent There is little information on the patients in whom the approved for obsessive-compulsive dis­ toxicity ofbuspirone. Because dysphoria arder ( OCD) and is marketed in the may occur at higher doses of 20-40 mg, 7 sedation and U.S. for this indication. there is low potential for abuse. There psychomotor also is little evidence rhat withdrawal Pharmacology. Clomipramine inhib­ occurs with sudden discontinuation of impairment are its reuptake of serotonin and norepi­ the drug. For acute roxicity, there are no intolerable. nephrine like the other tricyclic amide­ specifie antidotes and treatment usually pressants and is the most potent seroto­ involvessupportive care. The lethal dose nin reuptake blocker in its class.10 The in humans is unknown.4 Studies have shown that buspirone is as activity of clomipramine is thought to effective as benzodiazepines for these be due toits inhibitory effect on seroto­ Drug interactions. Drug interactions disorders.8 In severe anxiety, however, nin. This activity increases serotonin include elevated blood pressure in pa­ buspirone is lesseffective than lorazepam levels, and long-term treatment may lead tients with concurrent MAOI use. and diazepam. 5 Previous treatment with to a clown regulation of the serotonin Therefore, ir is not recommended to benzodiazepines is often associated with receptors. However, its exact mecha­ 7 9 10 give both concomitantly, and there disappointment in buspirone therapy. s, nism is unknown. •

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Pharmacokinetics. Absorption is nent and include dry mouth, constipa­ treatment oftriey clic antidepressant tox­ rapid and complete from the Gl system, tion, sweating, blurred vision and uri­ icity. The guidelines can change; there­ but the drug undergoes first pass effect. nary retention.9 Cardiac effects include fore, a poison center should be ca lied for Systemic bioavailability is about 50%.11 orthostatic hypotension, syncope, pal­ updated information. 12 The distribution pattern has yet to be pitations and tachycardia. 9 Seizures have completely determined. The mean ap­ been reported at an incidence of 0.7% Indications. Clomipramine, unlike parent volume of distribution is and were more common with high doses most of the other tricyclic antidepres­ 12 L/kg. 11 lt is 98% protein bound to ( >300 mg/day) and with intravenous sants, is used to treat obsessive compul­ plasma proteins.9·11 Clomipramine isex­ administration.9 One particularly dis­ sive disorder and panic disorder. Early tensively metabolized to a variety of turbing problem to patients is sexual studies have shown thar clomipramine metabolites. Demethylclomipramine, dysfunction, although normal function is superior to other tricyclic antidepres­ 9 10 the major metabolite and a result of first retums withdiscontinuation of the drug.9 sants in treating OCD. • pass demethylation, is active. Approxi­ Weight gain can also be a problemY lt is mately 50-60% of the oral dose is found essential to counsel patients about these Dosing and administration. The start­ in the urine and the rest is in the feces. two side effects. ln sorne trials there is a ing dose for domipramine in OCD is 25 The mean elimination half-life of dropout rate of up to 28%.9 mg two to three times daily. 10 The dose clomipramine is 32 hours while should be increased slowly depending demethylclomipramine's mean half-life Acute toxicity with clomipramine is on response and tolerance ofside effects, is 69 hoursP similar to those of other tricyclic amide­ up to 100-150 mg, although 250 mg has pressants. Symptoms include severe an­ been used. Drug effect can take as long as Adverse effects. Clomipramine has ticholinergic effects. ln extreme cases, five to six weeks to manifestY Once the same adverse effect profile as the hypotension, coma, cardiac abnormali­ symptoms have been alleviated the dose other tricyclic antidepressants.9 The ties, convulsions and respiratory arrest should be brought down to the lowest anticholinergic effects are most promi- may occur. T rearment involves the usual effective level.

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Quazepam (Dorai@) There have been rare reports of confu­ made as necessary.8 sion and psychotic-like symptoms at the Quazepam is a benzodiazepine intro­ 30 mg dose, but none are reported at the Indications. Quazepam is used pri­ duced in 1990. The action of quazepam, 15 mg dose. 14 Rebound insomnia is not marily as a hypnotic. lt shares a similar like other benzodiazepines, revolves a problem with quazepam due to the pharmacokinetic profile as flurazepam around its actions on GABA. Quazepam long half-life ofDOQ.D With respect to and is very comparable in terms of effi­ and one of its metabolites, 2- cacy and side effect profile. Flurazepam oxoquazepam ( OQ), have selectivity for may have better long-term effective­ type 1 benzodiazepine receptors. 13 This ness, however.14 When compared with is a unique quality which is shared by • temazepam, quazepam appears to be more only one ether benzodiazepine, When compared with effective with short-term use, and there halazepam. The significance of this se­ also seems to be less tolerance develop­ lectivity is yet to be elucidated. 14 temazepam, ment when quazepam is used longer quazepam appears to term. 13•14 Phannaeokinetics. Quazepam is ab­ sorbed rapidly and its bioavailability is be more effective Dosing and administration. 8 approxima tely 80%. There is, however, with short-term use, Quazepam is available in oral form and extensive first pass metabolism in ani­ given only a bedtime. The starting dose mals which has not been quantified in and there also seems is 15 mg in most adults. ln sorne people, humans. Quazepam is distributed into to be less tolerance 7.5 mg may be enough. The higher dose most tissues and body fluids, and the of 30 mg is sometimes used, but there is apparent volume of distribution is 5 L/kg development when generally more daytime sedation at that when given at bedtime and 8.6 L/kg quazepam is used dose. Quazepam and flurazepam share when given in the moming.14 Both the same active metabolite and will ;' quazepam and OQ distribute quickly longer term. therefore share many of the same prop­ into the CNS and are more than 95% erties. Quazepam may have advantages bound to plasma proteins.13 Quazepam over temazepam and triazolam, but seerns is extensivelymetabolized toOQ and N­ to have little over flurazepam. desalkyl-2-oxoquazepam (DOQ), which is identical to N-desalkylflurazepam. dependence, quazepam appears to have Estazolam (ProSom®) Both metabolites have similar activity a low potential for abuse due to its to the parent drug. The half-life of carryover effects and decreased incidence lntroduced in 1991, Estazolam is an­ quazepam and OQ is about 40 hours.U' 14 ofrebound insomnia. No definitive state­ other new benzodiazepine. The half-life of DOQ is about 70-75 ments can be made though untillarger hours.13 In the elderly, the most signifi­ numbers of patients use this drug and Pharmacology. Like other benzodi­ cantchange in half-life is in DOQ, which more studies are done.14 azepines, estazolam's actions are due to can increase to 190 hours.l4 Both me­ its effects on GABA. It is unknown tabolites are metabolized ultimately via Drug interactions. Drug interactions whether estazolam has selectivity for conjugation with glucuronide formation. include additive CNS effects with other either benzodiazepine type 1 or 2 recep­ Quazepam is excreted both in urine and CNS depressants, anticonvulsants and tors. feces with very little in its original form. alcohol. If drugs from both classes need to be used together, reductions in doses Pharmacokinetics. Estazolam is both Adverse effects. Adverse effects of will be required to prevent overdosage. rapidly and well-absorbed from the GI quazepam are similar to other benzodiaz­ Administration ofdisulfiram and benzo­ tract. The bioavailability is approxi­ epines. These indude CNS depression diazepines which undergo oxidative mately 98%. It distributes widely into and physical dependence. Quazepam merabolism may result in a decreased most tissues and fluids, and it appears to may cause more daytime sedation than metabolism of the benzodiazepine.8 cross the blood-brain barrier.8 The half­ other benzodiazepines with shorter half­ Since quazepam is one ofthe these agents, life ranges from 8-31 hours. 2 Estazolam is lifes. Sedation is also more of a problem patients taking both these agents should metabolized hepatically, and its metabo­ at the higher dose of 30 mg. 13 Side ef­ be watched for a greater response to lites have little activity. The two princi­ fects are usuaU y most pronounced in the quazepam. This is also the case with pal ones are 4-hydroxyestazolam and 1- first few days and may diminish with concomitant cimetidine administration. oxo-estazolam. Both estazolam and its ti me or with decreases in dosage. At one Cimetidine may inhibit the clearance of metabolites are primarily excreted in week and four weeks of therapy, there quazepam; therefore, response must again urine with a small percent excreted in appears to be little daytime drowsiness. 15 be monitored and dosage reductions feces.

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Adverse effects. The side effect pro­ nificant advantage over previous agents. obsessive compulsive disorder and panic file is essentially the same as that for Buspirone appears to be a breakthrough disorder. Drugs 1990:39(1);136-153. quazepam, as is the drug interaction pro­ in rhat it is significantly different from 11. Peters MD, Davis SK, Austin LS. Clomipramine: an antiobessional tricylic file. In a study looking at long-term previous agents. It has specifie effects, antidepressant. Clinical Pharmacy administration, no tolerance was seen low incidence of side effects and little, if 1990:9;165-J 78. during the six weeks of therapy.16 The any, addiction potential. However, its 12. Physicians Desk Reference, 46th Edi!lon. same study showed that rebound insom­ long onset of action is a disadvantage. Medical Economies Data 1992. nia could occur with sudden withdrawal, Clomipramine also has sorne advantages 13. Kales A. Quazepam: hynotic efficacy and 16 side effects. Pharmacotherapy 1990: 10(1 ); 1- but that this was just temporary. in that it has increased efficacy over 12. imipramine in the treatment of OCD; 14. Ankier SI, Goa KL. Quazepam: a prelimi­ Drug interactions. Estazolam is oxi­ however, it has many of the same side nary review of its pharmacodynamie and datively metabolized; therefore, there is effects. The two newer benzodiazepines pharmacokinetic properties, and therapeu­ again the potential for its increased ac­ appear to have little advantage over the tic efficacy in insomnia. Drugs 1988:35;42- 62. tivity when given with cimetidine or older agents. Perhaps with continued 15. Hilbert JM, Battisra D. Quazepam and disulfiram. Doses should be adjusted use, more advantages and/or disadvan­ flurazepam: differentiai pharmacokinetic when given concomitantly with these tages will be revealed. It appears that the and pharmacodynamie characteristics. agents. search for the perfect anxiolytic and Journal of Clinical Psychiatry 1991: hypnotic will have to continue. 52(suppl);21-26. 16. Pierce MW, Shu VS. Efficacy of estazolam: Indications. Estazolam is used, as are the United States clinical experience. The other benzodiazepines, as a hypnotic. About the authors American]oumalofMedicine 1990:88(suppl Estazolam has an intermediate half-life 3A);6S-11S. which makes it less likely to cause day­ Lynn Osako, Pharm.D. is a resident 17. ScharfMB,RothPB, DominquezRA, Ware time sedation than th ose with long half­ in clinical phannacy at University of JC. Estazolam and flurazepam: a multicenter, placebo-controlled compara­ lives. It is also less likely to cause the California, San Francisco. Mary tive study in outpatients with insomnia. rebound insomnia seen when discon­ Gutierrez, Pharm.D. and Michael Journal of Clinical Pharmacology tinuing benzodiazepines with short haIf­ Wincor, Pharm.D. are assistant profes­ 1990:30(5);461-467. lives. Early studies show that estazolam sors of clinical pharmacy at the Univer­ has fewer side effects than flurazepam sity of Southem Califomia. and is equally efficacious as a hypnotic. 17 References Dosing and administration. 1. Hartmann E. The Sleeping PiU. Yale Uni­ To earn l hour of Estazolam is available in oral form only. versity Press 1978. The starting dose of estazolam in adults 2. YoungLY, Koda-KimbleMA. eds.Applied FREE is 1 mg at bedtime. The dose then may be Therapeutics: The Clinical Use ofDrugs, 5th continuing education slowly increased to 2 mg. In elderly pa­ Edition. Applied Therapeutics 1992. credit tiems, the dose should be started at 3. Mendelson WL. The Use and Misuse of Sleeping PiUs. Plenum Publishing Corpora­ 0.5 mg at bedtime. Wh en patients have tion 1980. been on therapy for long periods, they 4. Lader M, ed. Buspirone: A New Introduction should be tapered slowly to avoid with­ to the Treatment of Anxiety. Royal Society drawal. Estazolam has an intermediate of Medicine Services 1988. Turn to page 46 half-life and would be expected to be 5. Herfindal ET, Gourley DR, Hart LL, eds. similar to other benzodiazepines with Clinica!PharmacyandTherapeutics, 5th Edi­ tion. Williams and Wîlkins 1992. similar half-lives such as temazepam. 6. Coryell W, Winokur G, eds. The Clinicat This agent is not expected to have any Management of Anxiety Disorders. Oxford obvious advantages. Estazolam has only University Press 1991. been available for a year. Until there is 7. Jann MW. Buspirone: an update on a unique Free Journal C.E. is more widespread use of the drug, we will anxiolytic agent. Pharmacotherapy offered os a 1988:8(2);100-116. membership service not know if there are any clear advan­ 8. AHFS Drug Information. Amercian Soci­ tages or disadvantages. ety of Hospital Pharmacists, Inc. 1992. to CPhA members. 9. Kelly MW, Myers CW. Clomipramine: a The charge for Conclusion tricyclic antidepressant effective in obses­ nonmembers is Sl 0. sive compulsive disorder. DJCP, The An­ nais of Pharmacotherapy 1990:24;7.39-744. Although new anxiol ytics and 10. McTavish D, Benfield P. Clomipramine: hypnotics continue to appear on the anoverviewof its pharmacological proper­ market, very few of them have any sig- ties and a review of its therapeutic use in

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