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Central nervous system stimulants and drugs that suppress appetite
Reginald P. Sequeira
1
Central nervous system stimulants and drugs that suppress appetite
METHYLXANTHINES (SED-13, 1; SEDA-19, I; SEDA-20, 1; SEDA-21, 1)
the antihypertensive effect of/3-blockade was not attenuated by caffeine-ephedrine (7c).
Caffeine Caffeine reinforcement can be augmented as a result of two distinct mechanisms: (a) an acute stimulant effect and (b) withdrawal symptoms. The DSM-IV criterion for defining psychoactive drug dependence is that the substance is taken to relieve or avoid withdrawal symptoms (1R). R e c e n t studies have provided further support for the view that in those who consume caffeine in moderate or high amounts, caffeine is used primarily to relieve or avoid withdrawal symptoms (2c), (3 c) (see SEDA-20, 1). The effect of cimetidine on caffeine metabolism has been investigated in 11 children aged 2.5-15 years, by giving them oral 13C-labelled caffeine, followed by measurement of ~3C-labelled CO2 in the expired air (4c). Cimetidine did not inhibit the metabolism of caffeine. These results contrast with inhibition of the metabolism of caffeine (5 c) and theophylline (6c) by cimetidine in adults. The combination of caffeine (200 mg) with ephedrine (20 mg), used as an aid to slimming, has been evaluated in 136 patients with a basal metabolic index above 25 kg/m 2, to determine their safety in hypertensives. There were no changes in blood pressure acutely or during treatment for 6 weeks, either in normotensive or hypertensive obese patients. Furthermore, Interactions
9 t999 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 22 J.K. Aronson, ed.
Theophylline The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism have been studied in healthy young and elderly male and female smokers (8c). In healthy male and female smokers, the basal oxidative metabolism of theophylline falls with age but is unaltered by sex. Cimetidine and ciprofloxacin impaired the elimination of theophylline. In therapeutic doses, concomitant administration of both drugs caused greater inhibition of theophylline clearance and metabolite formation than with either drug alone. Neither age nor sex affected the inhibition of theophylline metabolism by cimetidine and ciprofloxacin. These findings may have significant clinical implications for the use of theophylline in old people. Age is the best predictor of major toxicity in cases of chronic theophylline overmedication, and elderly patients have a significantly higher risk of serious adverse effects from theophylline toxicity than younger patients, even at similar plasma concentrations (9c), (10c). Nevertheless, although cimetidine and ciprofloxacin had similar effects on theophylline metabolism in both age groups, lower baseline theophylline clearance as a result of age-related changes may increase the likelihood of drug-drug interactions in elderly people, necessitating careful monitoring. A case of apparent theophylline toxicity induced by fluvoxamine has been reported Or). Interactions
I
Chapter 1 A 40-year-old woman had depression with psychotic features, successfully treated with fluvoxamine 100mg/day and olanzapine 10rag/day. Five days after she started to take theophylline 300 mg bd for chronic obstructive pulmonary disease she developed nausea, vomiting, confusion, insomnia, poor appetite, and lack of energy. About 12 h after the last dose of theophylline, her plasma theophylline concentration was 144 mmol/1.The elimination halflife was 35 h. Theophylline was withdrawn and her condition resolved over the next 5 days. Theophylline toxicity in this patient was probably due to inhibition of CYP1A2, the major enzyme involved in theophylline detoxification, of which fluvoxamine is an inhibitor (12), (13or). Several previous reports (14c)-(16 c) have documented this interaction. In another study, fluvoxamine reduced the total clearance of theophylline from 80 to 24 ml/min and prolonged the elimination halflife from 6.6 to 22 h. The clearances of the theophylline metabolites, 1-methyluric acid, 3-methyluric acid, and 1,3-dimethyluric acid also fell (17c). In the same study griseofulvin increased the clearance of theophyiline in four subjects but had no effect in eight others (16c). The elimination half-life fell in all the subjects, but the fall was more pronounced in the four subjects in whom there was increased clearance. It is therefore possible that some subjects are more susceptible to induction by griseofulvin of the gene encoding for CYP1A2. In 12 volunteers grepafloxacin, a fluoroquinolone, inhibits theophylline metabolism (18~). Grepafloxacin (600 mg/day for 10 days) increased the Cmax and A U C of theophylline and reduced the apparent total clearance by about 50%.
STIMULANTS A N D A N O R E C T I C A G E N T S (SED-13, 13; SEDA-19, 2; SEDA-20, 2; SEDA-21, 2)
Cocaine (SED-13, 14) A young man had an acute inferior myocardial infarction following the Cardiovascular
application of cocaine as a topical anesthetic for nasal surgery. Coronary angiography showed occlusion of both posterior descend-
R.P. Sequeira
ing and posterolaterai arteries, which were resistant to intracoronary glyceryl trinitrate and verapamil, a finding consistent with thrombotic occlusion. A n angiogram 3 months later showed no residual lesion (19c). Interactions Coronary artery vasospasm occurred in a patient who was given ephedrine intravenously to correct hypotension during spinal anesthesia (20c). The authors speculated that the coronary vasospasm was due to cocaine use 4 days before, causing upregulation of a-adrenoceptors in vascular smooth muscle and an exaggerated response to endogenous catecholamines; studies in dogs support this hypothesis (21). However, other causes, such as severe hypotension or acute thrombus formation could not be excluded. The authors recommended the use of glyceryl trinitrate, calcium antagonists, or a-adrenoceptor antagonists to control a-adrenoceptor agonist-precipitated coronary artery vasospasm and to avoid /J-blockers, since these could worsen vasospasm (SEDA-21, 4). Interference with laboratory tests The effect of several abused drugs and cocaine metabolites on cocaine and cocaethylene binding to human serum proteins in vitro has been investigated using equilibrium dialysis technique (22). Binding of cocaine was enhanced by codeine, methamphetamine, and cocaethylene, whereas morphine and benzylecgonine reduced it. These findings have important implications for laboratory screening of drugs in blood, because multidrug abuse is common among abusers.
Fenfluramine, dexfenfluramine, and phentermine (SEDA-12, 9; SEDA-19, 2; SEDA-20, 2; SEDA-21, 2) Cardiovascular Vasospasm causing ischemic necrosis of the fingers had been attributed to dexfenfluramine (23c). A 44-year-old non-insulin-dependent diabetic developed pain and discoloration of the left index and small fingers. Three months before he had started to take dexfenfluramine 15 mg bd for mild obesity. Angiography showed occlusion of both digital arteries of the index and small fingers; one digital artery
Central nervous system stimulants and drugs that suppress appetite was occluded in each of the other fingers. Vasospasm in the carpal arch abated with an injection of tolazoline, Dexfenfluramine was discontinued, but despite therapy with local transdermal nitrate, local sympathetic blockade with bupivacaine, and oral nifedipine, the lesion progressed to necrosis, and amputation of the involved distal phalanges was required. Pathological examination showed thrombosis of the digital arteries with gangrenous necrosis but no vasculitis or emboli. He was instructed to awfid dcxfenfluramine. However, some weeks later hc developed mild discoloration of several fingers of the right hand after he look dexfenfluraminc again. Dcxfenfturamine can interfere with serotonin turnover (24cr), and it could be argued that serotonin-induced vasospasm was responsible for this adverse event. L o w e r extremity arterial ischemia has also b e e n reported in a patient who took dexfenfluramine and minocycline (25c). Coronary vasospasm can also be produced by dexfenfluramine, producing myocardial infarction (26r Pulmonary hypertension is a well-known complication of dexfenfluramine.
Cardiac valvulopathies in patients taking fenfluramine and related drugs During the past year several reports have provided evidence linking valvular heart disease to the use o f a combination o f widely used drugs, fenfluramine and phentermine. Phentermine was approved by the FDA in 1959 for single-drug, short-term treatment o f obesity. Subsequently in 1973, fenfluramine was approved on a similar basis. Dexfenfluramine was approved in 1976 as a single-drug, prescription-only appetite suppressant for longer term use in moderately obese people, with a warning that its safety beyond I year o f use had not been established. Recently, both fenfluramines have been used in combination with phentermine and for periods longer than a few weeks. Since 1995 more than 14 million prescriptions have been written for either fenfluramine or dexfenfiuramine, Most o f the use was in women and people aged over 60 years, Based on a median treatment course o f 3-12 months, an estimated 1.2-4.7 million people in the US have been exposed to these drugs.
Chapter 1
Reports and demographic features
Echocardiography in 24 women who were taking fenfluramine-phentermine showed unusual valvular morphology and regurgitation. Both right- and left-sided heart valves were involved. Eight o f these patients also had newly documented pulmonary hypertension. The heart valves had a glistening white appearance and the histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease (27c). These descriptions are limited by a lack of pathological confirmation in the majority o f cases. Many o f these patients continue to be treated medically and have not undergone invasive investigation. Consequently, neither direct inspection or histopathoIogical evahtation has been carried out in most cases. In addition, no routine pretreatment echocardiographic baseline studies were performed. In the absence o f a control group or a case-control study, definitive statements about a true association o f valvular heart disease with fenfluramine-phentermine therapy cannot be made. However, following this landmark publication, several other reports have substantiated these observations. Between October 1994 and July 1997, the Belgian Centre for Pharmacovigilance received 43 reports of valvular heart disease among women who had used anorectic drugs. Echocardiographic confirmation was available in 31 o f these patients, who had had past exposure to anorectic drugs such as fenfluramine (n = 8), fenfluramine and diethylpropion (n = 18), fenfluramine and phentermine ( n = 1), and fenfluramine, diethylpropion, and phentermine (n = 3). The mean duration o f exposure was estimated in 25 patients to be 40 months, and the mean age o f the patients was 42 years. The aortic valve was most frequent involved (in 18 eases). Thirteen patients presented with symptoms such as dyspnea (n = 6), primary pulmonary hypertension (n = 2), and chest pain, chest discomfort, angina, pulmonary edema, and peripheral edema in one patient each (28c). In July 1997the FDA issued a Public Health Advisory asking that other cases be reported, In response, the FDA received 28 additional reports from the US with similar disease; the median age was 45 years and all were women (29CR). The median daily dose o f fenfluramine
4 was 60 mg and o f phentermme 30 mg; the median duration o f therapy before diagnosis o f valvular disease was 10 months. Six patients underwent valve replacement surgery, o f whom one died. In a further update, by 30 September 1997 the FDA had received 144 individual spontaneous reports (including the 24 cases reported earlier) involving fenfluramine or dexfenfluramine with or without phentermine, in association with valvulopathy (30CR). Valvulopathy was defined as "documented aortic regurgitation o f mild or greater severity and or mitral regurgitation o f moderate or greater severity after exposure to these drugs". O f these 144 spontaneous reports 132 had complete information and 113 met the case definition. O f these 113 cases, 98% occurred among women; the median age was 44 years. Out o f these 113 cases 2% had used fenfluramine alone; 14% dexfenfluramine alone; 79% a combination o f fenfluramine with phentermine; and 5% a combination o f all three drugs; none had taken phentermine alone. The median duration o f drug use was 9 months (range 1-39). Overall, 87 (77.1%) o f the 113 cases were symptomatic. A total o f 27 (24%) patients required cardiac valve replacement and three died after surgery. Mechanism It has been postulated that fenfluramine and phentermine potentiate the effect or concentration o f circulating serotonin and could contribute to the development o f valvular injury, similar to that seen in patients with carcinoid syndrome or in those taking ergot derivatives. Serum serotonin and urinary 5-hydroxyindole acetic acid (5-HIAA) have been measured in seven subjects taking fenfluramine and phentermine for a mean duration o f 11 months as adjunct therapy in type 2 diabetes mellitus. None o f these subjects had raised concentrations o f serum serotonin or urinary 5-HIAA (31c). Thus, direct implication o f serotonin has not been substantiated. Two patients with valvular heart disease associated with fenfluramine-phentermine were also taking a selective serotonin reuptake inhibitor (SSR1) (27c). The suggestion that fluoxetine is a safer alternative to fenfluramine in the medical treatment o f obesity (32 c) should be viewed with scepticism. Valves affected Although most o f these pa-
Chapter 1
R.P. Sequeira
tients had either dyspnea or evidence o f congestive heart failure, 14% were asymptomatic. The mitral valve was affected in 24 (86%), the aortic valve in 19 (69%), the tricuspid valve in 11 (39%), and the pulmonary valve in one (4%). A left-sided valve was involved in all cases, and two or more valves were involved in 78%. Pulmonary hypertension was reported in 10 patients, four o f whom had left-sided valvular lesions only. Valvular disease did not resolve in any patient after withdrawal o f the appetite suppressants. Risk factors Factors that are potentially associated with cardiac valvulopathy, but not yet determined, are: ( i ) The natural history o f these lesions, including the relation between the development o f the lesions and the duration o f drug use, and whether the lesions generally resolve, progress, or remain unchanged on drug withdrawal; (2) The clinical importance o f mild valvulopathy in asymptomatic people without audible murmurs; and (3) The characteristics, if any, that might predispose someone to develop cardiac valve abnormalities during exposure to these drugs. Monitoring and prevention Color-flow Doppler echocardi'ographic surveillance o f all persons being treated with appetite suppressants, particularly asymptomatic women, has been recommended (33c). However, the optimal timing o f follow-up echocardiography to determine the progression, regression, or stabilization o f valvular lesions is currently unknown. The US Department o f Health and Human Services has issued the following interim recommendations for people previously exposed to fenfluramine or dexfenfluramine with cardiac valvulopathies (3OR): (1) All people exposed to fenfluramine for any period o f time, either alone or in combination with other anorectic agents, should undergo a medical history and cardiovascular examination by their physician to determine the presence or absence o f cardiopulmonary signs and symptoms. (2) Echocardiography should be performed
Central nervo~ system stimulants and drugs that suppress appetite
(3)
(4)
on all people who have been exposed to fenfluramine or dexfenfluramine for any period of time, either alone or in combination with other agents, and who have cardiopulmonary signs, including a new murmur or symptoms suggestive of valvular disease, such as dyspnea. Any echocardiographic findings that meet the American Heart Association (AHA) criteria for antimicrobial prophylaxis for endocarditis, regardless of whether they are attributable fenfluramine or dexfenfluramine, should be recognized as an indication for antimicrobial prophylaxis. For emergency procedures for which cardiac evaluation cannot be performed, empirical antibiotic prophylaxis should be administered according to A H A guidelines. Because of the prevalence of minimal degrees of regurgitation in the general population, the current definition of drug-associated valvulopathy should include exposed patients with echocardiographically demonstrated aortic regurgitation of mild or greater severity and~or mitral regurgitation of moderate or greater severity, based on published criteria.
Respiratory Pulmonary hypertension has b e e n r e p o r t e d in p a t i e n t s t a k i n g fenfluramine hydrochloride a n d p h e n t e r m i n e h y d r o c h l o r ide (34~ (35c). A 30-year-old woman had a basal metabolic index of 28 kg/m 2, but no history of pulmonary disease, drug abuse, HIV infection, recent pregnancy, immunological disease, or other drug use. After taking fenfluramine and phentermine for 4 weeks, she began to have dyspnea and stopped taking the anorexiants. Six months later she developed progressive dyspnea on exertion and edema and had a syncopal episode. Echocardiography showed right ventricular hypertrophy and dilatation. Cardiac catheterization confirmed the presence of severe pulmonary hypertension. She was given prostacyclin and warfarin. A few months later she died, and at post mortern examination the cause of death was attributed to pulmonary hypertension associated with the use of fcnfluramine-phentermine. Severe plexogenic pulmonary arteriopathy developed in a 29-year-old woman who had taken fenfluramine and phentermine for 23 days. She probably had not had any pre-existing disease, and the histo-
Chapter 1
5
logical age of the lesion was consistent with the time elapsed since she had taken the drugs. In b o t h of these cases, the short d u r a t i o n of drug e x p o s u r e is worth noting ( S E D A - 1 8 , 7; S E D A 21, 2). Nervous system Cerebral hemorrhage has b e e n a t t r i b u t e d to fenfluramine with p h e n t e r mine (36c). A 56-year-old woman suddenly developed weakness and clumsiness of her right leg and right arm. She had taken dl-fenfluramine 20 mg/day and phentermine 15 mg/day for obesity for 6 months. CT and MRI scans showed a hemorrhagc in the medial aspect of the left motor cortex with a small amount of surrounding edema. Fenfluramine and phentermine were withdrawn. Her right hcmiparesis gradually resolved over 3 months, when MRI showed complete resolution. A l t h o u g h the a u t h o r s of this r e p o r t suggested t h a t f e n f l u r a m i n e - p h e n t e r m i n e m a y h a v e c o n t r i b u t e d to the d e v e l o p m e n t of cerebral h e m o r r h a g e , o t h e r causes, particularly cryptic a r t e r i o v e n o u s m a l f o r m a t i o n s , could not b e c o m p l e t e l y excluded. T h e i n t e r m i t t e n t aspirin the p a t i e n t was using for b a c k pain could also have c o n t r i b u t e d (37R). Psychiatric V a r i o u s psychiatric a d v e r s e effects of d e x f e n f l u r a m i n e h a v e b e e n r e p o r t e d (38c), (39c). In the first case psychotic episodes associated with d e x f e n f l u r a m i n e w e r e p r o b a bly due to a n i n t e r a c t i o n of d e x f e n f l u r a m i n e with d o x e p i n (38c). In t h e s e c o n d a direct effect of d e x f e n f l u r a m i n e was suggested (39c). A 56-year-old white woman with bipolar depression developed distinct mood cycles 2 weeks after starting to take dexfenfluramine. Her symptoms included anger, homicidal thoughts, racing thoughts, and labile moods. She was unable to control her mood. Her sleep changed minimally with continued use of zolpidem. She reverted to a long-quiescent pattern of alcohol abuse. The dexfenfluramine was withdrawn and the dosage of alprazolam was increased to 2 mg bd. Her other medications (divalproex, carbamazepine, molindone, zolpidem) were unchanged. Within 3 days her mixed-manic, rapidcycling state improved and in 2 weeks she achieved baseline status. In a n o t h e r case psychotomania o c c u r r e d after t r e a t m e n t with fenfluramine a n d p h e n t e r m i n e in a d e p r e s s e d w o m a n (40c). O n two
Chapter I separate occasions she experienced similar symptoms with fenfluramine and phentermine. These reports emphasize the need to use appetite suppressants judiciously in patients with pre-existing psychiatric illness, although it is difficult to establish a definite association between these adverse effects and use of anorectic drugs (SEDA-19, 2).
Interaction Attention has been drawn to a possible interaction between fenfluramine and imipramine, mediated via the inhibition of cytochrome P450 (41c). A 55-year-old woman had generalized anxiety, in remission with imipramine 350 mg/day. During this period she also took hyoscyamine sulfate, 0.375 mg/day, and levothyroxine sodium 0.15 mg/day. Her imipramine concentration at the end of each of the previous years of treatment was 145218 mg/l. Four weeks after the addition of fenfluramine, 20 mg tds, she complained that she had momentarily fallen asleep while driving. Her imipramine plus desipramine concentration was 704 mg/l. Fenfluramine was withdrawn, and no further episodes of daytime sleepiness were reported. Her blood concentration of imipramine and desipramine 2 weeks later was 252 mg/l. hnipramine metabolism depends on CYP1A2, CYP2C, CYP2D6, and CYP3A4 (42R). Although fenfluramine might inhibit some of these isoenzymes, there is no published evidence that it does. It is prudent to be aware of the potential for fenfluramineimipramine interaction.
Ephedrine and pseudoephedrine (SED-13, 350; SEDA-21, 5) Skin and
appendages
A
non-pigmentary
fixed drug reaction has been attributed to ephedrine and pseudoephedrine (43c). A patch test and oral rechallenge produced eruptions at the same site. The dermis, rather than the epidermis, is the primary site of the drug sensitivity response in this type of dermatitis (44c).
R.P. Sequeira
vary amylase in about one-third of women with pre-term labor contractions (45c).
Methylphenidate (SEDA-20,
3;
SEDA-21, 6) Recent studies (46c)-(48 c) have addressed the safety issues related to the use of methylphenidate in children with attention deficit hyperkinetic disorder (ADHD). Nearly 80% of children treated with methylphenidate experienced appetite suppression, affecting body weight and height. However methylphenidate also exacerbated tics. In patients with marked anxiety, agitation, or psychotic disorders these symptoms may be precipitated methylphenidate. Patients with mental retardation and children under 6 years old are at risk of adverse effects such as irritability and depressed mood. The most common adverse effects of methylphenidate include sleep problems, anorexia, stomach ache, and headache (for a comprehensive review see (49R),
(50~)). Interactions A n interaction of methylphenidate with sertraline has been described (51c).
A 13-year-old white man with a history of ADHD and a depressive disorder had taken methylphenidate 1.8 mg/kg per day for nearly 10 months. Because of worsening of his mood disturbances, sertraline 25 rag/day was added. One week later he had a tonic-clonic seizure. Sertraline was withdrawn and methylphenidate continued unchanged. There was no recurrence. Although this may be first reported case of seizure activity in someone taking sertraline and methylphenidate, this report does not provide convincing evidence of an interaction, particularly because blood concentrations were not determined. The possibility of a cytochrome P450-mediated drug interaction as an underlying mechanism has yet to be explored.
Prolintane Effects on laboratory tests Clinical doses of /3-adrenoceptor agonists, including ritodrine and ephedrine, cause hypersecretion of sali-
Prolintane hydrochioride is available mainly in formulations containing multivita-
Central nervous system stimulants and drugs that suppress appetite rain supplements in many European countries, Australia, and South Africa. It has structural and pharmacological properties similar to dextroamphetamine. Its adverse effects include insomnia, nervousness, irritability, euphoria, headache, dizziness, and psychotic reactions. Acute overdosage can cause cardiorespiratory arrest and death. A patient who developed a panic attack after taking Katovit| (prolintane with multivitamins) has been reported to the Spanish Drug Surveillance Scheme (52c). The authors pointed out that none of the 30 physicians questioned about this formulation was aware that prolintane is related to amphetamine. They urged that in countries in which prolintane is marketed in combination with vitamins, this irrational combination should be withdrawn in view of the public health risk.
OTHER DRUGS
CENTRALLY
ACTING
(SEDA-19, 4, 148; SEDA-20, 4; SEDA-21, 6) Pemoline
(SEDA-21, 6)
There is considerable interest in giving pemoline to children with A D H D who do not respond to methylphenidate (53~), (54c). However, troubling adverse effects occurred when the maximum recommended dose was used. Among seven children, two developed tics and one hallucinations (54c).
Liver The available data on pemoline-associated hepatotoxicity have been reviewed and the need to establish an adverse reactions registry has been emphasized (55R). A 19year-old woman with A D H D was treated with methylphenidate and pemoline and developed reversible hepatitis (56c). There is no evidence that methylphenidate predisposed her to pemoline hepatotoxicity. However, there is no indication for using multiple stimulants to treat ADHD.
Chapter 1
7
Tacrine (SEDA-19, 4, SEDA-20, 4; SEDA-21, 6) The American Psychiatric Association has published practice guidelines for the treatment of patients with Alzheimcr's disease and other dementias of late life (57n). The F D A has described a 'Treatment-Investigational New Drng (TIND)" prolocol, whereby largc volumes of data related to clinical trials can be handled rapidly and effectively (58cr~). Serious adverse events have been reported directly to trained operators and summarizcd on a weckly basis for reporting to the FDA: 1951 physicians agreed to participate and 10 187 patients wcre enrolled; 9861 (96.8%) of these were taking tacrine. One or more serious adverse events were reported by 1148 (12%) patients (1206 events in all), the most frequently reported adverse event being a raised A1T (337 patients). A comprehensive review of risk:benefit assessment of tacrine in the treatment of Alzheimer's disease, including treatment guidelines for prescribing tacrine and recommendations for monitoring toxicity, has been described (59R). Since only about one-third of patients with Alzheimer's disease respond favorably to tacrine, the search for prcdictors of favorable/unfavorable responses continues. Patients with white matter low attenuation, also known as leukoaraiosis (periventricular hypodense areas on CT scan), can still respond to tacrine, although the rate of withdrawal from treatment is much higher in these patients (60c). The small number of patients in this study (n = 72) precludes firm conclusions as to whether leukoaraiosis is a predictor of the efficacy and tolerability of tacrine.
Psychiatric Two cases of tacrine-associated depression have been reported (61~). Two elderly women (aged 82 and 70 years) had taken tacrine hydrochloride 40 mg/day for at lcast 1 month. They developed symptoms of depression and had Hamilton Depression Rating Scale Scores of 27 and 29. The 82-year-old did not respond to fluoxetine 201)mg/day for 35 days, but improved with a course of ECT; the other improved with fluoxetine alone. Tacrine was withdrawn. Based on the evidence provided, it is diffi-
Chapter 1 cult to accept with any d e g r e e of certainty that i n d e e d t h e r e is an association b e t w e e n tacrine t r e a t m e n t a n d depression. Considering the use of tacrine in a large n u m b e r of patients with A l z h e i m e r ' s disease, the association, if any, is p r o b a b l y very weak. A n t i d e p r e s s a n t s , such as fluvoxamine, are o f t e n given to p a t i e n t s with
Interactions
A l z h e i m e r ' s disease who are also given tacfine. T h e i n t e r a c t i o n b e t w e e n t h e m has therefore b e e n investigated in 13 h e a l t h y volunteers in a d o u b l e - b l i n d , r a n d o m i z e d crossover c o m p a r i s o n of t h e effects of fluvoxamine (100 mg/day for 6 days) a n d p l a c e b o o n the p h a r m a c o k i n e t i c s of a single dose of tacrine
R.P. Sequeira
(40 m g ) (62c). F l u v o x a m i n e r e d u c e d the app a r e n t n o n - r e n a l clearance of tacrine a n d inc r e a s e d the plasma c o n c e n t r a t i o n s of its t h r e e m o n o h y d r o x y l a t e d m e t a b o l i t e s . T h e s e results are a t t r i b u t a b l e to i n h i b i t i o n by fluvoxamine of C Y P 1 A 2 , which is r e s p o n s i b l e for the biot r a n s f o r m a t i o n of tacrine to its inactive hydroxylated m e t a b o l i t e s a n d its reactive m e t a b o lites, which are p o t e n t i a l l y toxic if not c o n j u g a t e d with g l u t a t h i o n e (63R). Five subjects h a d gastrointestinal a d v e r s e effects, b u t the clinical c o n s e q u e n c e s of c o n c o m i t a n t prescription of tacrine a n d inhibitors of C Y P 1 A 2 , such as fluvoxamine (12), in p a t i e n t s with A l z h e i m e r ' s disease c a n n o t b e e x t r a p o l a t e d from this study.
REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of the Mental Disorders, 4th edition. Washington DC: American Psychiatric Association 1994:175-272. 2. Schuh KJ, Griffiths RR. Caffeine reinforcement: the role of withdrawal. Psychopharmacology 1997;130:320-6. 3. Phillips-Bute BG, Lane JD. Caffeine withdrawal symptoms following brief caffeine deprivation. Physiol Behav 1997;63:35-9. 4. Parker AC, Pritchard P, Preston T, Dalzell AM, Choonara I. Lack of inhibitory effect of cimetidine on caffeine metabolism in children using the caffeine breath test. Br J Clin Pharmacol 1997 ;43:467-70. 5. Broughton LJ, Rogers HJ. Decreased systemic clearance of caffeine due to cimetidine. Br J Clin Pharmacol 1981;12:155-9. 6. Roberts RK, Grice J, Wood L, Petroff V, McGuffie C. Cimetidine impairs the elimination of theophylline and antipyrine. Gastroenterology 1981;81:19-21. 7. Ingerslev J, Svendsen TL, Mork A. Is ephedrine caffeine treatment contraindicated in hypertension? Int J Obes 1997;21:666-73. 8. Loi CM, Parker BM, Cusack BJ, Vestal RE. Aging and drug interactions. III. Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in healthy male and female nonsmokers. J Pharmacol Exp Ther 1997;280:627-37. 9. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993; 119:1161-7. 10. Shannon M, Lovejoy FH Jr. The influence of age vs. peak serum concentration on life-threatening events after chronic theophylline intoxication. Arch Intern Med 1990;150:2045-8. 11. Devane CL, Markowitz JS, Hardesty SJ,
Mundy S, Gill HS. Fluvoxamine-induced theophylline toxicity. Am J Psychiatry 1997;154:131718. 12. Brosen K, Skelbo E, Rasmussen BB. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993;45:1211-14. 13. Rasmussen BB, Maenpaa J, Pelkonen O, Loft S, Poulssen HE, Lykkesfeldt J, Brosen K. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995;39:151-9. 14. Diot P, Jonville AP, Gerard F, Bonnelle N, Autret E, Breteau M , Lemarie E, Lavandier M. Possible interaction between theophylline and fluvoxamine. Thrrapie 1991;46:170-1. 15. Sperber AD. Toxic interaction between fluvoxamine and sustained release theophylline in an ll-year-old boy. Drug Saf 1991;6:460-2. 16. Van der Breckel AM, Harrington L. Toxic effects of theophylline caused by fluvoxamine. Can Med Assoc J 1994;151:1289-90. 17. Rasmussen BB, Jeppesen U, Gaist D, Brosen K. Griseofulvin and fluvoxamine interaction with the metabolism of theophylline. Ther Drug Monit 1997;19:56-62. 18. Efthymiopoulos C, Bramer SL, Maroli A, Blum B. Theophylline and warfarin interaction studies with grepafloxacin. Clin Pharmacokinet 1997;33(Suppl 1):39-46. 19. Williams MJA, Stewart RAH. Serial angiography in cocaine-induced myocardial infarction. Chest 1997;111:822-4. 20. Lustik SJ, Chhibber AK, Van Vliet M, Pomerantz RM. Ephedrine induced coronary artery vasospasm in a patient with prior cocaine use. Anaesth Analg 1997;84:931-3. 21. Jones LF, Tacket RL. Chronic cocaine treatment enhances the responsiveness of the left an-
Central nervous system stimulants and drugs that suppress appetite terior descending coronary artery and the femoral artery to vasoactive substances. J Pharmacol Exp Ther 1990;255:1366-70 22. Bailey DN. Effect of drugs and cocaine metabolites on cocaine and coca-ethylene binding to human serum in vitro. Ther Drug Monit 1997; 19:427-30. 23. Marinella MS, Barrettoni BA. Digital necrosis associated with dexfenfluramine. New Engl J Med 1997;337:1776-7. 24. McCann UD, Selden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine: a systematic review of the evidence. J Am Med Assoc 1997;278:666-72. 25. Prate B, Spreux A, Chichmanian RM. Isch6mie subaiguE distale du membre infErieur gauche au cours et traitment associant dexfenfluramine et minocycline. Th6rapie 1992; 47: 438-9. 26. Evard P. Myocardial infarction associated with dextrofenfluramine. Br Med J 1990; 301:1050. 27. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. New Engl J Med 1997;337:581-8. 28. Kurz X, Van Ermen A. Valvular heart disease associated with fenfluramine-phentermine. New Engl J Med 1997;337:1772-3. 29. Graham D J, Green L. Further cases of valvular heart disease associated with fenfluraminephentermine Ill. New Engl J Med 1997;337:635. 30. Bowen R, Glicklich A, Khan M, Rasmussen S, Wadden T, Bilstadt J, Graham D, Green L, Lumpkin M, O'Neil R, Sobel S, Hubbard VS, Yanovski S, Sopko G. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services Interim Public Health Recommendations, November 1997. J Am Med Assoc 1997 ;278:1729-31. 31. Redmon B, Raatz S, Bantle JP. Valvular heart disease associated with fenfluramine-phentermine. New Engl J Med 1997;337:1773-4. 32. Anchors M. Fluoxetine is a safer alternative to fenfluramine in the medical treatment of obesity. Arch Intern Med 1997;157:1270. 33. Rasmussen S, Corya BS, Glasman RD. Valvular heart disease associated with fenfluraminephentermine. New Engl J Meal 1997;337:1773. 34. Dillon KA, Putnam KG, Avorn JL. Death from irreversible pulmonary hypertension associated with short use of fenfluramine and phentermine. J Am Med Assoc 1997;278:1320. 35. Mark E J, Patalas EO, Chang HT, Evans R J, Kessler SC. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. New Engl J Med 1997; 337: 602-6. 36. Wen PY, Feske SK, Teoh SK, Stieg PE. Cerebral hemorrhage in a patient taking fenfluraminc and phentermine for obesity. Neurology 1997;49:632-3.
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37. Kase CS. Bleeding disorders. In: Kase CS, Caplan LR, eds. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann 1994:117-53. 38. Preval H, Pakyurek AM. Psychotic episode associated with dexfenfluramine. Am J Psychiatry 1997;154:1624-5. 39. Bowden CL, Dickson J Jr. Mania from dexfenfluramine. J Clin Psychiatry 1997;58:5489. 40. Raison CL, Klein HM. Psychotic mania associated with fenfluramine and phentermine use. Am J Psychiatry 1997;154:711. 41. Fogelson DL. Fenfluramine and the cytochrome P450 system. Am J Psychiatry 1996; 154:436-7. 42. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153:311-20. 43. Gareia-Ortiz JC, Terron M, Bellido J. Nonpigmentary fixed exanthema from cphedrine and pseudoephedrine. Eur J Allergy Clin Immunol 1997 ;52:229-30. 44. Shelley WB, Shelley ED. Nonpigmentary fixed drug eruption as a distinctive reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrozoline. J Am Acad Dermatol 1987;17:403-7. 45. Takahashi T, Minakami H, Tamada T, Sato !. Hyperamylasemia in response to ritodrine or ephedrine administered to pregnant women. J Am Coll Surg 1997;184:31-6. 46. Effron D, Jarman F, Barker M. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double blind, crossover trial. Pediatrics 1997; 100:662-6. 47. Musten LM, Firestone P, Pisterman S, Bennett S, Mercer J. Effects of methylphenidate on preschool children with ADHD: cognitive behavioral functions. J Am Acad Child Adolesc Psychiatry 1997;36:1407-15. 48. Schachar RJ, Tannock R, Cunningham C, Corkum PV. Behavioral, situational and temporal effects of treatment of ADHD with methylphenidate. J Am Aead Child Adolesc Psychiatry 1997 ;36:754-63. 49. Cantwell D. Attention deficit disorders. A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:978-87. 50. Rappley MD. Safety issues in the use of mcthylphenidate. An American perspective. Drug Saf 1997;17:143-8. 51. Feeney DJ, Klykylo WM. Medication induced seizures. J Am Child Adolesc Psychiatry 1997; 36:1018-19. 52. Martinez-Mir I, Catalan C, Palop V. Prolintane: a masked amphetamine. Ann Pharmacother 1997;31:256. 53. Pelham WE, Swanson JM, Furman MB, Swindt H. Pemoline effects on children wth ADHD: a time response analysis on classroom measures. J Am Acad Child Adolesc Psychiatry 1995;34:1504-13.
10 54. Winsberg B, Barbato M. Pemoline in ADHD. J Am Acad Child Adolesc Psychiatry 1997; 36:1649-50. 55. Shevell M, Schreiber R. Pemoline associated hepatic failure: a critical analysis of the literature. Pediatr Neurol 1997;16:14-16. 56. McCurry L, Cronquist S. Pemoline and hepatotoxicity. Am J Psychiatry 1997;154:713-14. 57. American Psychiatry Association. Practice guidelines for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatry 1997;Suppl 154:1-39. 58. Symons JP, Ibara M, Kraemer DF, Luscombe FA. Tacrine hydrochloride treatment IND: methods for rapid physician patient enrolment and data retrieval. Pharmacoepidemiol Drug Saf 1997;6:409-16. 59. Samuels SC, Davis KL. A risk:benefit assessment of tacrine in the treatment of Alzheimer's disease. Drug Saf 1997;16:66-77.
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60. Amar K, Wilcock GK, Scot M, Lewis T. The presence of leukoaraiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from nonresponders. Age Aging 1977;26:25-9. 61. Pancrazi-Boyer MP, Arnaud-Castiglioni R, Michel B, Azorin JM. Tetraaminotacrine treatment and depression. Alzheimer's Res 1997; 3:115-17. 62. Becquemont L, Regueneau I, Le Bot MA, Riche C, Funck-Brentano C, Jallon P. Influence of the CYPIA2 inhibitor fluvoxamine on tacrine pharmacokinetics in humans. Clin Pharmacol Ther 1997;61:619-27. 63. De Vane CL, Gill HS. Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design. J Clin Psychiatry 1997;58 Suppl:714.
1
Central nervous system stimulants and drugs that suppress appetite
METHYLXANTHINES (SED-13, 1; SEDA-19, I; SEDA-20, 1; SEDA-21, 1)
the antihypertensive effect of/3-blockade was not attenuated by caffeine-ephedrine (7c).
Caffeine Caffeine reinforcement can be augmented as a result of two distinct mechanisms: (a) an acute stimulant effect and (b) withdrawal symptoms. The DSM-IV criterion for defining psychoactive drug dependence is that the substance is taken to relieve or avoid withdrawal symptoms (1R). R e c e n t studies have provided further support for the view that in those who consume caffeine in moderate or high amounts, caffeine is used primarily to relieve or avoid withdrawal symptoms (2c), (3 c) (see SEDA-20, 1). The effect of cimetidine on caffeine metabolism has been investigated in 11 children aged 2.5-15 years, by giving them oral 13C-labelled caffeine, followed by measurement of ~3C-labelled CO2 in the expired air (4c). Cimetidine did not inhibit the metabolism of caffeine. These results contrast with inhibition of the metabolism of caffeine (5 c) and theophylline (6c) by cimetidine in adults. The combination of caffeine (200 mg) with ephedrine (20 mg), used as an aid to slimming, has been evaluated in 136 patients with a basal metabolic index above 25 kg/m 2, to determine their safety in hypertensives. There were no changes in blood pressure acutely or during treatment for 6 weeks, either in normotensive or hypertensive obese patients. Furthermore, Interactions
9 t999 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 22 J.K. Aronson, ed.
Theophylline The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism have been studied in healthy young and elderly male and female smokers (8c). In healthy male and female smokers, the basal oxidative metabolism of theophylline falls with age but is unaltered by sex. Cimetidine and ciprofloxacin impaired the elimination of theophylline. In therapeutic doses, concomitant administration of both drugs caused greater inhibition of theophylline clearance and metabolite formation than with either drug alone. Neither age nor sex affected the inhibition of theophylline metabolism by cimetidine and ciprofloxacin. These findings may have significant clinical implications for the use of theophylline in old people. Age is the best predictor of major toxicity in cases of chronic theophylline overmedication, and elderly patients have a significantly higher risk of serious adverse effects from theophylline toxicity than younger patients, even at similar plasma concentrations (9c), (10c). Nevertheless, although cimetidine and ciprofloxacin had similar effects on theophylline metabolism in both age groups, lower baseline theophylline clearance as a result of age-related changes may increase the likelihood of drug-drug interactions in elderly people, necessitating careful monitoring. A case of apparent theophylline toxicity induced by fluvoxamine has been reported Or). Interactions
I
Chapter 1 A 40-year-old woman had depression with psychotic features, successfully treated with fluvoxamine 100mg/day and olanzapine 10rag/day. Five days after she started to take theophylline 300 mg bd for chronic obstructive pulmonary disease she developed nausea, vomiting, confusion, insomnia, poor appetite, and lack of energy. About 12 h after the last dose of theophylline, her plasma theophylline concentration was 144 mmol/1.The elimination halflife was 35 h. Theophylline was withdrawn and her condition resolved over the next 5 days. Theophylline toxicity in this patient was probably due to inhibition of CYP1A2, the major enzyme involved in theophylline detoxification, of which fluvoxamine is an inhibitor (12), (13or). Several previous reports (14c)-(16 c) have documented this interaction. In another study, fluvoxamine reduced the total clearance of theophylline from 80 to 24 ml/min and prolonged the elimination halflife from 6.6 to 22 h. The clearances of the theophylline metabolites, 1-methyluric acid, 3-methyluric acid, and 1,3-dimethyluric acid also fell (17c). In the same study griseofulvin increased the clearance of theophyiline in four subjects but had no effect in eight others (16c). The elimination half-life fell in all the subjects, but the fall was more pronounced in the four subjects in whom there was increased clearance. It is therefore possible that some subjects are more susceptible to induction by griseofulvin of the gene encoding for CYP1A2. In 12 volunteers grepafloxacin, a fluoroquinolone, inhibits theophylline metabolism (18~). Grepafloxacin (600 mg/day for 10 days) increased the Cmax and A U C of theophylline and reduced the apparent total clearance by about 50%.
STIMULANTS A N D A N O R E C T I C A G E N T S (SED-13, 13; SEDA-19, 2; SEDA-20, 2; SEDA-21, 2)
Cocaine (SED-13, 14) A young man had an acute inferior myocardial infarction following the Cardiovascular
application of cocaine as a topical anesthetic for nasal surgery. Coronary angiography showed occlusion of both posterior descend-
R.P. Sequeira
ing and posterolaterai arteries, which were resistant to intracoronary glyceryl trinitrate and verapamil, a finding consistent with thrombotic occlusion. A n angiogram 3 months later showed no residual lesion (19c). Interactions Coronary artery vasospasm occurred in a patient who was given ephedrine intravenously to correct hypotension during spinal anesthesia (20c). The authors speculated that the coronary vasospasm was due to cocaine use 4 days before, causing upregulation of a-adrenoceptors in vascular smooth muscle and an exaggerated response to endogenous catecholamines; studies in dogs support this hypothesis (21). However, other causes, such as severe hypotension or acute thrombus formation could not be excluded. The authors recommended the use of glyceryl trinitrate, calcium antagonists, or a-adrenoceptor antagonists to control a-adrenoceptor agonist-precipitated coronary artery vasospasm and to avoid /J-blockers, since these could worsen vasospasm (SEDA-21, 4). Interference with laboratory tests The effect of several abused drugs and cocaine metabolites on cocaine and cocaethylene binding to human serum proteins in vitro has been investigated using equilibrium dialysis technique (22). Binding of cocaine was enhanced by codeine, methamphetamine, and cocaethylene, whereas morphine and benzylecgonine reduced it. These findings have important implications for laboratory screening of drugs in blood, because multidrug abuse is common among abusers.
Fenfluramine, dexfenfluramine, and phentermine (SEDA-12, 9; SEDA-19, 2; SEDA-20, 2; SEDA-21, 2) Cardiovascular Vasospasm causing ischemic necrosis of the fingers had been attributed to dexfenfluramine (23c). A 44-year-old non-insulin-dependent diabetic developed pain and discoloration of the left index and small fingers. Three months before he had started to take dexfenfluramine 15 mg bd for mild obesity. Angiography showed occlusion of both digital arteries of the index and small fingers; one digital artery
Central nervous system stimulants and drugs that suppress appetite was occluded in each of the other fingers. Vasospasm in the carpal arch abated with an injection of tolazoline, Dexfenfluramine was discontinued, but despite therapy with local transdermal nitrate, local sympathetic blockade with bupivacaine, and oral nifedipine, the lesion progressed to necrosis, and amputation of the involved distal phalanges was required. Pathological examination showed thrombosis of the digital arteries with gangrenous necrosis but no vasculitis or emboli. He was instructed to awfid dcxfenfluramine. However, some weeks later hc developed mild discoloration of several fingers of the right hand after he look dexfenfluraminc again. Dcxfenfturamine can interfere with serotonin turnover (24cr), and it could be argued that serotonin-induced vasospasm was responsible for this adverse event. L o w e r extremity arterial ischemia has also b e e n reported in a patient who took dexfenfluramine and minocycline (25c). Coronary vasospasm can also be produced by dexfenfluramine, producing myocardial infarction (26r Pulmonary hypertension is a well-known complication of dexfenfluramine.
Cardiac valvulopathies in patients taking fenfluramine and related drugs During the past year several reports have provided evidence linking valvular heart disease to the use o f a combination o f widely used drugs, fenfluramine and phentermine. Phentermine was approved by the FDA in 1959 for single-drug, short-term treatment o f obesity. Subsequently in 1973, fenfluramine was approved on a similar basis. Dexfenfluramine was approved in 1976 as a single-drug, prescription-only appetite suppressant for longer term use in moderately obese people, with a warning that its safety beyond I year o f use had not been established. Recently, both fenfluramines have been used in combination with phentermine and for periods longer than a few weeks. Since 1995 more than 14 million prescriptions have been written for either fenfluramine or dexfenfiuramine, Most o f the use was in women and people aged over 60 years, Based on a median treatment course o f 3-12 months, an estimated 1.2-4.7 million people in the US have been exposed to these drugs.
Chapter 1
Reports and demographic features
Echocardiography in 24 women who were taking fenfluramine-phentermine showed unusual valvular morphology and regurgitation. Both right- and left-sided heart valves were involved. Eight o f these patients also had newly documented pulmonary hypertension. The heart valves had a glistening white appearance and the histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease (27c). These descriptions are limited by a lack of pathological confirmation in the majority o f cases. Many o f these patients continue to be treated medically and have not undergone invasive investigation. Consequently, neither direct inspection or histopathoIogical evahtation has been carried out in most cases. In addition, no routine pretreatment echocardiographic baseline studies were performed. In the absence o f a control group or a case-control study, definitive statements about a true association o f valvular heart disease with fenfluramine-phentermine therapy cannot be made. However, following this landmark publication, several other reports have substantiated these observations. Between October 1994 and July 1997, the Belgian Centre for Pharmacovigilance received 43 reports of valvular heart disease among women who had used anorectic drugs. Echocardiographic confirmation was available in 31 o f these patients, who had had past exposure to anorectic drugs such as fenfluramine (n = 8), fenfluramine and diethylpropion (n = 18), fenfluramine and phentermine ( n = 1), and fenfluramine, diethylpropion, and phentermine (n = 3). The mean duration o f exposure was estimated in 25 patients to be 40 months, and the mean age o f the patients was 42 years. The aortic valve was most frequent involved (in 18 eases). Thirteen patients presented with symptoms such as dyspnea (n = 6), primary pulmonary hypertension (n = 2), and chest pain, chest discomfort, angina, pulmonary edema, and peripheral edema in one patient each (28c). In July 1997the FDA issued a Public Health Advisory asking that other cases be reported, In response, the FDA received 28 additional reports from the US with similar disease; the median age was 45 years and all were women (29CR). The median daily dose o f fenfluramine
4 was 60 mg and o f phentermme 30 mg; the median duration o f therapy before diagnosis o f valvular disease was 10 months. Six patients underwent valve replacement surgery, o f whom one died. In a further update, by 30 September 1997 the FDA had received 144 individual spontaneous reports (including the 24 cases reported earlier) involving fenfluramine or dexfenfluramine with or without phentermine, in association with valvulopathy (30CR). Valvulopathy was defined as "documented aortic regurgitation o f mild or greater severity and or mitral regurgitation o f moderate or greater severity after exposure to these drugs". O f these 144 spontaneous reports 132 had complete information and 113 met the case definition. O f these 113 cases, 98% occurred among women; the median age was 44 years. Out o f these 113 cases 2% had used fenfluramine alone; 14% dexfenfluramine alone; 79% a combination o f fenfluramine with phentermine; and 5% a combination o f all three drugs; none had taken phentermine alone. The median duration o f drug use was 9 months (range 1-39). Overall, 87 (77.1%) o f the 113 cases were symptomatic. A total o f 27 (24%) patients required cardiac valve replacement and three died after surgery. Mechanism It has been postulated that fenfluramine and phentermine potentiate the effect or concentration o f circulating serotonin and could contribute to the development o f valvular injury, similar to that seen in patients with carcinoid syndrome or in those taking ergot derivatives. Serum serotonin and urinary 5-hydroxyindole acetic acid (5-HIAA) have been measured in seven subjects taking fenfluramine and phentermine for a mean duration o f 11 months as adjunct therapy in type 2 diabetes mellitus. None o f these subjects had raised concentrations o f serum serotonin or urinary 5-HIAA (31c). Thus, direct implication o f serotonin has not been substantiated. Two patients with valvular heart disease associated with fenfluramine-phentermine were also taking a selective serotonin reuptake inhibitor (SSR1) (27c). The suggestion that fluoxetine is a safer alternative to fenfluramine in the medical treatment o f obesity (32 c) should be viewed with scepticism. Valves affected Although most o f these pa-
Chapter 1
R.P. Sequeira
tients had either dyspnea or evidence o f congestive heart failure, 14% were asymptomatic. The mitral valve was affected in 24 (86%), the aortic valve in 19 (69%), the tricuspid valve in 11 (39%), and the pulmonary valve in one (4%). A left-sided valve was involved in all cases, and two or more valves were involved in 78%. Pulmonary hypertension was reported in 10 patients, four o f whom had left-sided valvular lesions only. Valvular disease did not resolve in any patient after withdrawal o f the appetite suppressants. Risk factors Factors that are potentially associated with cardiac valvulopathy, but not yet determined, are: ( i ) The natural history o f these lesions, including the relation between the development o f the lesions and the duration o f drug use, and whether the lesions generally resolve, progress, or remain unchanged on drug withdrawal; (2) The clinical importance o f mild valvulopathy in asymptomatic people without audible murmurs; and (3) The characteristics, if any, that might predispose someone to develop cardiac valve abnormalities during exposure to these drugs. Monitoring and prevention Color-flow Doppler echocardi'ographic surveillance o f all persons being treated with appetite suppressants, particularly asymptomatic women, has been recommended (33c). However, the optimal timing o f follow-up echocardiography to determine the progression, regression, or stabilization o f valvular lesions is currently unknown. The US Department o f Health and Human Services has issued the following interim recommendations for people previously exposed to fenfluramine or dexfenfluramine with cardiac valvulopathies (3OR): (1) All people exposed to fenfluramine for any period o f time, either alone or in combination with other anorectic agents, should undergo a medical history and cardiovascular examination by their physician to determine the presence or absence o f cardiopulmonary signs and symptoms. (2) Echocardiography should be performed
Central nervo~ system stimulants and drugs that suppress appetite
(3)
(4)
on all people who have been exposed to fenfluramine or dexfenfluramine for any period of time, either alone or in combination with other agents, and who have cardiopulmonary signs, including a new murmur or symptoms suggestive of valvular disease, such as dyspnea. Any echocardiographic findings that meet the American Heart Association (AHA) criteria for antimicrobial prophylaxis for endocarditis, regardless of whether they are attributable fenfluramine or dexfenfluramine, should be recognized as an indication for antimicrobial prophylaxis. For emergency procedures for which cardiac evaluation cannot be performed, empirical antibiotic prophylaxis should be administered according to A H A guidelines. Because of the prevalence of minimal degrees of regurgitation in the general population, the current definition of drug-associated valvulopathy should include exposed patients with echocardiographically demonstrated aortic regurgitation of mild or greater severity and~or mitral regurgitation of moderate or greater severity, based on published criteria.
Respiratory Pulmonary hypertension has b e e n r e p o r t e d in p a t i e n t s t a k i n g fenfluramine hydrochloride a n d p h e n t e r m i n e h y d r o c h l o r ide (34~ (35c). A 30-year-old woman had a basal metabolic index of 28 kg/m 2, but no history of pulmonary disease, drug abuse, HIV infection, recent pregnancy, immunological disease, or other drug use. After taking fenfluramine and phentermine for 4 weeks, she began to have dyspnea and stopped taking the anorexiants. Six months later she developed progressive dyspnea on exertion and edema and had a syncopal episode. Echocardiography showed right ventricular hypertrophy and dilatation. Cardiac catheterization confirmed the presence of severe pulmonary hypertension. She was given prostacyclin and warfarin. A few months later she died, and at post mortern examination the cause of death was attributed to pulmonary hypertension associated with the use of fcnfluramine-phentermine. Severe plexogenic pulmonary arteriopathy developed in a 29-year-old woman who had taken fenfluramine and phentermine for 23 days. She probably had not had any pre-existing disease, and the histo-
Chapter 1
5
logical age of the lesion was consistent with the time elapsed since she had taken the drugs. In b o t h of these cases, the short d u r a t i o n of drug e x p o s u r e is worth noting ( S E D A - 1 8 , 7; S E D A 21, 2). Nervous system Cerebral hemorrhage has b e e n a t t r i b u t e d to fenfluramine with p h e n t e r mine (36c). A 56-year-old woman suddenly developed weakness and clumsiness of her right leg and right arm. She had taken dl-fenfluramine 20 mg/day and phentermine 15 mg/day for obesity for 6 months. CT and MRI scans showed a hemorrhagc in the medial aspect of the left motor cortex with a small amount of surrounding edema. Fenfluramine and phentermine were withdrawn. Her right hcmiparesis gradually resolved over 3 months, when MRI showed complete resolution. A l t h o u g h the a u t h o r s of this r e p o r t suggested t h a t f e n f l u r a m i n e - p h e n t e r m i n e m a y h a v e c o n t r i b u t e d to the d e v e l o p m e n t of cerebral h e m o r r h a g e , o t h e r causes, particularly cryptic a r t e r i o v e n o u s m a l f o r m a t i o n s , could not b e c o m p l e t e l y excluded. T h e i n t e r m i t t e n t aspirin the p a t i e n t was using for b a c k pain could also have c o n t r i b u t e d (37R). Psychiatric V a r i o u s psychiatric a d v e r s e effects of d e x f e n f l u r a m i n e h a v e b e e n r e p o r t e d (38c), (39c). In the first case psychotic episodes associated with d e x f e n f l u r a m i n e w e r e p r o b a bly due to a n i n t e r a c t i o n of d e x f e n f l u r a m i n e with d o x e p i n (38c). In t h e s e c o n d a direct effect of d e x f e n f l u r a m i n e was suggested (39c). A 56-year-old white woman with bipolar depression developed distinct mood cycles 2 weeks after starting to take dexfenfluramine. Her symptoms included anger, homicidal thoughts, racing thoughts, and labile moods. She was unable to control her mood. Her sleep changed minimally with continued use of zolpidem. She reverted to a long-quiescent pattern of alcohol abuse. The dexfenfluramine was withdrawn and the dosage of alprazolam was increased to 2 mg bd. Her other medications (divalproex, carbamazepine, molindone, zolpidem) were unchanged. Within 3 days her mixed-manic, rapidcycling state improved and in 2 weeks she achieved baseline status. In a n o t h e r case psychotomania o c c u r r e d after t r e a t m e n t with fenfluramine a n d p h e n t e r m i n e in a d e p r e s s e d w o m a n (40c). O n two
Chapter I separate occasions she experienced similar symptoms with fenfluramine and phentermine. These reports emphasize the need to use appetite suppressants judiciously in patients with pre-existing psychiatric illness, although it is difficult to establish a definite association between these adverse effects and use of anorectic drugs (SEDA-19, 2).
Interaction Attention has been drawn to a possible interaction between fenfluramine and imipramine, mediated via the inhibition of cytochrome P450 (41c). A 55-year-old woman had generalized anxiety, in remission with imipramine 350 mg/day. During this period she also took hyoscyamine sulfate, 0.375 mg/day, and levothyroxine sodium 0.15 mg/day. Her imipramine concentration at the end of each of the previous years of treatment was 145218 mg/l. Four weeks after the addition of fenfluramine, 20 mg tds, she complained that she had momentarily fallen asleep while driving. Her imipramine plus desipramine concentration was 704 mg/l. Fenfluramine was withdrawn, and no further episodes of daytime sleepiness were reported. Her blood concentration of imipramine and desipramine 2 weeks later was 252 mg/l. hnipramine metabolism depends on CYP1A2, CYP2C, CYP2D6, and CYP3A4 (42R). Although fenfluramine might inhibit some of these isoenzymes, there is no published evidence that it does. It is prudent to be aware of the potential for fenfluramineimipramine interaction.
Ephedrine and pseudoephedrine (SED-13, 350; SEDA-21, 5) Skin and
appendages
A
non-pigmentary
fixed drug reaction has been attributed to ephedrine and pseudoephedrine (43c). A patch test and oral rechallenge produced eruptions at the same site. The dermis, rather than the epidermis, is the primary site of the drug sensitivity response in this type of dermatitis (44c).
R.P. Sequeira
vary amylase in about one-third of women with pre-term labor contractions (45c).
Methylphenidate (SEDA-20,
3;
SEDA-21, 6) Recent studies (46c)-(48 c) have addressed the safety issues related to the use of methylphenidate in children with attention deficit hyperkinetic disorder (ADHD). Nearly 80% of children treated with methylphenidate experienced appetite suppression, affecting body weight and height. However methylphenidate also exacerbated tics. In patients with marked anxiety, agitation, or psychotic disorders these symptoms may be precipitated methylphenidate. Patients with mental retardation and children under 6 years old are at risk of adverse effects such as irritability and depressed mood. The most common adverse effects of methylphenidate include sleep problems, anorexia, stomach ache, and headache (for a comprehensive review see (49R),
(50~)). Interactions A n interaction of methylphenidate with sertraline has been described (51c).
A 13-year-old white man with a history of ADHD and a depressive disorder had taken methylphenidate 1.8 mg/kg per day for nearly 10 months. Because of worsening of his mood disturbances, sertraline 25 rag/day was added. One week later he had a tonic-clonic seizure. Sertraline was withdrawn and methylphenidate continued unchanged. There was no recurrence. Although this may be first reported case of seizure activity in someone taking sertraline and methylphenidate, this report does not provide convincing evidence of an interaction, particularly because blood concentrations were not determined. The possibility of a cytochrome P450-mediated drug interaction as an underlying mechanism has yet to be explored.
Prolintane Effects on laboratory tests Clinical doses of /3-adrenoceptor agonists, including ritodrine and ephedrine, cause hypersecretion of sali-
Prolintane hydrochioride is available mainly in formulations containing multivita-
Central nervous system stimulants and drugs that suppress appetite rain supplements in many European countries, Australia, and South Africa. It has structural and pharmacological properties similar to dextroamphetamine. Its adverse effects include insomnia, nervousness, irritability, euphoria, headache, dizziness, and psychotic reactions. Acute overdosage can cause cardiorespiratory arrest and death. A patient who developed a panic attack after taking Katovit| (prolintane with multivitamins) has been reported to the Spanish Drug Surveillance Scheme (52c). The authors pointed out that none of the 30 physicians questioned about this formulation was aware that prolintane is related to amphetamine. They urged that in countries in which prolintane is marketed in combination with vitamins, this irrational combination should be withdrawn in view of the public health risk.
OTHER DRUGS
CENTRALLY
ACTING
(SEDA-19, 4, 148; SEDA-20, 4; SEDA-21, 6) Pemoline
(SEDA-21, 6)
There is considerable interest in giving pemoline to children with A D H D who do not respond to methylphenidate (53~), (54c). However, troubling adverse effects occurred when the maximum recommended dose was used. Among seven children, two developed tics and one hallucinations (54c).
Liver The available data on pemoline-associated hepatotoxicity have been reviewed and the need to establish an adverse reactions registry has been emphasized (55R). A 19year-old woman with A D H D was treated with methylphenidate and pemoline and developed reversible hepatitis (56c). There is no evidence that methylphenidate predisposed her to pemoline hepatotoxicity. However, there is no indication for using multiple stimulants to treat ADHD.
Chapter 1
7
Tacrine (SEDA-19, 4, SEDA-20, 4; SEDA-21, 6) The American Psychiatric Association has published practice guidelines for the treatment of patients with Alzheimcr's disease and other dementias of late life (57n). The F D A has described a 'Treatment-Investigational New Drng (TIND)" prolocol, whereby largc volumes of data related to clinical trials can be handled rapidly and effectively (58cr~). Serious adverse events have been reported directly to trained operators and summarizcd on a weckly basis for reporting to the FDA: 1951 physicians agreed to participate and 10 187 patients wcre enrolled; 9861 (96.8%) of these were taking tacrine. One or more serious adverse events were reported by 1148 (12%) patients (1206 events in all), the most frequently reported adverse event being a raised A1T (337 patients). A comprehensive review of risk:benefit assessment of tacrine in the treatment of Alzheimer's disease, including treatment guidelines for prescribing tacrine and recommendations for monitoring toxicity, has been described (59R). Since only about one-third of patients with Alzheimer's disease respond favorably to tacrine, the search for prcdictors of favorable/unfavorable responses continues. Patients with white matter low attenuation, also known as leukoaraiosis (periventricular hypodense areas on CT scan), can still respond to tacrine, although the rate of withdrawal from treatment is much higher in these patients (60c). The small number of patients in this study (n = 72) precludes firm conclusions as to whether leukoaraiosis is a predictor of the efficacy and tolerability of tacrine.
Psychiatric Two cases of tacrine-associated depression have been reported (61~). Two elderly women (aged 82 and 70 years) had taken tacrine hydrochloride 40 mg/day for at lcast 1 month. They developed symptoms of depression and had Hamilton Depression Rating Scale Scores of 27 and 29. The 82-year-old did not respond to fluoxetine 201)mg/day for 35 days, but improved with a course of ECT; the other improved with fluoxetine alone. Tacrine was withdrawn. Based on the evidence provided, it is diffi-
Chapter 1 cult to accept with any d e g r e e of certainty that i n d e e d t h e r e is an association b e t w e e n tacrine t r e a t m e n t a n d depression. Considering the use of tacrine in a large n u m b e r of patients with A l z h e i m e r ' s disease, the association, if any, is p r o b a b l y very weak. A n t i d e p r e s s a n t s , such as fluvoxamine, are o f t e n given to p a t i e n t s with
Interactions
A l z h e i m e r ' s disease who are also given tacfine. T h e i n t e r a c t i o n b e t w e e n t h e m has therefore b e e n investigated in 13 h e a l t h y volunteers in a d o u b l e - b l i n d , r a n d o m i z e d crossover c o m p a r i s o n of t h e effects of fluvoxamine (100 mg/day for 6 days) a n d p l a c e b o o n the p h a r m a c o k i n e t i c s of a single dose of tacrine
R.P. Sequeira
(40 m g ) (62c). F l u v o x a m i n e r e d u c e d the app a r e n t n o n - r e n a l clearance of tacrine a n d inc r e a s e d the plasma c o n c e n t r a t i o n s of its t h r e e m o n o h y d r o x y l a t e d m e t a b o l i t e s . T h e s e results are a t t r i b u t a b l e to i n h i b i t i o n by fluvoxamine of C Y P 1 A 2 , which is r e s p o n s i b l e for the biot r a n s f o r m a t i o n of tacrine to its inactive hydroxylated m e t a b o l i t e s a n d its reactive m e t a b o lites, which are p o t e n t i a l l y toxic if not c o n j u g a t e d with g l u t a t h i o n e (63R). Five subjects h a d gastrointestinal a d v e r s e effects, b u t the clinical c o n s e q u e n c e s of c o n c o m i t a n t prescription of tacrine a n d inhibitors of C Y P 1 A 2 , such as fluvoxamine (12), in p a t i e n t s with A l z h e i m e r ' s disease c a n n o t b e e x t r a p o l a t e d from this study.
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Chapter 1
R.P. Sequeira
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