Central nervous system stimulants and drugs that suppress appetite

Reginald P. Sequeira

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Central nervous system stimulants and drugs that suppress appetite

AMPHETAMINES

(SED-15, 180; SEDA-28, 4, 28; SEDA-29, 1; SEDA-30, 1)

Note on spelling: In International Nonproprietary Names (INNs) the digraph -phis usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (e.g. compare fenfluramine and phentermine) or when a name that begins with a phis modified by a prefix (e.g. chlorphentermine). For the amphetamines the spellings that are used in SEDA are as follows: amfetamine, benzfetamine, dexamfetamine, metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy); however, for the general term for the group of drugs the more common spelling “amphetamines” is used.

defined as twice per week for at least 3 months, or once a week for at least 1 year. In most cases, prior amphetamine exposure was unknown to the treating physician. The study did not distinguish between prescribed and non-prescribed use of amphetamines. A previous study had suggested amphetamine exposure as a possible risk factor for Parkinson’s disease (3c).

Ecstasy (3,4-methylenedioxymetamfetamine, MDMA) See Chapter 4.

Metamfetamine

(SEDA-29, 3;

SEDA-30, 2) Nervous system Two young women had strokes from carotid artery dissection following chronic metamfetamine use; extensive workup failed to reveal any other risk factors (1A). In a case–control study using a telephone survey in California, prolonged exposure to amphetamines (amfetamine, metamfeta­ mine, or dexamfetamine) was associated with an increased rate of Parkinson’s disease (2c). “Prolonged exposure” was Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03101-8 r 2009 Elsevier B.V. All rights reserved.

Cardiovascular Patients with idiopathic pulmonary arterial hypertension (PAH) are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension. In a retrospective study, rates of stimulant use were determined in 340 patients with idiopathic PAH, PAH with known susceptibility factors, or chronic thromboembolic pulmonary hypertension. “Stimulant” use was defined as any self-reported use of amfetamine, metamfetamine, or cocaine (4C). There was a history of stimulant use in 29% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor (such as portopulmonary hypertension,

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Reginald P. Sequeira

HIV-related pulmonary hypertension, col­ lagen vascular diseases, congenital sys­ temic-to-pulmonary shunts, persistent pulmonary hypertension of the newborn, and drug-related pulmonary hyperten­ sion), and 4.3% of patients with chronic thromboembolic pulmonary hypertension. The central finding was that metamfeta­ mine exposure appears to be strongly associated with idiopathic PAH. Patients with idiopathic PAH were about 10 times more likely to have a history of stimulant use than patients with PAH and known susceptibility factors and almost 8 times more likely to have a history of stimulant use than patients with chronic throm­ boembolic pulmonary hypertension, after adjustment for age. These ratios are similar to those found in studies with fenfluramine (5C,6C). Despite methodolo­ gical limitations inherent in a retrospective chart review study, these preliminary results are important, because of the widespread and increasing use of both prescription and illicit stimulants.

benzodiazepines (midazolam, lorazepam, or diazepam) and haloperidol were used to control agitation. A median dose of haloperidol (0.05 mg/kg) was given intra­ venously. There were no reports of respiratory depression, intubation, prolon­ gation of the QT interval, dystonic reac­ tions, or aspiration associated with the use of benzodiazepines and haloperidol (8c). However, the role of haloperidol as an adjunct to benzodiazepines in the man­ agement of metamfetamine-poisoned chil­ dren needs further evaluation. Some clinicians may have reservations about using haloperidol to sedate ampheta­ mine-poisoned patients, because of con­ cerns about its ability to impair heat dissipation and the risk of worsening hyperthermia associated with metamfeta­ mine toxicity. Furthermore, patients with different severities of illness may already have received haloperidol from another physician in the emergency department or ICU.

Susceptibility factors Genetic An Ala/ Val polymorphism of the superoxide dismutase 2 (SOD2) gene could be associated with a risk of metamfetamine psychosis (7C). Metamfetamine psychosis has been studied in 116 patients and 189 controls in Japan, and in 135 patients and 204 controls in Taiwan. Those who had taken metamfe­ tamine were divided into two clinical subtypes: a transient type of psychosis (i.e., a good prognosis) and a prolonged type of psychosis (i.e., a poor prognosis). There was a significant difference between individuals with prolonged metam-fetamine psychosis and controls from both Japan and Taiwan, in the genotypic and allelic frequen­ cies of an Ala/Val functional polymorphism in exon 2. These results suggest that an Ala/ Val polymorphism of the SOD2 gene could be associated with the risk of metamfetamine psychosis.

Atomoxetine

Management of adverse drug reactions In a case series of 18 children with metamfetamine poisoning, parenteral

Atomoxetine is a non-stimulant noradre­ naline reuptake inhibitor that is efficacious in the treatment of ADHD (9R). Sudden deaths of children and adolescents taking Adderall XRs have led to the need to screen children for risks of heart defect before beginning this stimulant medication. The label for atomoxetine has been altered to include a boxed warning and additional warning statements regarding an increased risk of suicidal thinking in children and adolescents treated with this medication. An association of ADHD and completed suicide, particularly in adolescent males, has been reported (10R). However, there is little evidence to suggest a direct link. Rather, co-morbidities (such as mood dis­ orders, conduct disorder, and substance abuse) that are commonly associated with ADHD may lead to an increased risk of completed suicide, and may be related to increased suicidal ideation in patients taking atomoxetine.

Central nervous system stimulants and drugs that suppress appetite

Methylphenidate

(SED-15, 2307; SEDA-29, 10; SEDA-30, 4)

The complexities and controversies of ADHD, including new treatment options, have been reviewed (9R). Transdermal methylphenidate produces blood concen­ trations and behavioral improvements simi­ lar to oral methylphenidate. Observational studies In a preliminary study in 32 women with breast cancerrelated fatigue, methylphenidate reduced the Brief Fatigue Inventory score (11c). Six patients (19%) withdrew owing to adverse events such as restlessness/anxiety (16%), dizziness (8%), headache (8%), palpitation (2%), and back spasm (2%). While evalua­ tion of fatigue, a subjective symptom whose presence or severity is difficult to prove, the quality of life of cancer patients is an important component of management. The promising results of this study need to be replicated in a randomized controlled trial. Cardiovascular Hypertension has been attributed to methylphenidate in a child with ADHD and ultrarapid metabolizer status of CYP2D6 (12A).
A 6-year-old Caucasian boy with ADHD took

methylphenidate 10 mg/day for 2 months and developed arterial hypertension; his blood pressure rose from 100/60 to 140/110 mmHg. A dosage reduction to 5 mg/day did not normalize the blood pressure; methylpheni­ date was withdrawn and the hypertension abated. He was subsequently given amitripty­ line, but the plasma concentrations were low and clomipramine was used instead.

Since the plasma concentration of amitriptyline was very low, genotyping and phenotyping of CYP2D6 was performed. He had three functional alleles and was therefore considered to be an ultrarapid metabolizer, confirmed by phenotyping with dextromethorphan. He was homozygous for a functional allele of the CYP2C9 gene and heterozygous for a nonfunctional allele of the CYP2C19 gene; these genotypes are compatible with normal enzyme activities. The metabolism of methylphenidate does not involve CYP2D6 (13c). Therefore, the

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CYP2D6 status of the child does not explain the arterial hypertension observed during treatment with methylphenidate. The formation of a toxic metabolite in ultrarapid metabolizers is speculative. Nervous system In a double-blind, pla­ cebo-controlled study there was no increased risk of first-onset tics in children with ADHD taking methylphenidate (14cr). Although there may be a close temporal relation in a few patients, the roles of treatment duration, dose of stimulant, genetic vulnerability, and developmental aspects need to be further explored to clarify possible pathophysiological mechan­ isms of the occurrence of tics in those taking stimulants. Earlier equivocal views about tics during methylphenidate treatment might be explained by the shortcomings of the few studies on first-onset tics during stimulant treatment, such as small sample sizes and unclear disentangling of first-onset tics from exacerbation of pre-existing tics. Important confounders include waxing and waning of tics and a high frequency of transient tics at an age when stimulant medication is usually started (15R). Methylphenidate-associated rabbit syndrome (a movement disorder characterized by involuntary, rapid, fine, rhythmic, vertical movements of the perioral muscles resem­ bling the chewing movements of a rabbit) has been described in an 8-year-old boy (16A). There were no associated tongue move­ ments or any other signs of extrapyramidal symptoms. He scored 5 (most severe) on the Abnormal Involuntary Movement Scale. There was complete resolution within 2 days after methylphenidate withdrawal. Psychological In a double-blind, placebocontrolled, crossover study in eight patients with a frontal variant of frontotemporal dementia, methylphenidate attenuated risk-taking on a laboratory measure of decision-making (the Cambridge Gamble Task) (17c). This was a relatively selective effect, since there were no measurable effects of drug treatment on recognition memory, planning, extradimensional shift­ ing, or working memory.

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Psychiatric An association between stimu­ lants and mania or psychosis, in therapeutic doses, has been described anecdotally (18r). It is estimated that toxicosis occurs in about 1 in 400 children taking stimulants, a proportion that suggests an infrequent but not rare adverse effect of therapeutic dosing.
After taking a modified-release formulation

of methylphenidate 40 mg/day for 8 months, a 7-year-old boy developed a flu-like illness and new symptoms, which included “complaints of hearing voices and seeing adults” when no one was present, a desire to “throw himself down the stairs,” high anxiety, tearfulness at school, irritability, and an unwillingness to leave his mother’s side (19A). The dose of methylphe­ nidate was reduced to 20 mg/day, and over the following 3 weeks the psychotic-like symptoms gradually resolved. Several months later, again after a flu-like illness, he developed a milder version of the same symptoms. During this episode, methylphenidate was withdrawn, and all his symptoms resolved within 36 hours. Methylphenidate was reintroduced a week later and the symptoms did not recur. His attention dysfunction markedly improved.

This case raises questions about the diagnosis and treatment of psychotic-like and manic-like symptoms that arise during stimulant use in children with ADHD. Susceptibility factors Genetic There was no association between the dopamine trans­ porter gene DAT1 and a variable number of tandem repeats (VNTR) and the therapeutic response to methylphenidate or cardiovas­ cular adverse effects in a double-blind, 6­ week, randomized, placebo-controlled, paral­ lel-design study of methylphenidate in 285 adults with ADHD (20C). Subjects homozy­ gous for the 10-repeat DAT1 allele were not distinguishable from heterozygous 9/10 or homozygous 9-repeat allele subjects in level of symptom reduction, dose required for response, cardiac adverse effects, or sponta­ neously reported adverse effects. In a previous study there was no difference in response based on DAT1 (21C). A lack of consistency in the literature could be due to etiological heterogeneity or, more likely, small sample sizes that lead to reduced power or falsepositive findings (22R). It is important to note

Reginald P. Sequeira

a limitation of this study: examining a single marker does not provide adequate informa­ tion about other variants across this large gene. A previous study examined three additional single nucleotide polymorphisms (SNPs) in the promoter region of the gene and failed to find any association with response to methylphenidate (21C). In methylphenidate-treated preschool children with ADHD there was an associa­ tion between symptom response and variants at the dopamine receptor DRD4 promoter and the synaptosomal membraneassociated protein 25 (SNAP 25) alleles T1065G and T1069C (23C). SNAP 25 variants were associated with tics, buccolin­ gual movements, and irritability. DRD4 variants were associated with picking. Increasing dose predicted irritability and social withdrawal with DRD4 variants. There were no significant effects of the dopamine transporter DRD1. These results require replication with more specific hypotheses, larger samples, and conserva­ tive levels of significance. Other candidate genes, additional variants, or haplotypes may better predict methylphenidate response. Effects may also be caused by unidentified polymorphisms in linkage dis­ equilibrium with the selected candidates. Genome-wide investigations that make no prior assumptions about likely candidates are better suited to assess genetic contribu­ tion to response, but are more expensive and require much larger sample sizes.

Effects of stimulant treatment on growth in children and adolescents with ADHD Stimulant medications are the most commonly used agents for the management of ADHD, and methylphenidate is the most widely prescribed. Its safety and efficacy have been established in more than 50 randomized controlled trials (24M) and after decades of clinical experience (25R). Because ADHD is a chronic condition that often persists into adolescence and adulthood, patients generally take stimulant drugs for many years.

Central nervous system stimulants and drugs that suppress appetite

There has been controversy as to whether stimulant treatment reduces growth in children with ADHD. Effects on growth in children with ADHD were first reported in the 1970s (26C, 27C, 28c), and were supported by several later studies (29c, 30C, 31C). However, other studies have contradicted these results (32C, 33C, 34c, 35c). Some have suggested that growth suppression is associated with ADHD rather than the medication (36C) and that the effect is limited to childhood and early adolescence (37C), and in females (38C). It is also possible that the risk of growth suppression is limited to a small subset of children with ADHD (39C). The use of Z scores (height data standardized according to age) is considered to be an accurate method for measuring growth deficits, especially when assessing growth across different ages (40H). Similar standardization can be applied to body weight data, although standardized body mass index is regarded as more useful measure of effects on weight. Recent studies that have evaluated effect of stimulants on growth parameters have used Z scores (36C, 38C). Other methodological issues are important: for example, dose and drug holidays can affect the effect size of stimulants on growth (41cr). Considerable variation in physiological growth velocity among children should also be considered when interpreting the effect size. The dose and formulation type change over time in response to the child’s clinical situation, and addition of medications may also be necessary for controlling symptoms. Most of the earlier studies on growth in children with ADHD taking stimulant medications rarely extended beyond 1 year. Differential effects of methylphenidate and mixed amfetamine salts on height in children with ADHD have been evaluated by retrospective analysis of data. Neither the type of stimulant used to treat ADHD nor the duration of treatment was related to changes in height Z scores. No effects of sex were evident. Linear regression showed a small but statistically significant negative relation between the cumulative dose of stimulant and change in height. Stimulant treatment appears to have an impact on weight, patients

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becoming thinner over time, and this effect was more pronounced in patients taking mixed amfetamine salts (42C). There remain many unanswered questions about growth in children with ADHD. To resolve the question of stimulant effects on growth, it may be necessary to study a sample of children with ADHD and matched controls, longitudinally, from the onset of treatment in childhood through adolescence and into young adulthood. Growth rates have been studied in 79 children with ADHD aged 6–12 years followed annually for up to 5 years after the start of stimulant treatment (43C). Annual height and weight, reported as Z scores, were standardized for age and sex. Methylphenidate dose was standardized in mg/kg and hierarchical linear modeling was used to determine the influence of dose and duration of stimulant treatment on the rate of growth in height and weight. Adherence to stimulant medication was defined as “the child taking methylphenidate (regular or slow-release), dextro-amfetamine (regular or slow-release), or pemoline for Z5 days/week, with the exception of drug holidays when not in school.” Drug holidays totaled not more than 14 weeks per year. There was a small but distinct risk of reduced rate of growth in children with ADHD who used stimulants for prolonged periods of time at doses equivalent to at least 42.5 mg/day methylphenidate for at least 4 years. The estimates for impaired growth after prolonged use revealed a dose-dependent pattern, with earlier effects at lower doses on the rate of weight gain than on the rate of height gain. Most probably, the appetite suppressant effect of stimulants is the cause of the reduced weight gain. In turn, compromised weight gain over several years may slow the rate of growth in height. There were several limitations to this study, such as the lack of an untreated control group and the use of standardized growth charts that do not provide specific information about the growth trajectories of children with ADHD, which presumably differ (44C). Pubertal staging was not considered in the growth model. Also, collapsing the data for dexamfetamine and methylphenidate into one dosepotency variable complicates the interpretation.

6 Because the study occurred in the 1990s in Canada, the results may not reflect patterns of growth that might occur with currently available modified-release formulations. A modified-release formulation of methylphenidate (OROS methylphenidate) has gradually replaced immediate-release methylphenidate as a stimulant for use in ADHD. The effect of OROS methylphenidate on growth has been evaluated for 21 months in 178 subjects in an open study (44C). The effect of prolonged OROS methylphenidate on growth was clinically insignificant and limited to a slight reduction in weight during the first months of therapy. Drug holidays did not reduce any impact on growth. The authors concluded that drug holidays are of unproven value for limiting potential effects of treatment on growth. Several assumptions have been made in the design and data analysis of this study. First, for ethical reasons, the study did not include an untreated control group. The putative effect on growth was determined by calculating Z scores. This assumes that the subjects in this study were representative of the general US population, which was not necessarily so. The assumptions that changes in Z scores reflect effects of stimulant therapy rather than other factors, such as diet, may not be appropriate. Second, most of the children in this study (86%) had previously received stimulant therapy. Because the impact on growth tends to be greater in stimulant-naive children, the study would have underestimated the initial effect on growth. Third, the study involved children aged 6–13 years old, so the data may not necessarily be applicable to younger children or to adolescents. In conclusion, there is now reasonable evidence to believe that typical doses of stimulants, equivalent to methylphenidate 1.5 mg/kg/day, are unlikely to produce clinically significant growth suppression in children with ADHD. Even so, regular monitoring of growth is necessary in all children exposed to stimulant treatment for several years. Whether any minimal changes in growth are of concern would depend on the individual child’s stature. The clinical management of a slowed rate of growth may include dosage adjustment, medication

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Reginald P. Sequeira

withdrawal, or consideration of alternative therapeutic agents. There seems to be no rationale for routine use of drug holidays in an attempt to maintain a normal pattern of growth in otherwise healthy children with ADHD. There is a need to study a cohort of children with ADHD and matched controls longitudinally from the onset of treatment in childhood through adolescence and into young adulthood. This is particularly true in an era when many children with ADHD continue taking stimulant treatment into late adolescence and adulthood.

Adverse effects of methylphenidate at different ages The adverse effects of methylphenidate in patients of different age groups with ADHD have been evaluated. Preschool children In 183 preschool children with ADHD, aged 3–5 years, there was a higher rate of methylphenidate withdrawal because of spontaneously reported adverse events than in school-age children. Also, the pattern of adverse events such as irritability, emotional outbursts, difficulty in falling asleep, repetitive behaviors and thoughts, and reduced appetite was more common, and resulted in treatment withdrawal in 11% of children (45C). These results are in agreement with a previous observation that preschool children with ADHD may experience more stimulant-related adverse events than older children (46c). Adolescents In a multisite, double-blind, placebo-controlled, four-phase study, OROS methylphenidate produced clinically and statistically significant improvements in ADHD in 220 adolescents aged 13–18 years (47C). Individualized dosages of OROS methylphenidate (a modified-release formulation) were titrated (18, 36, 54, or 72 mg/ day). Efficacy was measured using investigator, parent, and patient assessments. The most frequently reported adverse events considered by investigators to be treatmentrelated during the open dose-titration phase

Central nervous system stimulants and drugs that suppress appetite

of the study included headache (25%), reduced appetite (21%), insomnia (15%), and abdominal pain (9%). During the double-blind phase, 16 subjects (16%) taking placebo reported at least one adverse event deemed by the investigators to be probably or possibly related to the medication. Serious adverse events were reported in only one subject during the open dosetitrating phase: a 16-year-old woman with a history of depression and suicidal ideation threatened suicide on the third day; her symptoms resolved after withdrawal of methylphenidate. These findings should be interpreted in light of the methodological limitations of the study. Adolescents with unstable psychiatric and medical disorders and clinically important concurrent psychiatric co-morbidity requiring treatment were excluded. Moreover, the study design may have biased the results, favoring improved efficacy and tolerability in the double-blind phase. Accordingly, these findings may not be generalizable to routine clinical practice. Adults Treatment with OROS methylphenidate (a modified-release formulation) in daily doses of up to 1.3 mg/kg was effective in the treatment of 141 adults with ADHD (48C). These results were based on a randomized, 6-week, placebo-controlled, parallel-design study. Although methylphenidate was associated with a higher drop-out rate because of adverse effects (14% versus 4%), there were no serious adverse effects. Methylphenidate was associated with higher incidences of anorexia, dry mouth, moodiness and anxiety, insomnia, subjective cardiovascular complaints, and dizziness. In addition to subjective complaints of reduced appetite, those taking methylphenidate were statistically more likely to lose weight over the course of the 6-week study. There was an increase in heart rate and blood pressure in addition to the subjective reports of cardiovascular symptoms: a minority of those who took methylphenidate had systolic blood pressures over 140 mmHg (8%) and heart rates over 100 per minute (9%). Hence, adults with ADHD, particularly those with borderline hypertension or those who are underweight, should be monitored for

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changes in blood pressure or weight loss when they take methylphenidate.

Drug–drug interactions Cocaine Methyl­ phenidate did not significantly alter the pharmacokinetics of cocaine in seven non­ treatment-seeking cocaine-dependent indi­ viduals in a placebo-controlled, crossover study (49c). Two doses of oral methylphe­ nidate (60 and 90 mg) and two doses of cocaine (20 and 40 mg) were administered by infusion. Methylphenidate was well tolerated and did not alter the effects of cocaine on blood pressure and heart rate, and reduced some of its positive subjective effects. A similar finding that methylpheni­ date attenuates some of the subjective effects of cocaine has also been reported (50c). Although these studies provide evidence for the safe use of methylphenidate in a cocaine-abusing population, there were several deficiencies in the study design, conclusions, and generalizability of the results. The safety of methylphenidate among cocaine abusers with cardiovascular disease, including hypertension, is yet to be established.

Modafinil

(SED-15, 2369; SEDA-29, 10;

SEDA-30, 6) Placebo-controlled studies In a rando­ mized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines, modafinil increased certain aspects of cognitive function and improved participants’ ability to attend post-nightshift didactic classroom sessions, but made it more difficult for them to fall asleep whenever there was an opportunity (51C). The participants were emergency depart­ ment residents and attending physicians (n ¼ 25). The symptoms that they recorded after taking modafinil 200 mg included headache (n ¼ 2), anxiety (n ¼ 2), nervousness (n ¼ 2), nausea (n ¼ 1), euphoria (n ¼ 1), abnormal vision (n ¼ 1), and

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diuresis (n ¼ 1). The only symptom reported by participants taking placebo was diarrhea (n ¼ 1). Susceptibility factors Old age Elderly people may have an increased risk of drug-induced hyperkinetic movement disorders (52A).

Reginald P. Sequeira

average 35% increase in plasma concentra­ tions of caffeine in healthy men, probably because of a proportional reduction in its metabolic clearance mediated by CYP1A2 (54c). Concomitant administration of caf­ feine with propafenone should probably be avoided in patients with atrial fibrillation or atrial flutter and especially in those with reduced CYP2D6 activity.


A 76-year-old woman with a history of major

depressive disorder (DSM-IV) was given venlafaxine and zopiclone. Modafinil (200 mg/day) was added and there was rapid improvement and full remission from depres­ sion after 2 weeks. She was discharged taking venlafaxine 150 mg/day and modafinil 200 mg/ day. After 4 months of continuous treatment she developed bothersome, non-dystonic, hyperkinetic, involuntary movements affecting the orofacial region and legs. After modafinil withdrawal her movements improved and resolved within 4 days.

METHYLXANTHINES

(SEDA-

28, 1; SEDA-29, 1; SEDA-30, 5)

Caffeine (SED-15, 588; SEDA-29, 1; SEDA-30, 5) Drug–drug interactions Fluvoxamine Caffeine significantly reduced the plasma concentrations and total AUC of fluvoxamine in 12 healthy men (53c). Genotyping confirmed that none of the subjects was a poor metabolizer of CYP2D6. Caffeine did not change the tmax or terminal half-life of fluvoxamine and did not change its pharmacodynamic effects. There were two drawbacks in this study. First, caffeine treatment for 11 days might have been too short to produce full induction of CYP1A2. Second, caffeine concentrations were not measured when fluvoxamine was administered. Never­ theless, since patients taking antide­ pressants probably often consume caffeinated beverages, this study has important implications. Propafenone Concomitant administration of propafenone and caffeine leads to an

Theophylline (SED-15, 3361; SEDA-29, 1; SEDA-30, 5) Nervous system Encephalopathy has been reported in a patient taking theophylline (55c).
A 12-year-old girl who had been taking

theophylline for bronchial asthma developed an acute encephalopathy with refractory status epilepticus, and had bilateral mesial temporal and claustral lesions. A marker of oxidative stress, 8-hydroxydeoxyguanosine, was increased in the cerebrospinal fluid, plasma, and urine. The theophylline plasma concentration was in the target range.

The authors speculated that oxidative stress was associated with refractory status epilepticus, accompanied by neuronal damage, due to theophylline, despite the fact that the plasma concentration was not raised, which is often so in such cases (56cr). Serial measurements of oxidative stress markers, including 8-hydroxydeoxyguanosine, could clarify the relation between acute brain damage and free radicals. Susceptibility factors Liver disease Flu­ voxamine-induced inhi-bition of theophyl­ line clearance fell from 62% in healthy subjects (n ¼ 10) to 52% in patients with mild cirrhosis (Child class A; n ¼ 10) and 12% in those with severe cirrhosis (Child class C; n ¼ 10). CYP1A2-mediated forma­ tion of 3-methylxanthine and 1-methyluric acid was almost completely inhibited in control subjects, whereas they were only reduced by one-third in patients with severe cirrhosis. Inhibition of the formation of

Central nervous system stimulants and drugs that suppress appetite

1,3-dimethyluric acid, which is catalyzed by CYP1A2 and CYP2E1, progressively fell from 58% in healthy subjects to 43 and 7% in patients with mild and severe cirrhosis, respectively (57c). The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elim­ ination is a general phenomenon, indepen­ dent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less important as liver function deteriorates. The two impor­ tant mechanisms are: (a) reduced sensitivity to fluvoxamine of CYP1A2-mediated bio­ transformation in the cirrhotic liver, prob­ ably resulting from reduced uptake of the inhibitory drug, and (b) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.

DRUGS THAT SUPPRESS APPETITE (SEDA-28, 6; SEDA-29, 11; SEDA-30, 7)

Cardiovascular The adverse effects of drugs used for weight loss and the treatment of obesity have been reviewed (58R). The Surveillance of Pulmonary Hypertension in America (SOPHIA) Group has been monitoring both primary and secondary pulmonary hypertension. The data on newly diagnosed cases (n ¼ 1335) from 13 tertiary pulmonary hypertension centers showed no epidemic of anorexigen-related PAH. The SOPHIA registry was established 3 months after fenfluramines were withdrawn from the market. The use of fenfluramine derivatives and associated pulmonary hypertension in many cases is consistent with prior studies. The associations of PAH with St John’s wort and over-the­ counter diet pills that contain phenylpropanolamine were new and unexpected findings (59Cr).

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Phentermine (SED-15, 2804; SEDA-27, 4) Drug contamination Despite the with­ drawal of many appetite suppressants from the market, illegally imported “weight­ reducing products” may still contain these unsafe drugs. They are promoted to the general public through the electronic media, print advertisements, and health food stores. A case of cardiac arrhythmia caused by an illicit “weight-reducing pill” containing phentermine and chlorphena­ mine has been reported (60A).
A 23-year-old woman developed marked

lethargy and syncope. Her initial heart rate was 100 per minute and blood pressure 96/ 42 mmHg. There was prolongation of the QT interval and polymorphic ventricular tachycar­ dia. Her family stated that 3 days before admission she had started taking 1 capsule/day of an illegally imported weight-lowering pill. She was given intravenous magnesium sulfate and recovered uneventfully in 36 hours. A urine drug screen was positive for phenter­ mine and chlorphenamine. Serum drug con­ centrations were not measured.

Sibutramine

(SED-15, 3131; SEDA-28, 8; SEDA-29, 11; SEDA-30, 7)

Cardiovascular Post-marketing surveil­ lance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Program (IMMP) identified a case of QT interval prolongation and asso­ ciated cardiac arrest in a patient who had taken sibutramine for 25 days (61A). There was a novel mutation in a cardiac potassium subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase the susceptibility to long QT intervals. Assessment of further IMMP reports identified five other patients who had palpitation associated with syncope or presyncopal symptoms, one of whom had a QTc interval at the upper limit of the reference range. Assessment of reports from the WHO database identified three reports of QT interval prolongation and one fatal case of torsade de pointes in a patient who was also taking cisapride. Sibutramine may cause potentially fatal dysrhythmias in

10 patients with long QT syndrome or in those taking other medications known to prolong the QT interval. Hematological Evidence from postmarketing surveillance suggests that there is a causal association between sibutramine and bruising/ecchymosis. In an IMMP cohort of 9532 patients who took sibutra­ mine between February 2001 and Novem­ ber 2002, there were five reports of ecchymosis (62A). Search of the WHO– UMC database identified a further 89 reports, of which 39 were classified as ecchymosis. Of these 39 reports, 31 had sufficient information for causality assess­ ment. In 11 of these 31 cases there was a positive dechallenge; of these, 1 patient had recurrence of ecchymosis on rechallenge. In the remaining 10 cases with a positive dechallenge, either the outcome of rechal­ lenge was unknown or rechallenge was not performed. In two of these cases either aspirin or co-trimoxazole had also been used. The time to onset for these events was 1–86 days. Four patients developed bruising within 2 days of starting sibutramine. The case with a positive rechallenge developed ecchymosis 86 days after starting sibutra­ mine. The incidence of ecchymosis in premarketing trials of sibutramine was under 1%. Although it appears that bruis­ ing/ecchymosis is not a common adverse reaction to sibutramine, a potential concern is that it may be associated with more serious hemorrhagic events. Drug contamination A metabolite of sibu­ tramine was identified in a urine sample of a 16-year-old girl by gas chromatography and mass spectrometry. Her parents had noticed a conspicuous mood change and her mother found a package labelled “LiDa Dai Dai Hua Jiao Nang,” a Chinese “pure herbal” weight loss product (63A). In another case a 20-year-old woman devel­ oped severe headache, vertigo, and numb­ ness within 2 days after starting LiDa Dai Dai Hua Jiao Nang capsule. Sibutramine was identified in the urine, as well as in the capsule. Each capsule contained sibutra­ mine base 27.4 mg (64A).

Chapter 1

Reginald P. Sequeira

DRUGS USED IN ALZHEIMER’S DISEASE (SEDA-28, 9; SEDA-29, 12; SEDA-30, 8)

Donepezil

(SED-15, 1179; SEDA-28, 9; SEDA-29, 12; SEDA-30, 8)

Observational studies In the symptomatic treatment of Alzheimer’s disease over several years, early treatment with donepezil produces a slight benefit (65C). The longterm efficacy and safety of donepezil has been established. Nevertheless, one should define what will be a clinically important outcome for an individual patient in Alzheimer’s disease (66r), and explore the use of outcome measures such as goal-attainment scaling (67c). Comparative studies The duration and the dose of donepezil or galantamine were not related to an increase in mortality in patients with Alzheimer’s disease. The related variables were advanced age, the severity of the dementia, being male, heart failure, and treatment with atypical anti­ psychotic drugs (68c). Placebo-controlled studies Donepezil improves cognition and preserves function in individuals with severe Alzheimer’s disease who live in nursing homes (69C). In a 6-month, double-blind, parallel group, placebo-controlled study in 248 patients with severe Alzheimer’s disease (mini mental state examination score 1–10) who were living in assisted care nursing homes in Sweden, patients were given donepezil (5 mg/day for 30 days and up to 10 mg/day thereafter; n ¼ 128) or matched placebo (n ¼ 120). The primary end-points were change from baseline to month 6 in the Severe Impairment Battery (SIB) and mod­ ified Alzheimer’s disease Cooperative Study Activities of Daily Living Inventory for severe Alzheimer’s disease (ADCS-ADL-severe). Patients who took donepezil improved more in SIB scores and declined less in ADCDADL-severe scores at 6 months after starting treatment compared with baseline than controls (mean difference 5.7, 95% CI ¼ 1.5, 9.8, P ¼ 0.008; and mean difference 1.7,

Central nervous system stimulants and drugs that suppress appetite

CI ¼ 0.2, 3.2, P ¼ 0.03, respectively). The incidences of adverse events were comparable (donepezil 82% versus placebo 76%). Most of the adverse events were transient and were mild to moderate severity. More patients discontinued treatment because of adverse events in the donepezil group (n ¼ 20) than in the placebo group (n ¼ 8). Cardiovascular Donepezil-induced reductions in heart rate and increases in PR interval were observed only in patients with Alzheimer’s disease who were not treated with negatively chronotropic or dromotropic drugs; these changes were not associated with bradycardia-induced syn­ cope (70c). These findings provide reassur­ ance about the safety of donepezil in patients taking concomitant cardioactive medications.
An 82-year-old patient with Alzheimer’s dis­

ease developed complete atrioventricular block and a ventricular tachyarrhythmia with dizziness and syncope 1 month after starting donepezil. A temporary ventricular pacing catheter placed in the right ventricle restored sinus rhythm on the fourth day (71A).

Nervous system Leg pain has been attrib­ uted to donepezil (72A).
An 85-year-old woman with a 4-year history of

Alzheimer’s dementia and glaucoma and hypertension controlled with timolol eyedrops and candesartan, respectively, was given donepezil 5 mg/day, gradually increasing to 10 mg/day; within 10 days of the increase in dose she developed bilateral leg pain, which was continuous, severe in the morning, and reducing in severity by evening, resulting in severe distress.

The authors argued that donepezil had contributed to leg pain, in view of the temporal association, dechallenge, and lack of recurrence of the symptoms after switchover to galantamine. It is important to exclude any interaction between candesar­ tan and donepezil. Psychiatric Behavioral effects have been attributed to donepezil (73A).
An 80-year-old White woman developed

alcohol abuse and other behavioral changes, such as outbursts and irritations after starting

Chapter 1

11

to take donepezil; the compulsive behavior ceased after dechallenge and recurred on rechallenge.

Gastrointestinal Two episodes of upper gastrointestinal bleeding occurred in an 86-year-old woman with Alzheimer’s dis­ ease treated with donepezil 5 mg/day; she required blood transfusion and intravenous omeprazole (74A). In the absence of other risk factors, bleeding was possibly attribu­ table to donepezil. Monitoring therapy Preliminary data in 42 Italian patients with Alzheimer’s disease compared with 48 matched elderly Italian healthy volunteers from the same geogra­ phical region suggest that CYP2D6 poly­ morphism influences both donepezil metabolism and the therapeutic outcome (75c). Knowledge of a patient’s CYP2D6 genotype together with donepezil plasma concentration measurement might be useful in improving clinical efficacy.

Rivastigmine (SED-15,3072;SEDA-30,10) Monitoring therapy Treatment with rivastigmine produced modest neuronal functional recovery in the frontal cortex only, measured as reversal of a diseaserelated reduction in N-acetylaspartate/ creatine ratio but did not alter the diseaserelated myoinositol/creatine ratio in any cortical regions (76c). Since the modest clinical changes correlated with small changes in metabolite ratios, magnetic resonance spectroscopy could be useful in monitoring the response to drug treatments in Alzheimer’s disease. Butyryl cholinesterase wild-type carriers younger than 75 years had a significantly greater treatment response to rivastigmine over 2 years than patients taking donepezil. In contrast, butyrylcholinesterase K-variant carriers experienced similar long-term treatment effects with both agents, although adverse events were more frequent in those taking rivastigmine (77c). These differences may reflect an ability of rivastigmine to inhibit both butyrylcholinesterase and acet­ ylcholinesterase enzymes.

12

Chapter 1

Reginald P. Sequeira

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