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Brian F. Hoffman Gerald Shugar : Uses and Abuses SUMMARY SOMMAIRE Anxiety is ubiquitous in our society. L'anxiete est omnipresente dans notre societe. Bien Although non-drug treatments should qu'on devrait toujours faire usage de therapies non-m6dicamenteuses, les benzodiazepines sont des always be used, benzodiazepines are the medicaments de choix lorsqu'une medication est drugs of choice when drugs are indicated. indiquee. Dans des etudes a double insu, les In double blind studies the benzodiazepines benzodiazepines sont superieures aux placebo pour are superior to placebo in controlling acute controler l'anxiete aigue et la suractivite dans les anxiety and autonomic over-activity in desordres psychosomatiques. Elles sont aussi utiles pour une variete d'autres etats tels que le traitement psychosomatic disorders. They are also ou la prevention des spasmes et douleurs useful in a variety of other conditions such musculaires, le status epilepticus, le syndrome de as the treatment or prevention of muscle sevrage medicamenteux, les desordres du sommeil spasms and pain, status epilepticus, drug de stade 4 et l'akathisie. Toutefois, les withdrawal, stage 4 sleep disorders and benzodiazepines comportent de nombreux effets akathisia. secondaires, occasionnent les syndromes de However, benzodiazepines have tolerance, de dependance et de retrait et on devrait many side effects, produce tolerance, en faire un usage prudent. I1 n'y a pas d'evidence dependence and withdrawal syndromes que les benzodiazepines soient utiles dans le and should be used cautiously. There is no traitement de l'anxiet6 chronique. Les medicaments evidence that benzodiazepines are useful in a courte dur6e d'action sont plus su'rs pour les chronic The are personnes agees et celles souffrant de maladie anxiety. short-acting drugs hepatique ou d'hypoalbuminemie. Des prescriptions safer with elderly patients and those with de petites quantites de benzodiazepines devraient hepatic disease or hypoalbuminemia. Small etre faites pour une peiode la plus courte possible. amounts of prescription benzodiazepines On devrait augmenter le nombre de programmes should be used for the shortest possible educationnels concernant l'usage approprie des period. Educational programs concerning benzodiazepines. the proper use of benzodiazepines should be increased. (Can Fam Physician 1982; 28:1630-1639).

Dr. Hoffman is a staff THE EFFICACY and ethics of patient for being too demanding and psychiatrist at the Clarke Institute using minor tranquilizers are fre- the pharmaceutical industry for exces- of Psychiatry and an assistant quently debated in our society. Two sive advertising. 3 4 professor of medicine at the opposite points of view emerge. The In the 'liberal' view, a person in this University of Toronto. Dr. Shugar 'conservative-stoic' view is that anxi- highly complex, technological, anxi- is chief of in-patient services at the ety is normal and must be coped with; ety-provoking society has the right to Clarke Institute of Psychiatry and the person who resorts to using benzo- use any available methods to cope with an associate professor of medicine diazepines is weak in character and the his individual stresses.: The benzodia- at the University of Toronto. use of such pills will decrease his will- zepines are the least of several evils- Reprint requests to: Dr. B. F. power, motivation and problem- they are less dangerous than incapaci- Hoffman, Cla,rke Institute of solving abilities. 1 2 This viewpoint tating anxiety, alcoholism or other Psychiatry, 250 College Street, blames the overuse of these drugs on addictions. Toronto, ON. M5T 1R8. the physician for over-prescribing, the These two extreme views ignore a

1630 CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 rational approach based on knowing respiratory, digestive, skin, etc.) or pro- who takes benzodiazepines and why, (46%) duces more rapid and reliable clinical for what conditions, with what effi- Patients with physical disorders are effects than IM injections of the same cacy and with what dangers. It is im- given benzodiazepines as frequently, dose. IM administration results in de- portant to know how these drugs work, even though the basic indications for layed and incomplete absorption of what alternative coping mechanisms prescribing these drugs are the preven- chlordiazepoxide and diazepam, as and treatments are available and how tion or alleviation of psychic and emo- well as delayed appearance of their ac- the decision to use medication is tional distress. 6' 10 tive desmethyl metabolites, because reached. The stereotyped image of the benzo- the drug crystallizes in muscles. El- diazepine abuser is a pill-popping, derly patients and those with hepatic bored, middle-class, self-indulgent, disease metabolize these drugs more Extent of Use young suburban housewife. In fact, slowly and are more likely to have side abusers are most effects or toxicity. They should there- Over 10% of adult Canadians and frequently middle-aged housewives fore receive only half of the usual Americans take benzodiazepines by (working outside the home or not) dose. Some of the long-acting benzo- prescription in any one year.5 This is from the lowest socioeconomic stra- diazepines (e.g., diazepam) are similar to rates in Europe, although tum with less than grade school educa- quickly absorbed and highly lipid solu- France and Belgium have even higher tion, trying to cope with many real bi- ble so that they have a rapid onset of rates.3 The use of minor tranquilizers ological, psychological and socio- action. They may be useful is more common than the total use of cultural problems.3 in the short term. all other psychotropic medications, in- Conversion of the short-acting drugs cluding and antipsy- Pharmacological Action by conjugation to an inactive glu- chotics. Diazepam is probably the curonide is extrahepatic and is not most commonly used drug in the west- All the benzodiazepines are similar decreased by age or liver dis- ern world. in structure and pharmacological ac- ease. 2 8, 12, 13 Therefore, cumulative Females take these drugs twice as tion. Although differences in their me- effects during prolonged therapy are frequently as males (20% versus tabolism include absorption, distribu- much less significant than with the 8%). 3, 6 We do not know whether this tion, degradation and excretion, these long-acting drugs. If the short-acting is due to role stereotyping, the nature must be interpreted cautiously because drugs are used as daytime anxiolytics, of the relationship between female pa- of high variation in individuals' me- divided doses (at least bid) are re- tients and male physicians, or the bio- tabolism and sensitivity to the clinical quired. Maximum effects are reached logical concomitants of being female effects of benzodiazepines. For in- within a few days and residual effects (menstrual cycle, pregnancy, child- stance, the dose of diazepam required terminate quickly. birth, and menopause). Probably for relaxation for gastroscopy may males more frequently employ other vary 22-fold.2 Nevertheless, rational Neurotransmitters remedies for anxiety, including the use use of the benzodiazepines does re- of and marijuana. quire some knowledge of the various The effects of the benzodiazepines Similarly, the elderly receive a dis- compounds' pharmacokinetics. are mediated by several distinct mech- proportionate number of prescriptions The benzodiazepines can be divided anisms. 1416 The neurotransmitters that for benzodiazepines.5 7 They are more into two groups based on the half-lives have been implicated include norepin- likely to have difficulty metabolizing of parent compounds and their active ephrine, serotonin, GABA and gly- the long-acting benzodiazepines and metabolites: the long-acting and the cine. Specific benzodiazepine recep- are therefore more likely to have un- short-acting groups.2' 5, 8, 11-13 (See tors have been identified in human wanted side effects and toxicity.2' 8, 9 Table 1.) brain tissue, 17 suggesting that there They are also more likely to be taking may be specific benzodiazepine-like TABLE 1 molecules in the brain whose activity other drugs and to suffer from complex Half Lives (Hours) of drug regimens and interactions. Al- Benzodiazepines Marketed in Canada produces an endogenous anxiolytic ef- though the depressive syndromes are fect. more prevalent in this age group, anti- Long-Acting Drugs Short-Acting Drugs Stimulation of the benzodiazepine' receptors enhances the effects of depressants are as underused as tran- 50-100 5-20 quilizers are overused.4 40-100 10-15 GABA, the principal inhibiting neuro- Most prescriptions for benzodiaze- Diazepam 20-50 2- 5 transmitter. 8 14 The resulting depolari- pines are written by family physicians Chlordiazepoxide zation and decreased production of 5-30 8-10 norepinephrine and serotonin cause se- and internists.3' 6 Ofpatients who have Nitrazolam 18-28 10-15 used a psychotherapeutic drug, 85% 30-50 6-20 dation and anti-anxiety effects by de- have never seen a psychiatrist. A na- 18-50 creasing electrical activity in'the pun- tional survey3 showed that benzodia- ishment and inhibitory areas of the zepines were prescribed for the follow- The long-acting drugs accumulate brain. Diazepam is also a glycine re- ing diagnoses: when taken daily. They are converted ceptor stimulator; because glycine nor- 1. Mental disorder (anxiety, depres- in the liver to active metabolites, mally inhibits motor neurones, diaze- sion etc.) (37%) which also have long half-lives. There pam functions as a . 2. Senility and related symptoms may be excessive sedation the next (17%) morning or several days later, even on Uses of Benzodiazepines 3. Physical disorders (circulatory, a fixed dose. Oral administration of In animals, these drugs cause disin- 1632 CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 hibition, and an increase in spontane- tried. These treatments include reas- of seizure activity originating from a ous and exploratory activity.8 They surance, ventilation, exploration of the focus. It has a similar molecular con- suppress operant avoidance behavior symbolic meanings of stressors, prob- figuration to diphenylhydantoin and and restore behavior suppressed by lem solving, relaxation training, may interact with similar receptor sites punishment. 15' 18 They attenuate the socialization, and desensitization.19 If in the CNS.8 appears to effects of stress and frustration, and acute anxiety is severe or if chronic have more antiepileptic activity and decrease aggression and hostility. In anxiety presents with marked flare- has been used prophylactically with humans, the benzodiazepines appear ups, then benzodiazepines may be use- grand-mal seizures and infantile to influence these same behaviors, re- ful for a short and strictly-enforced spasms. Clonazepam21 is used in the ducing acute anxiety and accompany- period of time (two to four weeks). treatment of absence seizures refrac- ing inhibition. PRN use to a daily limit may be prefer- tory to ethosuximide or valproic acid, able to a fixed dosage schedule when and in seizure disorders associated In Anxiety symptom severity varies. with myoclonus. The benzodiazepines have a wide In Depression In-Alcohol Withdrawal variety of uses8 (see Table 2). They are more effective than The depressive syndrome includes a Benzodiazepines are also widely and in controlling anxi- dysphoric mood, loss of appetite and used to attentuate alcohol withdrawal ety with less sedation and other central weight, loss of sleep with early morn- states, especially delirium tremens. nervous system side effects. They are ing awakening, and a diurnal variation Although they do decrease severe less prone to abuse and addiction, less in which a patient feels worse in the withdrawal complications they do not dangerous in overdose, and cause less morning and better as the day pro- alter the subsequent drinking pattern. microsomal enzyme indiction in the gresses. The treatment of choice is an Alcoholics often tend to abuse these liver, so that there are fewer drug in- adequate trial of antidepressants, al- drugs and run the risk of a double ad- teractions. though minor tranquilizers may be diction. useful if agitation is also present. The benzodiazepines are not useful in schi- In Sleep Disorders TABLE 2 zophrenic decompensations, although Benzodiazepines do decrease Stage Uses of Benzodiazepines they are useful in the acute psychoses 4 sleep and are useful in treating som- caused by hallucinogens. Sometimes nambulism, enuresis and night terrors, 1. Neurotic anxiety the antidepressants cause restlessness which are Stage 4 disorders. Their use 2. Agitated depression or agitation as a side effect during the in simple insomnia is more controver- 3. Side effects from antidepressants treatment of some- and neuroleptics depression and, sial, because tolerance to their hyp- 4. Hallucinogenic psychosis what more frequently, the neuroleptics notic effect occurs quickly (less than 5. Neuromuscular diseases cause akathisia, which is an extrapyra- one week).8 6. Seizures midal side effect. The benzodiazepines The benzodiazepines decrease REM -status epilepticus be useful for these -other may symptoms.2" sleep or dreaming less than other hyp- 7. Alcohol withdrawal notics such as barbiturates, glutethi- 8. Sleep disturbances In Neuromuscular Conditions mide, methylprylon and possibly -stage 4 disorders The benzodiazepines facilitate the hydrate.8 The subjective un- -? insomnia 9. Anesthesia and surgery action of brain stem inhibitory inter- pleasantness of REM sleep and dream 10. Psychosomatic disorders (with neurones, with less effect on the spinal rebound does not occur when benzo- primary/secondary anxiety) cord, and this causes muscle relaxation diazepines are withdrawn, although re- which may be beneficial in neuromus- bound insomnia is reported. The cular conditions (see Table 3). danger of drug dependence is Anxiety attacks have a short dura- less than with barbiturates. tion and therefore patients will fre- TABLE 3 As hypnotics, the short-acting ben- quently have a spontaneous remis- Musculoskeletal Disorders That zodiazepines are superior to the long- sion.4 In addition, anxious patients Benefit from Benzodlazepines acting drugs because they do not accu- will respond to a placebo 50% of the Cerebral palsy mulate as much, thereby lessening time.4 Because of this, a practitioner Multiple sclerosis daytime sedation, cognitive and motor who prescribes anxiolytics after an ini- Parkinsonism impairment or toxicity. However, the tial assessment may be misled by the Amyotrophic lateral sclerosis short-acting benzodiazepines may in- positive response that many patients Cerebral vascular accidents crease the incidence of rebound insom- report. Nevertheless, these drugs have Traumatic spinal cord lesions nia and withdrawal symptoms. Al- proven more effective than placebo in Disc disease though benzodiazepines are effective double blind trials with non-psychotic Muscle strains and sprains in acute situational insomnia (e.g., jet anxious patients. 8' 11 lag, grief reaction or hospitalization), In recurrent panic disorders, the tri- they should not be routinely used, cyclic antidepressants are generally In Seizure Disorders especially where reassurance, support, more useful. Acute anxiety attacks While diazepam is extremely useful relaxation, and exploration of personal tend to be self-limiting and if the se- in status epilepticus, it is less useful in difficulties are likely to be effective. verity is mild or moderate, non-phar- seizure prophylaxis. Diazepam inhib- Severe insomnia may require investi- macological treatments should be its the propagation and generalization gation at a sleep laboratory. CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 1633 In Anesthesia and Analgesia serum albumen). Residual daytime se- EKfhIeOX cephalexin The benzodiazepines have a number dation and mild cognitive impairment are more likely to occur with the long- DESCRIPTION: Keflex is a semisynthetic cephalosporin antibiotic of applications in anesthesia, labor and intended for oral administration It is I(D a amino a phenylaceta acting drugs. mido) 3 methyl 3 cephem 4-carboxylic acid monohydrate are used in ACTION: Cephalexin is bactericidal against many gram positive and surgery.' They endoscopy Psychological effects occasionally gram negative organisms In vitro tests demonstrate that the cephalo and before general anesthesia or car- sporins are bactericidal through their inhibition of cell wall synthesis dioversion. They increase analgesia, occur and include sleep disturbances INDICATIONS: Keflex may be indicated in the treatment of bacterial such as rebound insomnia24 hypnago- infections of the respiratory tract, including otitis media, genitourinary decrease opiate requirements and en- tract, bones and .oints, skin and soft tissue when the infection is gic hallucinations and nightmares. caused by susceptible organisms hance subjective amnesia. The usual CONTRAINDICATIONS: Keflex is contraindicated in patients with Acute depression and suicidal ideation known allergy to the cephalosporin group of antibiotics clinical doses given before delivery PRECAUTIONS: Antibiotics, including Keflex. should be administered are reported. Paradoxical rage reac- cautiously to any patient who has demonstrated some form of allergy, cause no important adverse effects particularly to drugs upon the neonate. However, in high tions may occur, particularly in those in penicillin allergic patients. cephalosporin antibiotics should be whose anger is kept in check by their used with caution There is some evidence of partial cross allergenicity doses they have been associated with of the penicillins and the cephalosporins Of 7,450 clinical trial anxiety, who are frustrated by their en- patients, 291 had histories of penicillin allergy Nineteen of them prolonged neonatal lethargy, hypo- (about 6 5 percent) were among those in whom possible allergic vironment or who have a history of reactions to cephalexin were observed tonia, hypothermia and respiratory de- Patients should be followed carefully so that any side effects or outbursts and impulsiveness. 8 9 unusual manifestations of drug idiosyncrasy may be detected. If an pression. In anesthesia, surgery and allergic reaction to Keflex occurs, the drug should be discontinued and With intravenous diazepam, occa- the patient treated with the usual agents (e g epinephrine or other labor, the short-acting drugs should be pressor amines. . or corticosteroids) sional pain or phlebitis will occur at Prolonged use of Keflex may result in overgrowth of non-suscep used more commonly. tible organisms Careful observation of the patient is essential If the injection site. Life-threatening ad- superinfection occurs during therapy, appropriate measures should be verse reactions, including respiratory taken Keflex should be administered with caution in the presence of In Psychosomatic Disor-ders depression and cardiac arrest, occur in markedly impaired renal function Under such conditions, careful clinical observation and laboratory studies should be made because The benzodiazepines are frequently 1.7% of patients after IV diazepam, safe dosage may be lower than that usually recommended If Keflex is to be used for long term therapy. periodic monitoring of used in organic or psychosomatic dis- especially if severe pulmonary or car- hematology, renal and hepatic functions should be donie Indicated surgical procedures should be pedormed in conjunction with antibiotic orders in which anxiety is believed to diovascular disease exists. IV diaze- therapy. e g the incision and drainage of abscesses Safety of this product for use during pregnancy has not been have a precitipating or exacerbating pam should be given slowly (less than established 2.5 mg/min.)9 and only in settings Positive direct Coombs tests have been reported during treatment role.'3 Lasagna"i and Ayd22 reviewed with the cephalosporin antibiotics In hematologic studies or in trans where cardiopulmonary support sys- fusion cross matching procedures when antiglobulin tests are per the literature on the effects of benzo- formed on the minor side or in Coombs testing of newborns whose diazepines on psychosomatic illnesses. tems are available. mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs test may be due to the They reported that lorazepam de- drug Drug abuse and addiction have been In patients being treated with Keflex, a false positive reaction for creased anxiety, hypertension and gas- glucose in the urine may occur with Benedict's or Fehling's solutions reported. Any benzodiazepine can be or with Clinitest tablets. but not with Tes Tape trointestinal complaints, including ADVERSE REACTIONS: Gastro-intestinal-Diarrhea has been reported aerophagy, irritable colon and nervous abused and produce physiological ad- in only 15 percent of 7,450 clinical trial patients. It was very rarely diction if large doses are taken over a severe enough to warrant cessation of therapy Nausea. vomiting, dyspepsia. Diazepam resulted in de- dyspepsia and abdominal pain have also occured. long period of time. This danger is Hypersensitivity-Allergies (in the form of rash, urticaria and angio creased gastric secretion when patients edema) have been observed These reactions usually subsided upon much less than with other drugs.' Al- discontinuation of the drug with duodenal ulcer and dyspepsia Other reactions have included genital and anal pruritus, genital though addiction is rare, withdrawal moniliasis, vaginitis and vaginal discharge. dizziness, fatigue, and were stimulated by pentagastrin."' headache Eosinophilia. leucopenia due to neutropenia. and slight Chlordiazepoxide resulted in less nar- effects have been reported including elevations in SGOT and SGPT have been reported anxiety, tremor, insomnia, nausea and SYMPTOMS AND TREATMENT OF OVERDOSAGE: No information is cotic use in the first 24 hours on a available on the treatment of overdose with Keflex There is no vomiting. These symptoms occur three specific antidote coronary care unit than . In MICROBIOLOGY: Keflex is active agairist the following organisms in to ten days after withdrawal of long- vitro the treatment of essential hyperten- Beta hemolytic and other streptococci (many strains of entero- sion, Lasagna speculates that benzo- acting benzodiazepines and within 24 cocci. e g Streptococcus faecalis, are resistant) of Staphylococci including coagulase positive. coagulase negative, diazepines may be more useful than hours 'withdrawing short-acting and penicillinase producing strans (a few strains of staphylococci are They are rare when short resistant to cephalexin) and antihypertensive drugs.24 Diplococcus pneumoniae Heniophilus influenzoe courses are given at recommended Escherichia coli Proteus riirabilis drugs, which result in significant side Klebsiella pneunioniae Neisseria catarrhalis therapeutic dosage. These symptoms, Keflex is not active against most strains of Enterobacter sp Pr, effects and non-compliance. In coron- morganii, and Pr vulgaris It has no activity against Pseudomonas or whether psychological or physiologi- Herellea species When tested by in vitro methods, staphylococci ary artery disease, benzodiazepines exhibit cross resistance between Keflex and methicillin type may be useful in allaying anxiety and cal in origin, may falsely convince the antibiotics patient or doctor of the need for con- DOSAGE AND ADMINISTRATION: Keflex is admrinistered orally The autonomic overactivity. They may de- adult dosage ranges from 1 to 4 g daily in divided doses The usual tinuing medication. Those patients adult dose is 250 mg every siX hours For niore severe infections or crease the incidence of arrythmias and those caused by less susceptible organisms. larger doses may be motivated to discontinue the drug needed If daily doses of Keflex greater than 4 g are required. sudden death in coronary care units. parenteral cephalosporins, in appropriate doses should be considered should be encouraged. The recorimended daily dosage for children is 25 to 50 mg per kg Successful withdrawal can be ac- divided into four doses Kelfex Suspension _ complished by dividing the total daily Child's Weight 125 mg,5 ml 250 mg 5 ml Unwanted Effects 10kgl(22lb) 'to ltsp qid dose into four spaced administrations. 2Okg(441lb Ito2tsp qid ' to tsp qid And Hazards This interrupts the usual pattern of 40kg(881lb 2to4tsp qid Ito2tsp qid In severe infections, the dosage may be doubled Neurological effects2 8 23 include drug-taking immediately before antici- In the therapy of otitis media, clinical studies have shown that a dosage of 75 to 100 mg per kg per day in four divided doses is depression, fatigue, drowsiness, som- pated stresses. Successive reductions required In the treatment of beta hemolytic streptococcal infections, antibi nolence, muscle weakness, nys- of 2-5 mg (in diazepam equivalents) otic therapy should be administered for at least ten days To obtain mraximum peak levels, cephalexin should be administered tagmus, and dysarthria. These effects each can be made at the administration ui an empty stomach are and are more time chosen by the patient. Each re- DOSAGE FORMS: dose-dependent Tablets Keller equivalent to 250 mg cephalerin (No 10941. Identi likely to occur in the elderly, and in duction may be followed by several Code 057 are supplied In boDIles of 100 and 500 Tablets Keller ertuivalent to 500 rng cephalerin (No 10951 Identi those with low serum albumen. Seda- days of mild anxiety and physiological Code 009 are supplied In boDtles sf 100 and 250 Keller for Oral Suspension, equivalent to 125 mg cephalerin per tion occurs in 3%c of patients (9%T if arousal. When this settles, the patient 5 ml teaspooniful. IS supplied In a 100 ml size package INn M 2011. Identi Code W21 the serum albumen is low, since ben- is ready for the next reduction. Expla- Keller for Oral Suspension, equivalent to 250 mg cephalerin per nirl teaspoonful. IS supplied In a 100 ml size package INn M 2021. zodiazepines are normally bound to nation of the pharmacology and physi- Identi Code W6O 1634 CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 ology of drug withdrawal is extremely useful and supportive. Of overdosed patients presenting at an emergency department, 31% have taken benzodiazepines.2 These are rarely fatal unless combined with other drugs. The benzodiazepines potentiate the and lethal effects of alco- hol and other CNS depressants, and this combination, if abused, may inter- fere with cognitive, intellectual and psychomotor functioning. Dependence on benzodiazepines is more likely to occur with alcoholics, even if their drinking pattern doesn't change. On the other hand, caffeine or caf- feine-containing beverages may coun- teract the effects of the benzodiaze- pines, 26 so that the patient continues NOW AN APMR taking a minor tranquilizer or increases the dose unnecessarily. Benzodiazepines are not well ab- MAY HAVE COMPLETED sorbed in the presence of antacids, achlorhydria, or anticholinergic drugs. Diazepam is a highly lipid soluble POSTGRADUATE agent and should not be given with mineral oil, which will prevent its ab- sorption. STUDIES Benzodiazepines are not entirely safe during pregnancy or the postnatal period. They have been associated, if AS WELL used in the first trimester, with cleft lips and palates.25 High doses at deliv- APMR continuingeducation programs are designed to upgrade the ery may produce the 'floppy infant' syndrome, characterized by apnea, hy- professional competence of phannaceutical representatives and potonia, poor sucking, risk of aspira- enhance their value to you as a primary source of information. In tion and hypothermia.2 Diazepam and other benzodiazepines readily cross 1979, an important new step toward this objective was taken by the the placenta and reach higher concen- Council. To supplement the basic one year Accreditation course trations in the fetal circulation than in and final a new APMR maternal blood. They are also excreted rigorous examination, postgraduate in breast milk.22 program was established to provide for advanced study in specific fields of therapy, e.g. Dnrgs Affecting Cardiovascular And Renal Functions, Infectious Disease And Its Therapy. Conclusions We believe that APMR programs and objectives are to Benzodiazepines are more effective important and safer than barbiturates, meproba- you as a health professional. When you talk to an APMR, we think mate or alcohol. In double-blind trials you'll notice the difference. they have been shown to be superior to placebo in treating acute anxiety, in controlling anxiety and sympathetic over-activity in psychosomatic dis- orders and in treating muscble spasms from many causes.4' 8, 11 However, the routine treatment of anxiety should involve other ap- Council for the Accreditation of proaches before the prescription of Pharmaceutical Manufacturers Representatives of Canada. benzodiazepines. In acute anxiety of mild or moderate severity, supportive psychotherapy, environmental manip- ulation or relaxation training may be preferred treatment.19 In severe acute anxiety, benzodiazepines may be use-

1636 CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 ACTIVE DUODENAL ULCER, NON-MALIGNANT GASTRIC ULCER, ful for a short period of time-less GASTROESOPHAGEAL REFLUX DISEASE than four weeks. In chronic anxiety of Tagamels 600 mg twice a day (at breakfast and bedtime) or 300 mg four times a day (with meals and at moderate or severe intensity, benzo- bedtime). Therapy for duodenal ulcer should continue for at least 4 weeks; for gastric ulcer diazepines show no superiority over PHARMACOLOGICAL CLASSIFICATION 6 weeks; for reflux disease 8-12 weeks. placebo. Continuous use should be Histamine H2-Receptor Antagonist Prophylaxis of Recurrent Duodenal Ulcer: ACTION 400 mg at bedtime or 300 mg twice a day, avoided; medication should be re- Cimetidine competitively inhibits the action at breakfast and bedtime. Therapy should served for prn use in acute or intolera- of histamine at the histamine H -receptor. It continue for at least 6-12 months. inhibits daytime and nocturnal Basal gastric UPPER GASTROINTESTINAL HEMORRHAGE ble flare-ups. Often the mere availabil- acid secretion and also gastric acid secretion If bleeding is of sufficient magnitude as to ity of medication is sufficient stimulated by food, histamine, pentagastrin, require blood transfusions, 'Tagamet' should caffeine and insulin. Total pepsin output is be administered parenterally, preferably by reassurance to make this use unneces- reduced as a result of the decrease in volume intravenous or intermittent infusion, until 48 of gastric juice. Cimetidine has no effect on the hours after active bleeding has stopped. Oral sary. Consultation with a psychiatrist rate of gastric emptying or lower esophageal administration may then be instituted. or therapist should be considered, par- sphincter pressure. Oral: 600 mg twice a day (at breakfast and bed- INDICATIONS time) or 300 mg every 6 hours. ticularly before committing any patient *Duodenal ulcer and prophylaxis of recurrent Intramuscular Injection: 300 mg every 6 hours. to continuous longterm drug use. duodenal ulcer Intravenous Injection: 300 mg every 6 hours. *Non-malignant gastric ulcer Dilute 'Tagamet' in Sodium Chloride Injection Benzodiazepines should be used *Gastroesophageal reflux disease 0.9% (or other compatible i.v. solution) to a total 'Management of upper gastrointestinal volume of 20 mL; inject slowly over at least cautiously in all age groups and should hemorrhage 2 minutes. Avoid this method in patients with be used less frequently with increasing *Pathological hypersecretion associated with cardiovascular disease. Zollinger-Ellison Syndrome, systemic Intermittent intravenous infusion: 300 mg every age. Short-acting benzodiazepines are mastocytosis and multiple endocrine 6 hours. Dilute 'Tagamet' in 100 mL of Dextrose preferable to long-acting ones in all adenomas. Injection 5% (or other compatible i.v. solution); 'Prophylaxis of stress ulceration infuse over 15-20 minutes. If necessary, age groups, especially the elderly. Pa- *Prophylaxis of acid aspiration pneumonitis increases should be made by more frequent tients over 65 should be given half the CONTRAINDICATIONS administration of a 300 mg dose; total daily None known. dose should not exceed 2400 mg. usual daily dose.2' 5. 13 Long-acting cu- PRECAUTIONS PATHOLOGICAL HYPERSECRETORY mulative drugs should be reserved for Use in Pregnancy, Nursing Mothers: Exper- CONDMONS (e.g., Zollinger-Ellison Syndrome) ience in pregnant patients is limited. Animal 300 mg four times a day, with meals and at bed- conditions where daytime sedation is studies have revealed no evidence of impaired time. It may be necessary to administer higher acceptable, e.g., acute alcohol with- fertility or harm to the fetus. 'Tagamet' crosses or more frequent doses to control symptoms. If the placental barrier. It is secreted in human intravenous administration is required, refer to drawal or brief applications requiring a milk. Anticipated benefits should be weighed schedule under UPPER GASTROINTESTINAL combination of night-time hypnotic against potential risks. 'Tagamet' has been HEMORRHAGE. used in clinical trials for the prevention of acid PROPHYLAXIS OF STRESS ULCERATION and daytime anxiolytic given in a sin- aspiration pneumonitis in women undergoing 300 mg intravenously every 6 hours, or more cesarean section or vaginal delivery without frequently to maintain a gastric pH above 4. gle bedtime dose. harm to the fetus. (See Intravenous administration above.) Longterm use of these drugs (for Use in Children: In limited experience, 20- PROPHYLAXIS OF ACID ASPIRATION 40 mg/kg/day has been administered in PNEUMONITIS more than one month) is of minimal or divided doses by mouth or intravenously. Emergency surgery: 300 mg intramuscularly 1 Anticipated benefits should be weighed hour before induction of anesthesia and 300 mg no pharmacological benefit and should against potential risks. intramuscularly or intravenously every 4 hours be discouraged. A small percentage of Use in Impaired Renal Function: A reduced untilpatientrespondstoverbalcommands. dosage should be administered to patients with Elective surgery: As above, but an oral dose of users (10-13%) refuse to stop, de- impaired renal function. (See DOSAGE AND 300 mg may be given the night before the crease or change their use of benzodia- ADMINISTRATION.) operation. Drug Interactions: 'Tagamet' may reduce the Forintravenousadministrationrefertoschedule zepines. Most of these patients have hepatic metabolism of warfarin-type anti- under UPPER GASTROINTESTINAL HEMOR- been using the drug for years. Having coagulants, , propranolol, chlor- RHAGE. diazepoxide, diazepam and theophylline, DOSAGE ADJUSTMENT FOR PATIENTS them stop these drugs may do them thereby causing increased blood levels of WITH IMPAIRED RENAL FUNCTION more harm than good.5 these drugs. Benzodiazepines metabolized 300 mg every 12 hours orally or intravenously. by other systems do not exhibit this effect. If required, frequency of dosing may be Continuing medical education pro- Since clinically significant effects have been increased to every 8 hours or further with reported with warfarin anticoagulants, close caution. In severe renal failure the lowest grams on the use of minor tranquilizers monitoring of prothrombin time is recom- frequency of dosing compatible with an ade- could also be improved. Education of mended, and adjustment of anticoagulant dose quate patient response should be used. Liver may be necessary. impairment may necessitate further reductions. family physicians in a university-based Use in Gastric Ulcer: Symptomatic response to Hemodialysis: More than 80% of a 300 mg hospital using audiovisual programs 'Tagamet' does not preclude the presence of a intravenous dose is cleared in one 4 hour gastric malignancy. period of hemodialysis. If possible, adjust and feedback has been shown to im- Rapid Intravenous Injection: Rare cases of car- dosage schedule to coincide with end of in a con- diac arrhythmias and hypotension have been hemodialysis. prove prescription patterns; reported following the rapid administration Peritoneal dialysis: 'Tagamet' is not removed to trolled study it was shown to be more of 'Tagamet' Injection by intravenous bolus. any appreciable extent. (See DOSAGE AND ADMINISTRATION.) STABIIITYOFINJECTABLEFORM effective than giving simple guide- ADVERSE REACTIONS 'Tagamet' Injection, when added to or diluted lines.5 Each physician who practices Mild and transient diarrhea, tiredness, dizzi- with most intravenous solutions, is stable for 48 a receive a com- ness and rash have occurred in a small hoursatroomtemperature. within hospital could number of patients. A few patients have 'TagaMet' Injection should not be refrigerated. puter-generated profile of his or her developed mild, reversible gynecomastia AVAILABILITY the during prolonged treatment. A few cases of Tlblets: 200, 300, 400 and 600 mg cimetidine. prescribing pattern compared with the following have been reported: decreased Liquid: Cimetidine hydrochloride equivalent to patterns of other physicians. Audits or white blood cell counts (including agranulo- 300 mg cimetidine per 5 mL. (Alcohol content cytosis), thrombocytopenia, aplastic anemia; 2.85% v/v.) rounds should be conducted to discuss reversible confusional states, usually in Injection: Cimetidine hydrochloride equiva- elderly and/or severely ill patients with renal lent to 300 mg cimetidine per 2 mL. the reasons for individual variations of insufficiency or organic brain syndrome; prescribing practices. fever; hepatitis; interstitial nephritis; pancrea- Product Monograph available to physicians titis; small increases in plasma creatinine and and pharmacists on request. In teaching hospitals, staff physi- serum transaminases. OVERDOSAGE cians should countersign orders for Oral ingestion of up to 20 grams has caused problem drugs and promote discussion no untoward effects. Recovery has been SK&F~~~~PA uneventful. about benzodiazepine prescribing. Treatment: Emesis and/or gastric lavage, aSmihleopn Some educational feedback monitoring and supportive therapy. Assisted pro- respiration may be of value. grams have not decreased the number DO5AGE AND ADMINISTRTION - ADULTS (Experience in children is limited - see PRE- of prescriptions, but changed the pre- CAUJTIONS.) In clinical studies, 'Tagamet' has been used in SMITH KLINE &FRENCH CANADA LTD. CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 divided doses of up to 2400 mg per day. Mississauga, Ontario L5N 2V7 The gentle power of scribing pattern to a more desirable 9. Gottlieb RM, Nappi T, StrainIJJ: The one, including greater use of short-act- physician' s knowledge of psychotropic ing benzodiazepines, at lower doses, drulgs: Preliminaryi-esults. Aim J Psychia- try 1978; 135:29-32. f[Onisolide solution 0.025% nasal mist: for shorter periods of time.13 10. Greeniblatt DJ, Shader RI, Divoll M, et Corticosteroid Diazepam and chlordiazepoxide al: Benizodiazepines.: A summary of phar- m(lcokinetic properties. Br J Cliti Pharina- Action: FIiunisolide is a corticosterord with antr-unflammatory topical should not be given by the IM route activity on the nasal mucous membrane with minimal associated because of erratic and incomplete ab- col 1981; II.IIS-16S. systemic activity at the low spray doses administered 11. Shader RI, Greeniblatt DJ: Clinical im- Indications: RHINALAR Is indicated for treatment of perennial and sorption.2 If an IM injection is re- seasonal allergic rhonitis when tolerance to or effectiveness of plicatiotns of benzodiaZepine pharm-Iaco- conventional treatment s unsat slactory quired, lorazepam is best. In the el- Contraindications: dynamics. A m J PsvchiatrY 1977; 134:652 - Actiue or quiescent tuberculosis or untreated flngal bacterial or vIral derly, and in patients with liver disease 656. nfiectirors 2 Hypersensiti ity to the product or low serum albumen, the short-act- 12. Greeniblatt DJ, Shaidir Rl: Prazepamn 3 Children under 6 years of age ing drugs such as lorazepam or oxaze- anid lorazepam, two nlew ben-zodiazepines. Warnings: Newt Enigl J Med 1978; 299:1342-1344. Glucocorticoids may mask some signs of srifectiorl and new infections pam are preferable. nmay appear during their ose 13. Tierney MG, McLean WM: Pharmaco- 2 The safety )f RHINALAR in oregnancy has not been established Use ol kinetics of of clini- RHINALAR during the ftrst three months of pregnancy s not benzodiazepines-Lack recommended It used dLuring the second and third trimester the Alternate Solutions cal relevance: A commentarv. Mod Med expected benefits shouild be weighed against the potential hazards to the Can 1980; 35:208-2 12. letLus Lastly, further study is required to 3 In patients previously on high doses of systemic steroids withdrawal 14. Snyider SR. Ennaii SJ, Yolunig AB: Brain of steroids may cause symptoms such as tiredness, aches and pains and learn why certain populations are such mechanisms associated with therapeutic detpression In severe cases adrenal insufficiency may occur necessitat- rig a temporary resumption ol systemic steroids frequent recipients of benzodiazepine actions of benzodiazepines.- Foclus oni Precautions: neurotransmnitters. Amin J Psvchiatrv 1979; Replacement of systemic sternids withl RHINALAR should be gradLial prescriptions. Alternative solutions are and carefully monitored by toe physic an 134:662-665. 2 Although absorption stlff c ent to produce systemic effects has not needed for women, single parents, the 15. Steini L, Bellluzzi JD, Wise CD: Betuzo- been shown n clinical studies with RHINALAR Nasal Mist the potential o1 adrenal suppression sto ex sts and thrs must be considered as a elderly, the poor and the uneducated, dia-zepiiies: Behavi'ioural and nelurochemni- possibility with prolonged excessive LJsage Patients on long-term in with cal inecihaisms. Amn J Psvchiatrv therapy shoL,ld be reassessed per,odically ts) avoid unniecessary dealing anxiety and stresses 1977; ront nted se partly caused by social factors and vo- 134. 665-669. 3 S rice onset of act on may be somewhat slirwer thar topical or nral 16. Blooimi FE: Neuri-ail mechanisms of beni- sumpathornirretic arorries or airt histamines RHINALAR should be used cational and role conflicts. Ideally, for several days before evaluat ng therapy zodiazepine actions. Am J Psychiatrm 4 If benef cial effect s not evident after approximately 7 days the specific interventions must be devel- 1977; 134:669-672. patient shnould be re-evaluated It hperserrsy tv ty reactions occur dur ng therapy the drug ShIOulld b0 oped to replace the non-specific symp- 17. Mohler H, Okada T: Benzodia-zepine discontinued and appropr ate treatment should be nst tuted receptor: Demionsti-ationi in1 the cenltral nem- 6 Cort costeroid therapy carn decrease resistance to localized nfection tomatic relief that the benzodiazepines nasirpharyngeal rifections occur during therapy, aopropriate treatment offer. vous system. Science 1977; 198:849-851. shorild be instituted 18. Uhlenihutth EH: Evaluating anitiatnxiety 7 Despite the very low level of absorption Of fIlUrisol de adrnin stered ntrariasally the following must be kept 0n m nd agents in humn05s: Exrperiment(il parca- al curt costernid eflects may be enhanced r patients with digm.s. Am J Psychiatry 1977; 134:659- hypothyroidcisn and in those with cirrhosis bi n hypoprorthrormbnem a, acetylsalicyclc acid should be Lsed 661. catioulsly n conLinctiori wvvth corticosteroids References 19. Fi-iedinani DE: A swithetic capproach to Patients shouild be advised ts) nform subsequent phys c ans Of thie pr or u'se of cort costero ds 1. Makeimer DI, Davidson ST, Batlte MB, the ti-eatmnwenit of anxiety. Psychiatrv 1972; 9 Pur ng local corticosteroid therapy the possibility or atropth rcC ri s et cil: Populair attitudes antid beliefts Ololit 35:336-344. and or pharyngeal candidiasis should be kept in m nd Adverse Reactions: Sode elfects nouted w th RHINALAR have been tranquilizers. A in J PsYchiatrY 1 973; 20. Hoffman1sl BF: The diaigniosis citid treait- consistent with what one would expect n applying a topical medication 130:1246-1251. mnent of nieuiroleptic-iniduced Pacrkintsoniisitn. to an already nflamed membrane The most freqgient side effect observed was a mild transient riasal burning and stinging Occas onallv 2. Sellart-s EM: Clinical pharmacology antid Hosp Commni12l#ity PsYchiatry 1981; tOis was severe enough to warrant discontinuation of RHINALAR therapy therapeutics oj'benzodi(azepines. Cciii Med 32:110-114. Other side effects seen n patients treated with RHINALAR. n order of decreasing prevalence were nasal irritation epistaxis runny arid stuIffy AssocJ 1978; 118:1533-1538. 21. Bi-unii J: Aniti-epileptic diulgs. Mod nose, sore throat hoarseness and throat rritation Pxceptronally these 3. Parry HJ, Baiter MB, Mellinger GD, et Med Canii 1980; 35:1377-1384. may requilre discnirntinuation of therapy al: 22. Avd F. A niewi, dose Symptoms and Treatment of Overdosage: Acute overdosage has not NCationial paitterntIs of' psychotherapeuitic Lorazep(ai: low1 been reported When used at excessive doses the potential of sterold dlrulg luse. Arch Geni Psychiatry 1973; lbeiizodiazepine anxviolytic. Int Di-ug Ther etfects such as 'hypercorticism ant adrenal suJppress1or does exist 28:769-783. Newslett 1978; 13:1-7. Decreasrig the dose will abolish these m3nifestatlons Dosage and Administration: RHINALAR Nasal Mist is for admiri stra- 4. Blackwell B: Minior tranquilizers: Use, 23. Achonig MR. Bavne JRD, Gersoni LW, tion by the intranasal route only et al. of psychotic drugs for Usual Starting Dose: Adult 2 sprays leach approxomately 25 yog nto misuse or- overuse? Psychosoniatics 1975; Prescribiiig each nostril twice a day Increase to maximurn 3 tines a day needed 16:28-3 1. chronically, ill elderly patients. Can Med Children Por coildren 6 to 14 years of age one spray lapproximrately 25 5. Rosser WW. JCG Patteni et Assoc J 1978; 118:1503-1508. ug! 1nto each nostril 3 times daly Si,n)ns DW, Maintenance Dose: Alter the desired clinical effect is obtained, the (7l: Ihnproving benc-odiazepine prescribing 24. Kales A, Schaif MB, Koles JD, et ail: maintenance dose should be the smallest amoLrnt necessary to control review Rebolunid inisomniaii: A potentital hazard fol- the symptoms Some patients may be maintained on as little as nne spray inl family practice thr-ough anId edit- lapproxinately 25 ugl to each nostril per dav Patients orn long-term caitioli. Canii Med Assoc J 1981; 124:147- lowing withdrawal of certain benizodiaize- therapy shourld be reassessed per odically to aoicd unnecessary 153. pinies. JAMA 1979; 24 1:1692-1695. continLued use there is no euidence that exceeding the maximum recorTmerided dosage s more eflectlie Therefore, maximuim dalay dose 6. Laisaigna(i L: The role of benzodiazepines 25. LaiPierri-e YD: Benzodia-zepine wtlith- shoulId not exceed 6 sprays in each rnostril for aduilts and 3 sprays in each in nonpsvychiatric medical practice. Aml J drawal. Can J Psvchiatrv 1981; 26:93-95. rinstril for children tnder 14 years of age The effect of RHINALAR. unlike that of vasoconstrictors is not Psvchiatry 1977; 134:656-658. 26. Bezchlibnvk KZ, Jeffries JI. Should mmediate Frill therapeLutic bereFit requlires regular usage The absence 7. Rossel W-W.' Patterns af' benzodiazepine psYchiatric patienits drink coeff9ee (edito- of an iomediate effect should be explained to the patient in order to ensLure cooperatrorn and cont noiation or treatrrernt with the regular lsage in a family miledicine c'entm'e. Can riial). Can Med Assoc J 1981; 124:357- dosage schednile Faini Physician 1980; 26:718-720. 358. In the presence of excessive nasal mucus secretion or edema of tire rniasal nrmcosa the drug may fal to reach the site of action In such cases 8. Gr-eeniblctt DJ, Shladir RI: Dr'ug therapyv 27. Avd F. Teratogenicitx of miinwor tm-ani- is aduisable tn uise a nasal vasoconstr ctor otr two or three days prior to benzodiacepines. Nelt' Emigl J Med 1974; qcuilizers. Itit Drug Tlier Newslett 1976; RHINALAR Dosage Form: RHINALAR Nasal Mist IS art O 025°o aqueous solLutiorn of 291:1011-1015. 11:17-18. fllrnisolrde 0n a 2h ml plastic bottle fitted with a metered piJmp device which delivers approximately 25 4g of fl(inisolide per spray via a nolzle which is inserterl into the nostr Flunisolide is dissolved n an aqueous solnitlon containing propylene glycol polyethylene glycol, citric acid, sodLiM citrate and benzalkonium chloride as a preservative It contains no ilirorocarbons References: 1. Pakes GP Rrogdeo RN. Heel RC, Speight PM. Avery GS Plunisolide A Review of its Pharmacological Properties and Pheraperiric Pllrcacy in Roinitis Drugs 19R0 19 397-4tt 2. Kammermeyer JK Rajrora bW. Anriras J Ricoerson FF6 Clrinical Pualuatron of Irntranasal Popical Plulnisolide ITrerapy in Allergic Rhiortis JAllerg Chin Imini 1977 59 267 293 3. Mygrod N, vesterharie S Aerosol bistribrition 0n rOe l\nose Rhroology t97R 16 79 WI R)Reg PM SYNTEX< N4fMEiE;[p A B1 Syintex Inc Mississauga Ontario | p M ^ C ] 1 C C P P |Montreal Quebec 1639