Clinical pharmacology and therapeutics of benzodiazepines EDWARD M. SELLERS,* MD, PH D, FRCP[C]
Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chiordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chiordiazepoxide or diazepam In one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time. Les benzodiaz6pines comptent parmi les m6dicaments les plus prescrits au monde. Contrairement . leur emploi repandu, les indications th.rapeutiques
et le potentiel des benzodiazepines sont limit6s. Toutes les benzodiaz6pines disponibles au Canada possedent des structures et des propri.tes pharma. cologiques similaires. Peu presente des avantages specifiques sur les autres. Par exemple, aucune benzodiazepine ne sest montree sup6rieure au chlordiaz6. poxide dans le traitement de l'anxi6te aigue, de l'anxiet6 n6vrotique chronique ou de l'insomnie. Les barbituriques ne devraient pas .tre prescrits pour ces affections puisque les benzodiaz6pines sont tout aussi efficaces et plus sOres. Chez les personnes de plus de 70 ans Ia dose d'attaque devrait 6tre 500/o moms Mev.e que celle prescrite chez les personnes plus jeunes, et les personnes souffrant de cirrhose devraient recevoir le chlordiazepoxide au tiers de Ia dose habituelle; chez ces deux groupes de patients on devrait envisager l'emploi d'oxazepam ou de lorazepam. Le diazepam et le chlordiazepoxide ne doivent pas .tre administr6s par Ia vole intramusculaire. Les benzodiaz6pines ne devraient .tre prescrites que lorsqu'elles sont clairement indiqu6es et que pour Ia periode de temps necessaire.
Benzodiazepines are among the most commonly prescribed drugs in the world.1-3 Approximately 1 in 10 Canadians receive a prescription for a benzodiazepine each year, and more than 30% of hospitalized patients are given these agents.4-6 In contrast *Director, division of clinical pharmato the extensive use of benzodiazecology, department of medicine, Toronto pines, their therapeutic indications Western Hospital-Addiction Research Foundation clinical institute; associate and potential are limited. professor, departments of medicine and Should such widespread use of pharmacology, University of Toronto these agents be a cause for concern? Prepared on behalf of the Pharmacological Excess prescribing or use of any drug Society of Canada will be associated with increased Reprint requests to: Dr. E.M. Sellers, health care costs and disability due Addiction Research Foundation, 33 to adverse effects in patients who Russell St., Toronto, Ont. M55 2S1
don't need the drug.7'8 Despite their safety and low liability of physical dependence benzodiazepines share disadvantages with barbiturates :1.2 they produce drowsiness and "mental clouding", interact with other psychotropic drugs including alcohol, and produce psychologic dependence even after short-term use. The longer-term behavioural and societal consequences of persistent administration of drugs that subtly modify the function of the central nervous system are not known. Drug use may substitute for the learning of effective and flexible ways of solving problems and adapting to new stressful situations. Therapeutic indications Benzodiazepines are somewhat inappropriately referred to as "minor tranquillizers" despite their similarity to older sedative-hypnotics and their distinct differences from the neuroleptic "major tranquillizers", or antipsychotic phenothiazines.1'3 Seven benzodiazepine derivatives are available in Canada (Table I). Many others are available or under investigation elsewhere, and some will eventually be marketed in Canada. Pharmaceutical claims notwithstanding, these drugs are all similar structurally and in their pharmacologic actions. Few have specific advantages over others (Table II)..'.'. The majority are approved for treatment of acute anxiety states or chronic anxiety neurosis or both.1'3 Other uses include the treatment of continuous seizures (e.g., with diazepam), petit mal "absence attacks" (e.g., with clonazepam), alcohol with-
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Table l-Benzodiazepines marketed in Canada Nonproprietary name Trade name Manufacturer Chlordiazepoxide hydrochloride Librium and many others Hoffmann-La Roche Ltd. and many others Clonazepam Rivotril Hoffmann-La Roche Ltd. Clorazepate dipotassium Tranxene Abbott Laboratories, Ltd. Diazepam Valium and many others Hoffmann-La Roche Ltd. and many others Flurazepam hydrochloride Dalmane Hoffmann-La Roche Ltd. Lorazepam Ativan Wyeth Ltd. Oxazepam Serax Wyeth Ltd.
Principal clinical Range of usual daily condition used for dose for adults (mg) Anxiety 15 - 100
Dose sizes available (mg) (5, 10, 25)
Seizure disorders Anxiety
(0.5, 2.0) (3.75, 7.5, 15.0)
Anxiety
6 - 40
Insomnia Anxiety Anxiety
15 - 30 1 -4 30 - 120
Table Il-Advantages and disadvantages of benzodiazepines Drug Advantages Chlordiazepoxide Familiarity; inexpensive Clonazepam Clorazepate
Superior control of petit mal seizures None
Diazepam
Familiarity; easy parenteral formulation; inexpensive
Flurazepam
None
Lorazepam
Disadvantages* Poor intramuscular bioavailability' intermediate half-life; active metabolites; parenteral formulation inconvenient Potent Active metabolite with slow elimination; expensive Poor intramusuclar bioavailability; long half-life; slow cumulation; active metabolites Active metabolite with long half-life and slow cumulation; expensive Intermediate half-life; potent; expensive
Metabolism not impaired by liver disease or in elderly patients; intramuscular bioavailability complete; intravenous formulation Oxazepam Short half.life; metabolism not im- No parenteral formulation; slow abpaired by liver disease or advanced sorption after oral administration age may impair onset of sedation; expensive *From the point of view of what most frequently contributes to clinical problems. The existence of active metabolites and their slow elimination could be considerable advantages for the treatment of anxiety but would not be for a drug to help a patient fall asleep and besparedahangover the next day.
Table Ill-Pharmacokinetics of benzodiazepines in humans Mean half-life of parent drug and range (h) 10 (4 -16)
1.5 - 20 11.25 - 60
Serum protein binding Drug (%) Metabolites in blood Chlordiazepoxide 93 Active: desmethylchlordiazepoxide,* demoxepam, oxazepam Clonazepam 19-60 Clorazepate Very short; active Active: desmethyldiazemetabolite cumulates pam,* oxazepam in blood Desmethyldiazepam* 51 95 Active: oxazepam (44-55) Diazepam 31 98.6 Active: desmethyldiaze(50-170) (97.9-99.1) pam,* temazepam, oxazepam Flurazepam Short; active metabolite Active: desalkylflurazepam cumulates in blood Desalkylflurazepam 47-100 Lorazepam 14 85 Inactive glucuronide (10.5-16.8) (84.1-86.8) Oxazepam 7 86 Inactive glucuronide (3.6-9.1) 0Major metabolite in the blood, often with slower elimination than the parent drug. The total elimination (clearance) of benzodiazepines is determined by the elimination rate constant, the volume of distribution and the concentration of free drug. The large variation In clearance of benzodiazepines is due to considerable differences between patients in each of these parameters. The data are from many sources in the literature and include unpublished findings.
(2, 5, 10) (15, 30) (1, 2) (10, 15, 30)
drawal (e.g., with chlordiazepoxide, diazepam or oxazepam), neuromuscular disorders including cerebral palsy, tetanus and stiff-man syndrome (e.g., with diazepam), insomnia (e.g., with flurazepam) and a variety of problems for which their efficacy is unclear, such as backache and muscle trauma, psychosis, anxiety with depression, and phobic disorders, as well as amnestic therapy. No benzodiazepine has been shown to be superior to chlordiazepoxide for the treatment of acute anxiety, chronic anxiety neurosis, alcohol withdrawal or insomnia.2'10 Prescribing any benzodiazepine for acute mild or moderately severe anxiety or insomnia is usually unnecessary, possibly dangerous, and of questionable efficacy and consequence; for example, prescribing these agents for pre-exam jitters, prior to a driving test, prior to public speaking or to ease bereavement could result in the opposite of the desired therapeutic goal. The wide margin of safety of benzodiazepines permits their use in a variety of clinical situations in which the objective is simply to produce sedation or amnesia (e.g., endoscopy bronchoscopy, preanesthesia sedation and anesthesia induction, cardioversion and delivery). In these situations diazepam is the most common benzodiazepine used and is given intravenously; it is at least as effective as, and safer than, barbiturates,1'3 but is probably not superior to other parenterally administered benzodiazepines. Phannacokinetics
Absorption With oral administration the absorption of chlordiazepoxide and diazepam is rapid, the plasma con-
centration peaking about 1 hour after ingestion.1'3 Diazepam has a systemic bioavailability of 70% to 100%; rapid absorption accounts for the acute subjective "high", drowsiness, "spaced-out" feeling or motor impairment after the drug is ingested. Oxazepam is absorbed more slowly, its plasma concentration peaking 2 to 3 hours after ingestion; the bioavailability of oxazepam taken orally is about 50% to 70% .11 Clorazepate is converted by acid hydrolysis in the stomach to its active form, desmethyldiazepam; antacids slow the rate of conversion and decrease ,the peak effects of the active agent. After intramuscular injection of diazepam in healthy persons or of chlordiazepoxide in healthy persons, chronic alcoholics or alcoholics in withdrawal, absorption is slow (the plasma concentration peaking at 10 to 12 hours) and erratic, but eventually complete.12'13 As a consequence clinical effects are delayed and unpredictable. Neither chlordiazepoxide nor diazepam should be given intramuscularly. Protein binding (Table III) All benzodiazepines are extensively bound to serum albumin.2'14'15 The binding decreases the concentration of free active drug in equilibrium with the sites of action and elimination, thereby decreasing and prolonging the effect and slowing the elimination. Glomerular filtration of unchanged benzodiazepines is low because of their extensive serum binding. Conversely, in persons with cirrhosis and hypoalbuminemia the concentration of free active drug is higher and side effects of drowsiness are more common.15'16 Diazepam can be displaced from human serum albumin by its metabolites desmethyldiazepam and oxazepam. No clinically important interactions have been demonstrated that are based on benzodiazepine displacement from albumin by concurrently administered drugs. Biotransformation (Table III) All benzodiazepines undergo biotransformation in the liver by microsomal mixed-function oxidase."' Rates and patterns of benzodiazepine biotransformation vary considerably among healthy and sick humans. Chlordiazepoxide and diazepam each have at least two major active
metabolites that contribute to their clinical effects and toxicity: chlordiazepoxide is converted to desmethylchlordiazepoxide and then demoxepam; diazepam is converted to desmethyldiazepam and then oxazepam, itself a marketed benzodiazepine. Desmethyldiazepam has a longer mean half-life than the parent drug (50.9 ± 6.2 [standard error of the mean] v. 32.6 ± 11.3 hours).'7"8 By coincidence the half-life of diazepam is about equal to a patient's age; howver, there are many exceptions to this "rule". During long-term therapy the mean half-life of diazepam increases to 59.2 ± 17.4 hours, and both diazepam and its major active metabolite, desmethyldiazepam, accumulate.2".17"8 Little diazepam is excreted in the bile, and the enterohepatic circulation is not responsible for the slow elimination. These long half-lives and the extent of variation between patients make prediction of the time of maximum clinical effect or toxicity very difficult, but during long-term therapy cumulative and long-lasting effects can be expected. On average the times for cumulation to peak concentrations during long-term oral administration are: chlordiazepoxide 3 days, diazepam 7 days and desmethyldiazepam 10 days that is, approximately five times their respective half-lives. The slow cumulation of drug means that the full therapeutic effect or toxicity cannot be determined for a considerable time, and that the dosage should not be adjusted until cumulation is maximal.2'3'10 Conversely, elimination of the drug is slow. Because of the long half-lives of chlordiazepoxide and diazepam multiple daily doses are usually unnecessary and the drug can be given once or twice daily; because of their sedative effects bedtime is the best time for most of the daily dose to be given. The biotransformation of chlordiazepoxide, diazepam and desmethyldiazepam is impaired in patients with liver disease, and the half-life may increase up to sixfold.'8"9 The biotransformation of chlordiazepoxide and diazepam is inhibited by concurrent administration of disulfiram (Antabuse).20 The plasma half-life of chlordiazepoxide and diazepam may be prolonged in elderly patients; therefore initial doses for patients over the age of 70 years should be
half the usual amounts. Unlike the biotransformation of chlordiazepoxide and diazepam, that of oxazepam is simple glucuronide conjugation to an inactive metabolite." Furthermore, since the mean half-life of oxazepam is 7 hours, cumulation is minor and a full therapeutic response occurs after a few doses. Similarly, excessive sedation rapidly disappears. On the other hand, for the therapeutic effect to be maintained the drug should be given three times a day. Neither liver disease nor advanced age alters oxazepam's half-life.2' Oxazepam may be preferable for treating short-term problems such as insomnia, serious situational anxiety or alcohol withdrawal, when dose titration is required and hangover or daytime lethargy are particularly to be avoided. The slower absorption of oxazepam, however, somewhat detracts from its usefulness as a hypnotic. Lorazepam, a more potent benzodiazepine, is similar to oxazepam in structure and pattern of disposition, and its intramuscular bioavailability is complete.22 Flurazepam, though marketed as a hypnotic, has few properties to qualify it as such.2' The cumulation of the slowly eliminated active metabolite desalkylflurazepam over 7 to 10 days results in slow onset of the hypnotic effect and the side effect of drowsiness during long-term use. Older patients are particularly likely to experience toxic effects because they are more sensitive to various psychoactive drugs and may have altered biotransformation of the drug. Initial daily doses of flurazepam should not exceed 15 mg in patients over 70 years of age. Distribution Benzodiazepines are distributed widely in the body; tissue concentrations in brain, liver and spleen exceed those of unbound drug in the serum. Diazepam is more lipophilic than chlordiazepoxide and has a larger volume of distribution in the body."" The volumes of distribution of chlordiazepoxide and diazepam are larger in females and in patients over 70 years of age;'5 this larger volume accounts in part for the prolonged half-life in older patients.26 Chiordiazepoxide, diazepam and desmethyldiazepam enter the cerebro-
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spinal fluid in concentrations determined by their degree of serum protein binding.'7 Chlordiazepoxide and diazepam cross the placenta and appear in small amounts in breast milk. Clinical effects Responsiveness Dose requirements for patients vary greatly. The diazepam concentration required to produce sufficient sedation and relaxation to permit passage of a gastroscope varies 22fold;11 hence, there must be such differences in receptor responsiveness or sensitivity that it is virtually impossible to predict a clinical response at a particular dose in a particular patient. Sensitivity to benzodiazepines increases with age and liver disease and decreases with smoking and recent use of benzodiazepines, alcohol or other drugs that show cross-tolerance to benzodiazepines.10"''28'19 Tolerance, dependence and withdrawal Acute, subacute and chronic tolerance to benzodiazepines have been demonstrated in studies with animals and humans.1" During long-term administration tolerance commonly manifests itself as a decrease in side effects or a need to increase the dose to induce sleep or maintain symptomatic improvement. In theory physical dependence and the signs and symptoms suggesting withdrawal may develop in patients taking large amounts of diazepam (more than 40 mg/d) or chlordiazepoxide (more than 200 mg/d) when use of the drug is stopped.'0'31 However, elimination of diazepam and chlordiazepoxide (and their metabolites) is slow enough that a true withdrawal reaction is unlikely. Psychologic dependence can occur at any dose, and the resultant signs and symptoms are difficult to distinguish from those of an alleged withdrawal reaction and from those for which the drug may be given. Patients who have taken usual doses of benzodiazepines for a long time frequently experience severe anxiety when an attempt is made to discontinue the drug. Such psychologic dependence is no less a problem than true physical dependence and is far more common.
For most conditions for which efficacy of benzodiazepine therapy has been proven, only 2 to 4 weeks of therapy is required, and such shortterm therapy will not be associated with clinically important withdrawal symptoms. Sometimes the diagnosis is not clear and a trial of therapy with a benzodiazepine is reasonable. At the commencement of such a trial the desired therapeutic goal and the duration of therapy should be specified. Relation to plasma concentration Single measurements of the concentration of chlordiazepoxide or diazepam in whole blood or plasma do not relate closely to their therapeutic or toxic effects because of the presence of active metabolites, the variation between patients in the concentration of free drug, the development of tolerance and the inaccurate quantitation of the response. The drugs are slowly eliminated from the body; hence metabolites may be detected for weeks after administration of a single dose. Drug interactions Benzodiazepines interact with many psychoactive drugs. A list of such proven interactions is not helpful since patients must always be cautioned against driving a car or engaging in other activities in which there is risk to themselves or others when taking other psychoactive agents with benzodiazepines. Interactions among benzodiazepines, analgesics, antihistamines, phenothiazines and tricyclic antidepressants are well documented.""' Benzodiazepines do not induce the synthesis of drugmetabolizing enzymes, have less risk of interaction with coumarin anticoagulants than barbiturates, and are safer to use in combination with anticoagulants, antiarrhythmics, antineoplastic agents and antiepileptic drugs, with which metabolic interactions are most common. Unwanted effects Benzodiazepines are effective therapeutic agents that cause non-lifethreatening side effects in less than 10% of hospitalized patients who receive them.' The common adverse effects of benzodiazepines are direct extensions of their pharmacologic actions, namely drowsiness, lethargy and rarely coma. Of hospitalized pa-
1536 CMA. JOURNAL/JUNE 24, 1978/VOL. 118
tients administered flurazepam 3.1% have adverse reactions;" adverse reactions to this drug are 4-fold more common in patients over the age of 60 years and 20-fold more common with doses of 30 mg than with doses of 15 mg in patients over the age of 70 years. The frequency of side effects of flurazepam, chlordiazepoxide and diazepam therapy increases with age, dose, duration of therapy and presence of liver disease and hypoalbuminemia. Hematologic, renal and hepatic toxicity have seldom been reported for benzodiazepines. Various unusual responses have been reported, including nightmares, paradoxical delirium and confusion, depression, aggression and hostile behaviour."' Some patients experience a dry mouth, a metallic taste or headaches. Awareness of the sometimes bizarre effects of these drugs is important. Uncommon but important adverse effects after intravenous administration include respiratory or cardiac arrest or both, hypotension and phlebitis at the site of injection. Life-threatening adverse reactions occur with a frequency of 1.7% after intravenous administration of diazepam." Patients particularly at risk often have coexisting severe pulmonary or cardiac disease or have concurrently received cardiorespiratory depressant medications. Whenever possible and practical the rate of injection should be less than 12.5 mg/mm for chlordiazepoxide and less than 2.5 mg/mm for diazepam. Phlebitis is most common after repeated injection at the same site and can be minimized with a saline flush of 50 mL after each injection. Since the safety for the fetus of benzodiazepines administered to the mother is not proven, they should be prescribed only when their use is mandatory, and then for the shortest time possible. During 1975, 31% of persons admitted to the emergency departments of 21 metropolitan Toronto hospitals after taking a drug overdose reported having taken a benzodiazepine." Availability is probably a major determinant of what drug is taken in overdose.4'6'8" An overdose of benzodiazepines alone is rarely fatal." However, since 35 % of drug overdoses involve more than one drug, combinations of benzodiazepines and more dangerous drugs are more com-
mon and may cause death. The com- of drug metabolism. Habituation may bination of alcohol and an overdose occur with the use of benzodiazepines of benzodiazepines has been lethal.36 and may necessitate behaviourally oriented treatment directed at discontinuing the drug. Conclusions and recommendations Barbiturates should not be preBenzodiazepines should be pre- scribed for any condition for which scribed only when clearly indicated benzodiazepines are effective. and only for the minimum time necThe medical profession will be essary. When they are prescribed for held increasingly accountable and, the treatment of acute anxiety in particular, prescribing will come enough drug for 2 weeks is sufficient. under scrutiny because of its enDepressed patients should not receive tanglement with third-party drugprescriptions for amounts of drugs payment schemes.8 Responsible selfthat in combination with others might regulation seems preferable to conbe lethal. Few patients need refillable trol of drug use by legislation. prescriptions. The direct approach of I thank Drs. H. Kalant, J. McNeil and informing patients that the drugs are S.M. MacLeod for their comments and not needed since they won't help is suggestions about this manuscript. often well accepted because the patients are already aware that the drug References will not solve the problem. If, after GARATTINI 5, Mussmn E, RANDALL careful patient assessment and with 1. LO: Benzodiazepines, monograph of full knowledge of the limitations of the Mario Negri Institute for Pharmadrug therapy, a trial of chlordiazecological Research, Raven Pr, New York, 1973 poxide is begun, it should last for 2. GREENBLATT DJ, SHADER RI: Benzoonly 1 or 2 weeks. diazepines in Clinical Practice, Raven No benzodiazepine has been Pr, New York, 1974 shown to be superior to the oldest 3. Idem: Benzodiazepines (parts 1 and benzodiazepine, chlordiazepoxide, for 2). N Engi J Med 291: 1011, 1239; 1974 the treatment of acute anxiety, chronic anxiety neurosis or insomnia. 4. FEJER D, SMART R: The use of psychoactive drugs by adults. Can PsyInsomnia is a symptom that may chiatr Assoc J 18: 313, 1973 indicate a more serious underlying 5. CHAITON A, SPITZER WO, ROBERTS medical or psychiatric disorder. The RS, et al: Patterns of medical drug use - a community focus. Can Med use of hypnotic drugs may be unnecJ 114: 33, 1976 essary, irrational or contraindicated. 6. Assoc CooPERsTocK R: Psychotropic drug Long-standing sleep disorders necesuse among women. Can Med Assoc J sitate full evaluation rather than im115: 760, 1976 mediate prescription of a hypnotic. 7. SILVERMAN M, LEE PR: Pills, Profits and Politics, U of Cal Pr, Berkeley If the patient has both insomnia and Los Angeles, 1974 daytime anxiety, chlordiazepoxide, 8. and SELLERS EM, SELLERS 5: Systems for with its intermediate duration of acthe Control of Therapeutics and Drug tion, may be given. Two thirds of Utilization in Canada, WARDELL W (ed), Am Enterprise, Washington, the daily dose can be given at bed1978 time and the remainder 12 hours 9. BROWNE TR, PENRY JK: Benzodialater. zepines in the treatment of epilepsy. Diazepam and chlordiazepoxide Epilepsia 14: 277, 1973 should not be given intramuscularly. 10. Choice of benzodiazepine for treatment of anxiety or insomnia. Med Lorazepam is the only benzodiazeLett Drugs Ther 19: 49, 1977 pine with complete intramuscular GREENBLATr DJ, SHADER RI, KOCHbioavailability, but it is not presently 11. WESER J: Pharmacokinetics in clinical marketed as a parenteral formulation medicine: oxazepam versus other benin Canada. zodiazepines. Dis Nerv Syst 36: 6, 1975 Persons more than 70 years old Idem: Slow absorption of intramuscushould receive initial doses of benzo- 12. lar chlordiazepoxide. N Engi J Med diazepines 50% less than those pre291: 1116, 1974 scribed for younger persons, and in- 13. GREENBLArr D, SHADER RI, MACLEOD SM, et al: Absorption of oral and individuals with cirrhosis should retramuscular chlordiazepoxide. Eur J ceive chlordiazepoxide or diazepam Pharmacol (in press) in one third the usual dose; oxazepam 14. Clin KOCH-WESER J, SELLERS EM: Binding or lorazepam should be considered of drugs to serum albumin (parts 1 for these two groups of patients and and 2). N Engi J Med 294: 311, 526; 1976 for those receiving known inhibitors
15. THIESSEN JJ, SELLERS EM, DENBEIGH
P, et al: Plasma protein binding of diazepam and tolbutamide in chronic alcoholics. J Clin Pharmacol 16: 345, 1976 16. Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N Engi J Med 288: 277, 1973 17. KLo.rz U, ANTONIN KH, BIECK PR:
Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur J Clin Pharmacol 10: 121, 1976 18. KLOTZ U, ANTONIN KH, BRUGEL H, et al: Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther 21: 430, 1977 19. SELLERS EM, MACLEOD SM, GREEN-
BLATT DJ, et al: Influence of disulfiram and disease on benzodiazepine disposition (abstr). Ibid, p 117 20. MARTIN PR, BILLINGS BH, GILES HG,
et al: Inhibition of drug biotransformation by disulfiram (abstr). Can Fed Bid Soc Proc 20: 125, 1977 21. SHULL HJ JR, WILKINSON GR, JOHN-
SON R, et al: Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann intern Med 84: 420, 1976 22. GREENBLATr DJ, JOYCE TH, COMER
WH, et al: Clinical pharmacokinetics of lorazepam. II. Intramuscular injection. Gun Pharmacol Ther 21: 222, 1977 23. GEEENBLATT DJ, SHADER RI, KocH-
WESER J: Flurazepam hydrochloride, a benzodiazepine hypnotic. Ann intern Med 83: 237, 1975 24. GREENBLATT DJ, ALLEN MD, SHADER
RI: Toxicity of high-dose flurazepam in the elderly. Clin Pharmacol Ther 21: 355, 1977 25. MACLEOD SM, GILES HG, BENGERT
B, et al: The influence of age and sex on diazepam (D) pharmacokinetics (abstr). Clin Res 25: 676A, 1977 26. KLoTz
U,
AVANT
GR,
KOYUMPA
A, et al: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. I Clin invest 55: 347, 1975 27. STANSKI DR, GREENBLATT DJ, SEL-
WYN A, et al: Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its inetabolites in surgical patients. Clin Pharmacol Ther 20: 571, 1976 28. GILES HG, MACLEOD SM, WRIGHT JR,
et al: Influence of age and previous use on .Iiazepam dosage required for endoscopy. Can Med Assoc 1 118: 513, 1978
29. CASTLEDEN CM, GEORGE CF, MARCER
D, et al: Increased sensitivity to nitrazepam in old age. Br Med 1 1: 10, 1977
30. HOLLISTER LE, MOTZENBECKER FP,
DEGAN RO: Withdrawal reactions from chlordiazepoxide ("Librium"). Psychopharmacologia 2: 63, 1961
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31. PRESKORN SH, DENNER U: Benzo-
diazepines and withdrawal psychosis. JAMA 237: 36, 1977 32. WILLETrE RE (ed): Drugs and Driving, NIDA research monograph, ser 11, Dept of Health, Education and Welfare, Public Health Service, alcohol, drug abuse, and mental health administration, Washington, 1977 33. MACLEOD SM, GILES HG, PATZALEK G, et al: Diazepam actions and plasma concentrations following ethanol ingestion. Eur J Clin Pharmacol 11: 345, 1977
.
t
34. GREENBLATr DJ, KOCH-WESER J: Ad-
verse reactions to intravenous diazepam: a report from the Boston Collaborative Drug Surveillance Program. Am J Med Sci 266: 261, 1973 35. MACLEOD SM, SELLERS EM, KAPLAN
H, et al: Drug analysis in management of drug overdose (abstr). Ann R Coil Phys Surg Can 9: 57, 1976 36. GREENBLATT DJ, ALLEN MD, NOEL
BJ, et al: Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther 21: 497, 1977
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1538 CMA JOURNAL/JUNE 24, 1978/VOL. 118
BOOKS continued from page 1530 FOUNDATIONS OF MEDICINE: A Students Guide. Edited by Ronald Raven. 357 pp. IlIust. William Heinemann Medical Books Ltd., London, 1978. Price not stated. ISBN 0-433-27282-1 FRACTURES ETAGEES DU MEMBRE lNF.RIEUR, RACHIS, HANCHE. R. Judet, Ph. Blazy, J. Beneux et I'autres. 186 pp. Illust. Masson, Paris, 1978. $37.25, broch.. ISBN 2-225-49401-0 HEPATOTROPHIC FACTORS. Ciba Foundation Symposium 55 (new series). 405 pp. Illust. Elsevier/Excerpta Medical North-Holland, Amsterdam; Excerpta Medica, Amsterdam, 1978. $36. ISBN 0-444-90018-7 HORIZONS IN BIOCHEMISTRY AND BIOPHYSICS. Vol 4. Edited by E. Quagliariello, F. Palmieri and Thomas P. Singer. 302 pp. Illust. Addison-Wesley Publishing Company, Reading, 1977. $19.50. ISSN 0096-2708 IMMUNE EFFECTOR MECHANISMS IN DISEASE. Proceedings of the 4th Irwin Strasburger Memorial Seminar on Immunology. Edited by Marc E. Weksler, Stephen D. Litwin, Robert R. Tlggio and others. 241 pp. IlIust. Grune & Stratton, Inc., New York; Longman Canada Limited, Don Mills, 1977. $15.95. ISBN 0-80891069-8 INFECTIVE ENDOCARDITIS. Edited by Shahbucfln H. Rahimtoola. 386 pp. IlIust. Grune & Stratton, Inc., New York, 1978. $39.40. ISBN 0-8089-1052-3 PUBLIC EDUCATION ABOUT CANCER. Recent Research and Current Programmes. A Seventh Series of Papers. UICC Technical Report Series - Vol. 26. Edited by John Wakefield. 108 pp. lIlust. International Union Against Cancer, Geneva, 1977. PrIce not stated, paperbound
Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chiordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chiordiazepoxide or diazepam In one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time. Les benzodiaz6pines comptent parmi les m6dicaments les plus prescrits au monde. Contrairement . leur emploi repandu, les indications th.rapeutiques
et le potentiel des benzodiazepines sont limit6s. Toutes les benzodiaz6pines disponibles au Canada possedent des structures et des propri.tes pharma. cologiques similaires. Peu presente des avantages specifiques sur les autres. Par exemple, aucune benzodiazepine ne sest montree sup6rieure au chlordiaz6. poxide dans le traitement de l'anxi6te aigue, de l'anxiet6 n6vrotique chronique ou de l'insomnie. Les barbituriques ne devraient pas .tre prescrits pour ces affections puisque les benzodiaz6pines sont tout aussi efficaces et plus sOres. Chez les personnes de plus de 70 ans Ia dose d'attaque devrait 6tre 500/o moms Mev.e que celle prescrite chez les personnes plus jeunes, et les personnes souffrant de cirrhose devraient recevoir le chlordiazepoxide au tiers de Ia dose habituelle; chez ces deux groupes de patients on devrait envisager l'emploi d'oxazepam ou de lorazepam. Le diazepam et le chlordiazepoxide ne doivent pas .tre administr6s par Ia vole intramusculaire. Les benzodiaz6pines ne devraient .tre prescrites que lorsqu'elles sont clairement indiqu6es et que pour Ia periode de temps necessaire.
Benzodiazepines are among the most commonly prescribed drugs in the world.1-3 Approximately 1 in 10 Canadians receive a prescription for a benzodiazepine each year, and more than 30% of hospitalized patients are given these agents.4-6 In contrast *Director, division of clinical pharmato the extensive use of benzodiazecology, department of medicine, Toronto pines, their therapeutic indications Western Hospital-Addiction Research Foundation clinical institute; associate and potential are limited. professor, departments of medicine and Should such widespread use of pharmacology, University of Toronto these agents be a cause for concern? Prepared on behalf of the Pharmacological Excess prescribing or use of any drug Society of Canada will be associated with increased Reprint requests to: Dr. E.M. Sellers, health care costs and disability due Addiction Research Foundation, 33 to adverse effects in patients who Russell St., Toronto, Ont. M55 2S1
don't need the drug.7'8 Despite their safety and low liability of physical dependence benzodiazepines share disadvantages with barbiturates :1.2 they produce drowsiness and "mental clouding", interact with other psychotropic drugs including alcohol, and produce psychologic dependence even after short-term use. The longer-term behavioural and societal consequences of persistent administration of drugs that subtly modify the function of the central nervous system are not known. Drug use may substitute for the learning of effective and flexible ways of solving problems and adapting to new stressful situations. Therapeutic indications Benzodiazepines are somewhat inappropriately referred to as "minor tranquillizers" despite their similarity to older sedative-hypnotics and their distinct differences from the neuroleptic "major tranquillizers", or antipsychotic phenothiazines.1'3 Seven benzodiazepine derivatives are available in Canada (Table I). Many others are available or under investigation elsewhere, and some will eventually be marketed in Canada. Pharmaceutical claims notwithstanding, these drugs are all similar structurally and in their pharmacologic actions. Few have specific advantages over others (Table II)..'.'. The majority are approved for treatment of acute anxiety states or chronic anxiety neurosis or both.1'3 Other uses include the treatment of continuous seizures (e.g., with diazepam), petit mal "absence attacks" (e.g., with clonazepam), alcohol with-
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Table l-Benzodiazepines marketed in Canada Nonproprietary name Trade name Manufacturer Chlordiazepoxide hydrochloride Librium and many others Hoffmann-La Roche Ltd. and many others Clonazepam Rivotril Hoffmann-La Roche Ltd. Clorazepate dipotassium Tranxene Abbott Laboratories, Ltd. Diazepam Valium and many others Hoffmann-La Roche Ltd. and many others Flurazepam hydrochloride Dalmane Hoffmann-La Roche Ltd. Lorazepam Ativan Wyeth Ltd. Oxazepam Serax Wyeth Ltd.
Principal clinical Range of usual daily condition used for dose for adults (mg) Anxiety 15 - 100
Dose sizes available (mg) (5, 10, 25)
Seizure disorders Anxiety
(0.5, 2.0) (3.75, 7.5, 15.0)
Anxiety
6 - 40
Insomnia Anxiety Anxiety
15 - 30 1 -4 30 - 120
Table Il-Advantages and disadvantages of benzodiazepines Drug Advantages Chlordiazepoxide Familiarity; inexpensive Clonazepam Clorazepate
Superior control of petit mal seizures None
Diazepam
Familiarity; easy parenteral formulation; inexpensive
Flurazepam
None
Lorazepam
Disadvantages* Poor intramuscular bioavailability' intermediate half-life; active metabolites; parenteral formulation inconvenient Potent Active metabolite with slow elimination; expensive Poor intramusuclar bioavailability; long half-life; slow cumulation; active metabolites Active metabolite with long half-life and slow cumulation; expensive Intermediate half-life; potent; expensive
Metabolism not impaired by liver disease or in elderly patients; intramuscular bioavailability complete; intravenous formulation Oxazepam Short half.life; metabolism not im- No parenteral formulation; slow abpaired by liver disease or advanced sorption after oral administration age may impair onset of sedation; expensive *From the point of view of what most frequently contributes to clinical problems. The existence of active metabolites and their slow elimination could be considerable advantages for the treatment of anxiety but would not be for a drug to help a patient fall asleep and besparedahangover the next day.
Table Ill-Pharmacokinetics of benzodiazepines in humans Mean half-life of parent drug and range (h) 10 (4 -16)
1.5 - 20 11.25 - 60
Serum protein binding Drug (%) Metabolites in blood Chlordiazepoxide 93 Active: desmethylchlordiazepoxide,* demoxepam, oxazepam Clonazepam 19-60 Clorazepate Very short; active Active: desmethyldiazemetabolite cumulates pam,* oxazepam in blood Desmethyldiazepam* 51 95 Active: oxazepam (44-55) Diazepam 31 98.6 Active: desmethyldiaze(50-170) (97.9-99.1) pam,* temazepam, oxazepam Flurazepam Short; active metabolite Active: desalkylflurazepam cumulates in blood Desalkylflurazepam 47-100 Lorazepam 14 85 Inactive glucuronide (10.5-16.8) (84.1-86.8) Oxazepam 7 86 Inactive glucuronide (3.6-9.1) 0Major metabolite in the blood, often with slower elimination than the parent drug. The total elimination (clearance) of benzodiazepines is determined by the elimination rate constant, the volume of distribution and the concentration of free drug. The large variation In clearance of benzodiazepines is due to considerable differences between patients in each of these parameters. The data are from many sources in the literature and include unpublished findings.
(2, 5, 10) (15, 30) (1, 2) (10, 15, 30)
drawal (e.g., with chlordiazepoxide, diazepam or oxazepam), neuromuscular disorders including cerebral palsy, tetanus and stiff-man syndrome (e.g., with diazepam), insomnia (e.g., with flurazepam) and a variety of problems for which their efficacy is unclear, such as backache and muscle trauma, psychosis, anxiety with depression, and phobic disorders, as well as amnestic therapy. No benzodiazepine has been shown to be superior to chlordiazepoxide for the treatment of acute anxiety, chronic anxiety neurosis, alcohol withdrawal or insomnia.2'10 Prescribing any benzodiazepine for acute mild or moderately severe anxiety or insomnia is usually unnecessary, possibly dangerous, and of questionable efficacy and consequence; for example, prescribing these agents for pre-exam jitters, prior to a driving test, prior to public speaking or to ease bereavement could result in the opposite of the desired therapeutic goal. The wide margin of safety of benzodiazepines permits their use in a variety of clinical situations in which the objective is simply to produce sedation or amnesia (e.g., endoscopy bronchoscopy, preanesthesia sedation and anesthesia induction, cardioversion and delivery). In these situations diazepam is the most common benzodiazepine used and is given intravenously; it is at least as effective as, and safer than, barbiturates,1'3 but is probably not superior to other parenterally administered benzodiazepines. Phannacokinetics
Absorption With oral administration the absorption of chlordiazepoxide and diazepam is rapid, the plasma con-
centration peaking about 1 hour after ingestion.1'3 Diazepam has a systemic bioavailability of 70% to 100%; rapid absorption accounts for the acute subjective "high", drowsiness, "spaced-out" feeling or motor impairment after the drug is ingested. Oxazepam is absorbed more slowly, its plasma concentration peaking 2 to 3 hours after ingestion; the bioavailability of oxazepam taken orally is about 50% to 70% .11 Clorazepate is converted by acid hydrolysis in the stomach to its active form, desmethyldiazepam; antacids slow the rate of conversion and decrease ,the peak effects of the active agent. After intramuscular injection of diazepam in healthy persons or of chlordiazepoxide in healthy persons, chronic alcoholics or alcoholics in withdrawal, absorption is slow (the plasma concentration peaking at 10 to 12 hours) and erratic, but eventually complete.12'13 As a consequence clinical effects are delayed and unpredictable. Neither chlordiazepoxide nor diazepam should be given intramuscularly. Protein binding (Table III) All benzodiazepines are extensively bound to serum albumin.2'14'15 The binding decreases the concentration of free active drug in equilibrium with the sites of action and elimination, thereby decreasing and prolonging the effect and slowing the elimination. Glomerular filtration of unchanged benzodiazepines is low because of their extensive serum binding. Conversely, in persons with cirrhosis and hypoalbuminemia the concentration of free active drug is higher and side effects of drowsiness are more common.15'16 Diazepam can be displaced from human serum albumin by its metabolites desmethyldiazepam and oxazepam. No clinically important interactions have been demonstrated that are based on benzodiazepine displacement from albumin by concurrently administered drugs. Biotransformation (Table III) All benzodiazepines undergo biotransformation in the liver by microsomal mixed-function oxidase."' Rates and patterns of benzodiazepine biotransformation vary considerably among healthy and sick humans. Chlordiazepoxide and diazepam each have at least two major active
metabolites that contribute to their clinical effects and toxicity: chlordiazepoxide is converted to desmethylchlordiazepoxide and then demoxepam; diazepam is converted to desmethyldiazepam and then oxazepam, itself a marketed benzodiazepine. Desmethyldiazepam has a longer mean half-life than the parent drug (50.9 ± 6.2 [standard error of the mean] v. 32.6 ± 11.3 hours).'7"8 By coincidence the half-life of diazepam is about equal to a patient's age; howver, there are many exceptions to this "rule". During long-term therapy the mean half-life of diazepam increases to 59.2 ± 17.4 hours, and both diazepam and its major active metabolite, desmethyldiazepam, accumulate.2".17"8 Little diazepam is excreted in the bile, and the enterohepatic circulation is not responsible for the slow elimination. These long half-lives and the extent of variation between patients make prediction of the time of maximum clinical effect or toxicity very difficult, but during long-term therapy cumulative and long-lasting effects can be expected. On average the times for cumulation to peak concentrations during long-term oral administration are: chlordiazepoxide 3 days, diazepam 7 days and desmethyldiazepam 10 days that is, approximately five times their respective half-lives. The slow cumulation of drug means that the full therapeutic effect or toxicity cannot be determined for a considerable time, and that the dosage should not be adjusted until cumulation is maximal.2'3'10 Conversely, elimination of the drug is slow. Because of the long half-lives of chlordiazepoxide and diazepam multiple daily doses are usually unnecessary and the drug can be given once or twice daily; because of their sedative effects bedtime is the best time for most of the daily dose to be given. The biotransformation of chlordiazepoxide, diazepam and desmethyldiazepam is impaired in patients with liver disease, and the half-life may increase up to sixfold.'8"9 The biotransformation of chlordiazepoxide and diazepam is inhibited by concurrent administration of disulfiram (Antabuse).20 The plasma half-life of chlordiazepoxide and diazepam may be prolonged in elderly patients; therefore initial doses for patients over the age of 70 years should be
half the usual amounts. Unlike the biotransformation of chlordiazepoxide and diazepam, that of oxazepam is simple glucuronide conjugation to an inactive metabolite." Furthermore, since the mean half-life of oxazepam is 7 hours, cumulation is minor and a full therapeutic response occurs after a few doses. Similarly, excessive sedation rapidly disappears. On the other hand, for the therapeutic effect to be maintained the drug should be given three times a day. Neither liver disease nor advanced age alters oxazepam's half-life.2' Oxazepam may be preferable for treating short-term problems such as insomnia, serious situational anxiety or alcohol withdrawal, when dose titration is required and hangover or daytime lethargy are particularly to be avoided. The slower absorption of oxazepam, however, somewhat detracts from its usefulness as a hypnotic. Lorazepam, a more potent benzodiazepine, is similar to oxazepam in structure and pattern of disposition, and its intramuscular bioavailability is complete.22 Flurazepam, though marketed as a hypnotic, has few properties to qualify it as such.2' The cumulation of the slowly eliminated active metabolite desalkylflurazepam over 7 to 10 days results in slow onset of the hypnotic effect and the side effect of drowsiness during long-term use. Older patients are particularly likely to experience toxic effects because they are more sensitive to various psychoactive drugs and may have altered biotransformation of the drug. Initial daily doses of flurazepam should not exceed 15 mg in patients over 70 years of age. Distribution Benzodiazepines are distributed widely in the body; tissue concentrations in brain, liver and spleen exceed those of unbound drug in the serum. Diazepam is more lipophilic than chlordiazepoxide and has a larger volume of distribution in the body."" The volumes of distribution of chlordiazepoxide and diazepam are larger in females and in patients over 70 years of age;'5 this larger volume accounts in part for the prolonged half-life in older patients.26 Chiordiazepoxide, diazepam and desmethyldiazepam enter the cerebro-
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spinal fluid in concentrations determined by their degree of serum protein binding.'7 Chlordiazepoxide and diazepam cross the placenta and appear in small amounts in breast milk. Clinical effects Responsiveness Dose requirements for patients vary greatly. The diazepam concentration required to produce sufficient sedation and relaxation to permit passage of a gastroscope varies 22fold;11 hence, there must be such differences in receptor responsiveness or sensitivity that it is virtually impossible to predict a clinical response at a particular dose in a particular patient. Sensitivity to benzodiazepines increases with age and liver disease and decreases with smoking and recent use of benzodiazepines, alcohol or other drugs that show cross-tolerance to benzodiazepines.10"''28'19 Tolerance, dependence and withdrawal Acute, subacute and chronic tolerance to benzodiazepines have been demonstrated in studies with animals and humans.1" During long-term administration tolerance commonly manifests itself as a decrease in side effects or a need to increase the dose to induce sleep or maintain symptomatic improvement. In theory physical dependence and the signs and symptoms suggesting withdrawal may develop in patients taking large amounts of diazepam (more than 40 mg/d) or chlordiazepoxide (more than 200 mg/d) when use of the drug is stopped.'0'31 However, elimination of diazepam and chlordiazepoxide (and their metabolites) is slow enough that a true withdrawal reaction is unlikely. Psychologic dependence can occur at any dose, and the resultant signs and symptoms are difficult to distinguish from those of an alleged withdrawal reaction and from those for which the drug may be given. Patients who have taken usual doses of benzodiazepines for a long time frequently experience severe anxiety when an attempt is made to discontinue the drug. Such psychologic dependence is no less a problem than true physical dependence and is far more common.
For most conditions for which efficacy of benzodiazepine therapy has been proven, only 2 to 4 weeks of therapy is required, and such shortterm therapy will not be associated with clinically important withdrawal symptoms. Sometimes the diagnosis is not clear and a trial of therapy with a benzodiazepine is reasonable. At the commencement of such a trial the desired therapeutic goal and the duration of therapy should be specified. Relation to plasma concentration Single measurements of the concentration of chlordiazepoxide or diazepam in whole blood or plasma do not relate closely to their therapeutic or toxic effects because of the presence of active metabolites, the variation between patients in the concentration of free drug, the development of tolerance and the inaccurate quantitation of the response. The drugs are slowly eliminated from the body; hence metabolites may be detected for weeks after administration of a single dose. Drug interactions Benzodiazepines interact with many psychoactive drugs. A list of such proven interactions is not helpful since patients must always be cautioned against driving a car or engaging in other activities in which there is risk to themselves or others when taking other psychoactive agents with benzodiazepines. Interactions among benzodiazepines, analgesics, antihistamines, phenothiazines and tricyclic antidepressants are well documented.""' Benzodiazepines do not induce the synthesis of drugmetabolizing enzymes, have less risk of interaction with coumarin anticoagulants than barbiturates, and are safer to use in combination with anticoagulants, antiarrhythmics, antineoplastic agents and antiepileptic drugs, with which metabolic interactions are most common. Unwanted effects Benzodiazepines are effective therapeutic agents that cause non-lifethreatening side effects in less than 10% of hospitalized patients who receive them.' The common adverse effects of benzodiazepines are direct extensions of their pharmacologic actions, namely drowsiness, lethargy and rarely coma. Of hospitalized pa-
1536 CMA. JOURNAL/JUNE 24, 1978/VOL. 118
tients administered flurazepam 3.1% have adverse reactions;" adverse reactions to this drug are 4-fold more common in patients over the age of 60 years and 20-fold more common with doses of 30 mg than with doses of 15 mg in patients over the age of 70 years. The frequency of side effects of flurazepam, chlordiazepoxide and diazepam therapy increases with age, dose, duration of therapy and presence of liver disease and hypoalbuminemia. Hematologic, renal and hepatic toxicity have seldom been reported for benzodiazepines. Various unusual responses have been reported, including nightmares, paradoxical delirium and confusion, depression, aggression and hostile behaviour."' Some patients experience a dry mouth, a metallic taste or headaches. Awareness of the sometimes bizarre effects of these drugs is important. Uncommon but important adverse effects after intravenous administration include respiratory or cardiac arrest or both, hypotension and phlebitis at the site of injection. Life-threatening adverse reactions occur with a frequency of 1.7% after intravenous administration of diazepam." Patients particularly at risk often have coexisting severe pulmonary or cardiac disease or have concurrently received cardiorespiratory depressant medications. Whenever possible and practical the rate of injection should be less than 12.5 mg/mm for chlordiazepoxide and less than 2.5 mg/mm for diazepam. Phlebitis is most common after repeated injection at the same site and can be minimized with a saline flush of 50 mL after each injection. Since the safety for the fetus of benzodiazepines administered to the mother is not proven, they should be prescribed only when their use is mandatory, and then for the shortest time possible. During 1975, 31% of persons admitted to the emergency departments of 21 metropolitan Toronto hospitals after taking a drug overdose reported having taken a benzodiazepine." Availability is probably a major determinant of what drug is taken in overdose.4'6'8" An overdose of benzodiazepines alone is rarely fatal." However, since 35 % of drug overdoses involve more than one drug, combinations of benzodiazepines and more dangerous drugs are more com-
mon and may cause death. The com- of drug metabolism. Habituation may bination of alcohol and an overdose occur with the use of benzodiazepines of benzodiazepines has been lethal.36 and may necessitate behaviourally oriented treatment directed at discontinuing the drug. Conclusions and recommendations Barbiturates should not be preBenzodiazepines should be pre- scribed for any condition for which scribed only when clearly indicated benzodiazepines are effective. and only for the minimum time necThe medical profession will be essary. When they are prescribed for held increasingly accountable and, the treatment of acute anxiety in particular, prescribing will come enough drug for 2 weeks is sufficient. under scrutiny because of its enDepressed patients should not receive tanglement with third-party drugprescriptions for amounts of drugs payment schemes.8 Responsible selfthat in combination with others might regulation seems preferable to conbe lethal. Few patients need refillable trol of drug use by legislation. prescriptions. The direct approach of I thank Drs. H. Kalant, J. McNeil and informing patients that the drugs are S.M. MacLeod for their comments and not needed since they won't help is suggestions about this manuscript. often well accepted because the patients are already aware that the drug References will not solve the problem. If, after GARATTINI 5, Mussmn E, RANDALL careful patient assessment and with 1. LO: Benzodiazepines, monograph of full knowledge of the limitations of the Mario Negri Institute for Pharmadrug therapy, a trial of chlordiazecological Research, Raven Pr, New York, 1973 poxide is begun, it should last for 2. GREENBLATT DJ, SHADER RI: Benzoonly 1 or 2 weeks. diazepines in Clinical Practice, Raven No benzodiazepine has been Pr, New York, 1974 shown to be superior to the oldest 3. Idem: Benzodiazepines (parts 1 and benzodiazepine, chlordiazepoxide, for 2). N Engi J Med 291: 1011, 1239; 1974 the treatment of acute anxiety, chronic anxiety neurosis or insomnia. 4. FEJER D, SMART R: The use of psychoactive drugs by adults. Can PsyInsomnia is a symptom that may chiatr Assoc J 18: 313, 1973 indicate a more serious underlying 5. CHAITON A, SPITZER WO, ROBERTS medical or psychiatric disorder. The RS, et al: Patterns of medical drug use - a community focus. Can Med use of hypnotic drugs may be unnecJ 114: 33, 1976 essary, irrational or contraindicated. 6. Assoc CooPERsTocK R: Psychotropic drug Long-standing sleep disorders necesuse among women. Can Med Assoc J sitate full evaluation rather than im115: 760, 1976 mediate prescription of a hypnotic. 7. SILVERMAN M, LEE PR: Pills, Profits and Politics, U of Cal Pr, Berkeley If the patient has both insomnia and Los Angeles, 1974 daytime anxiety, chlordiazepoxide, 8. and SELLERS EM, SELLERS 5: Systems for with its intermediate duration of acthe Control of Therapeutics and Drug tion, may be given. Two thirds of Utilization in Canada, WARDELL W (ed), Am Enterprise, Washington, the daily dose can be given at bed1978 time and the remainder 12 hours 9. BROWNE TR, PENRY JK: Benzodialater. zepines in the treatment of epilepsy. Diazepam and chlordiazepoxide Epilepsia 14: 277, 1973 should not be given intramuscularly. 10. Choice of benzodiazepine for treatment of anxiety or insomnia. Med Lorazepam is the only benzodiazeLett Drugs Ther 19: 49, 1977 pine with complete intramuscular GREENBLATr DJ, SHADER RI, KOCHbioavailability, but it is not presently 11. WESER J: Pharmacokinetics in clinical marketed as a parenteral formulation medicine: oxazepam versus other benin Canada. zodiazepines. Dis Nerv Syst 36: 6, 1975 Persons more than 70 years old Idem: Slow absorption of intramuscushould receive initial doses of benzo- 12. lar chlordiazepoxide. N Engi J Med diazepines 50% less than those pre291: 1116, 1974 scribed for younger persons, and in- 13. GREENBLArr D, SHADER RI, MACLEOD SM, et al: Absorption of oral and individuals with cirrhosis should retramuscular chlordiazepoxide. Eur J ceive chlordiazepoxide or diazepam Pharmacol (in press) in one third the usual dose; oxazepam 14. Clin KOCH-WESER J, SELLERS EM: Binding or lorazepam should be considered of drugs to serum albumin (parts 1 for these two groups of patients and and 2). N Engi J Med 294: 311, 526; 1976 for those receiving known inhibitors
15. THIESSEN JJ, SELLERS EM, DENBEIGH
P, et al: Plasma protein binding of diazepam and tolbutamide in chronic alcoholics. J Clin Pharmacol 16: 345, 1976 16. Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N Engi J Med 288: 277, 1973 17. KLo.rz U, ANTONIN KH, BIECK PR:
Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur J Clin Pharmacol 10: 121, 1976 18. KLOTZ U, ANTONIN KH, BRUGEL H, et al: Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther 21: 430, 1977 19. SELLERS EM, MACLEOD SM, GREEN-
BLATT DJ, et al: Influence of disulfiram and disease on benzodiazepine disposition (abstr). Ibid, p 117 20. MARTIN PR, BILLINGS BH, GILES HG,
et al: Inhibition of drug biotransformation by disulfiram (abstr). Can Fed Bid Soc Proc 20: 125, 1977 21. SHULL HJ JR, WILKINSON GR, JOHN-
SON R, et al: Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann intern Med 84: 420, 1976 22. GREENBLATr DJ, JOYCE TH, COMER
WH, et al: Clinical pharmacokinetics of lorazepam. II. Intramuscular injection. Gun Pharmacol Ther 21: 222, 1977 23. GEEENBLATT DJ, SHADER RI, KocH-
WESER J: Flurazepam hydrochloride, a benzodiazepine hypnotic. Ann intern Med 83: 237, 1975 24. GREENBLATT DJ, ALLEN MD, SHADER
RI: Toxicity of high-dose flurazepam in the elderly. Clin Pharmacol Ther 21: 355, 1977 25. MACLEOD SM, GILES HG, BENGERT
B, et al: The influence of age and sex on diazepam (D) pharmacokinetics (abstr). Clin Res 25: 676A, 1977 26. KLoTz
U,
AVANT
GR,
KOYUMPA
A, et al: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. I Clin invest 55: 347, 1975 27. STANSKI DR, GREENBLATT DJ, SEL-
WYN A, et al: Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its inetabolites in surgical patients. Clin Pharmacol Ther 20: 571, 1976 28. GILES HG, MACLEOD SM, WRIGHT JR,
et al: Influence of age and previous use on .Iiazepam dosage required for endoscopy. Can Med Assoc 1 118: 513, 1978
29. CASTLEDEN CM, GEORGE CF, MARCER
D, et al: Increased sensitivity to nitrazepam in old age. Br Med 1 1: 10, 1977
30. HOLLISTER LE, MOTZENBECKER FP,
DEGAN RO: Withdrawal reactions from chlordiazepoxide ("Librium"). Psychopharmacologia 2: 63, 1961
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31. PRESKORN SH, DENNER U: Benzo-
diazepines and withdrawal psychosis. JAMA 237: 36, 1977 32. WILLETrE RE (ed): Drugs and Driving, NIDA research monograph, ser 11, Dept of Health, Education and Welfare, Public Health Service, alcohol, drug abuse, and mental health administration, Washington, 1977 33. MACLEOD SM, GILES HG, PATZALEK G, et al: Diazepam actions and plasma concentrations following ethanol ingestion. Eur J Clin Pharmacol 11: 345, 1977
.
t
34. GREENBLATr DJ, KOCH-WESER J: Ad-
verse reactions to intravenous diazepam: a report from the Boston Collaborative Drug Surveillance Program. Am J Med Sci 266: 261, 1973 35. MACLEOD SM, SELLERS EM, KAPLAN
H, et al: Drug analysis in management of drug overdose (abstr). Ann R Coil Phys Surg Can 9: 57, 1976 36. GREENBLATT DJ, ALLEN MD, NOEL
BJ, et al: Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther 21: 497, 1977
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Dosage: Apply one hour before exposure to the sun Reapply after swiminirie Contraindications: Not to be used b. nd duals serrsitioe to PABA Senior sire sulfonamides, or anil'rre dyes Supphed Earh 13 rilano 20Cm oxsvbottyPheSur Lotion and 85 g arid 140 g tube of Prehuri Qyl cnntar1s 5< tiara anrinnberznK hull Prescribng Info matins Ava lattle on Reouest
1538 CMA JOURNAL/JUNE 24, 1978/VOL. 118
BOOKS continued from page 1530 FOUNDATIONS OF MEDICINE: A Students Guide. Edited by Ronald Raven. 357 pp. IlIust. William Heinemann Medical Books Ltd., London, 1978. Price not stated. ISBN 0-433-27282-1 FRACTURES ETAGEES DU MEMBRE lNF.RIEUR, RACHIS, HANCHE. R. Judet, Ph. Blazy, J. Beneux et I'autres. 186 pp. Illust. Masson, Paris, 1978. $37.25, broch.. ISBN 2-225-49401-0 HEPATOTROPHIC FACTORS. Ciba Foundation Symposium 55 (new series). 405 pp. Illust. Elsevier/Excerpta Medical North-Holland, Amsterdam; Excerpta Medica, Amsterdam, 1978. $36. ISBN 0-444-90018-7 HORIZONS IN BIOCHEMISTRY AND BIOPHYSICS. Vol 4. Edited by E. Quagliariello, F. Palmieri and Thomas P. Singer. 302 pp. Illust. Addison-Wesley Publishing Company, Reading, 1977. $19.50. ISSN 0096-2708 IMMUNE EFFECTOR MECHANISMS IN DISEASE. Proceedings of the 4th Irwin Strasburger Memorial Seminar on Immunology. Edited by Marc E. Weksler, Stephen D. Litwin, Robert R. Tlggio and others. 241 pp. IlIust. Grune & Stratton, Inc., New York; Longman Canada Limited, Don Mills, 1977. $15.95. ISBN 0-80891069-8 INFECTIVE ENDOCARDITIS. Edited by Shahbucfln H. Rahimtoola. 386 pp. IlIust. Grune & Stratton, Inc., New York, 1978. $39.40. ISBN 0-8089-1052-3 PUBLIC EDUCATION ABOUT CANCER. Recent Research and Current Programmes. A Seventh Series of Papers. UICC Technical Report Series - Vol. 26. Edited by John Wakefield. 108 pp. lIlust. International Union Against Cancer, Geneva, 1977. PrIce not stated, paperbound
