Drugs that affect autonomic functions or the extrapyramidal system

M i c h a e l Schachter

13

Drugs that affect autonomic functions or the extrapyramidal system

It is not by choice that this chapter gets longer every year--the number of references has increased steadily since SEDA-20. Anyone who reads the lay press will see that the adverse effects of drugs are increasingly the subject of news reports. Indeed, at the time of writing the possible toxic effects of Ephedra may be the subject of criminal investigations in the USA, although this does not fall within the scope of this edition. Once again the many problems associated with the treatment of Parkinson's disease form the most prominent feature of this chapter, while the widespread use of anticholinergic drugs to mitigate bladder dysfunction has also drawn considerable attention. This year the chapter includes, in addition to the usual survey of the past year, a review of the safety and tolerability of midodrine, an alphal-adrenoceptor agonist used in some countries in the management of postural hypotension.

DRUGS THAT STIMULATE BOTH ALPHA- AND

BETA-ADRENOCEPTORS (SED-14, 414; SEDA-23, 155; SEDA-24, 163; SEDA-25, 166)

Ephedra, ephedrine, and pseudoephedrine Cardiovascular The cardiovascular effects, subjective effects, and abuse potential of single intranasal doses of ephedrine 5 mg and 9 2003 Elsevier Science B.V. All rights reserved.

Side EffectsofDrugs, Annual26 J.K. Aronson,ed. 156

10 mg have been compared with oral doses of (-)ephedrine 50 mg in 16 healthy Caucasian men with no drug/alcohol/nicotine abuse or dependence (lC). Intranasal ephedrine caused an increase in blood pressure but associated ortho-

static hypotension. The growing controversy about the toxic effects of Ephedra can be seen in the correspondence section of the New England Journal of Medicine. With reference to an earlier paper a pathologist, who is also consultant to the Ephedra Education Council, has questioned the involvement of Ephedra in the deaths of eight patients, pointing out that several had preexisting conditions such as chest pain and hypertension (2r). The authors responded, surely justifiably, that these were contraindications to the use of Ephedra in the first place, and they cast doubt on the adequacy of the warnings provided (3r). In the same issue of the Journal a group from the New York City Poison Control Center have reported a case of myocardial infarction attributed to Ephedra (4 A). 9 A previously healthy 19-year-old man took tablets containing a total of 24 mg of Ephedra alkaloids and 100 mg of caffeine, and I5 minutes later developed severe chest pain radiating down the left arm. An electrocardiogram showed an inferolateral myocardial infarct, confirmed by creatine kinase and troponin I measurements. He made a full recovery, and coronary angiography showed only minimal atherosclerotic disease of the left anterior descending artery. The authors emphasized the dangers of Ephedracontaining over-the-counter formulations, even in fit young people. Severe hypertension has been attributed to pseudoephedrine abuse (5A). 36-year-old man with hypertension taking no less than seven antihypertensive drugs had outpatient systolic pressures of over 190 mmHg.

9 A

Drugs that affect autonomic functions or the extrapyramidal system Investigations for primary causes of hypertension were negative and there was increasing suspicion of treatment non-compliance or factitious hypertension. Urine screening showed the presence of pseudoephedrine, which the patient could not explain. When he was given his normal antihypertensive drugs under close supervision his systolic blood pressure fell to 70 mmHg and his serum creatinine doubled. His blood pressure became normal when his medication was briefly suspended but he continued to deny any deliberate attempt to alter his blood pressure and discharged himself soon afterwards. The authors concluded that this represented factitious hypertension due to pseudoephedrine, the first such case reported and a very unusual example of Munchausen's syndrome.

Chapter 13

157

9 A 21-year-old man developed acute myocardiai ischemia. Smoking was the only risk factor for coronary artery disease and he denied using cocaine. Angiography showed normal coronary arteries. He had recently started to take amfebutamone for smoking cessation and pseudoephedrine as a non-prescription influenza remedy. The authors postulated that the combination of two sympathomimetics had caused acute coronary artery vasospasm. This is the first report linking amfebutamone to acute coronary syndrome, and one of a few cases associated with pseudoephedrine. It is also possible that erythromycin, which this patient was also taking, could have impaired the hepatic metabolism of amfebutamone.

Psychiatric

Pseudoephedrine is often used by scuba divers to avoid ear barotrauma. The psychometric and cardiac effects of pseudoephedrine have been evaluated at one atmosphere (100 kPa, sea level) and three atmospheres (30 kPa, 20 m) in a double-blind, placebo-controlled, crossover study in 30 active divers in a hyperbaric chamber (6c). Pseudoephedrine did not cause significant alterations in psychometric performance at 3 atmospheres.

Gastrointestinal

Ischemic coh?is has been attributed to pseudoephedrine abuse (7A).

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA-ADRENOCEPTORS (SED-14, 417; SEDA-23, 155; SEDA-24, 164; SEDA-25, 167)

Methoxamine

9 A 51-year-old woman presented for the second time in 4 months with abdominal pain. On this as on the previous occasion, emergency laparotomy was needed and she was found to have patchy infarction of the terminal ileum and the ascending colon. It emerged that she had been taking pseudoephedrine for 2 years, because she found that it relieved her headaches. In fact she had often noticed abdominal pain and distention, with occasional bloody diarrhea, after taking pseudoephedrine. Before each of her two admissions she had been taking the remarkably high dose of 900 mg/day, and on many other occasions had taken as much as 600 mg/day. She made a good recovery and was said to have stopped taking pseudoephedrine.

Methoxamine, a relatively selective alphaladrenoceptor agonist, has been used to a limited extent in the management of urinary stress incontinence. Its effects have been examined in a double-blind placebo-controlled trial in only six women (9c). There was little effect on maximum urethral pressure, the surrogate end-point used in the trial. The drug was given by intravenous infusion at a maximum dose of 1.0 mg/70 kg/min. There was a significant rise in systolic blood pressure of about 13 m m H g and a fall in pulse rate of some 18 beats/minute. All subjects taking methoxamine had headache, cold extremities, and piloerection. The authors understandably concluded that this is not a very promising treatment for stress incontinence.

The authors quoted seven other published cases of pseudoephedrine-related ischemic colitis, all occurring at much lower dosages, at most 240 mg/day.

Midodrine

Drug interactions

Acute coronary syndrome has been attributed to a combination of pseudoephedrine with amfebutamone (bupropion)

(8A).

Orthostatic hypotension Jbrms a potentially very disabling component o f several types r?] autonomic disturbance. It is relatively common in all age groups, but the cause varies. It

158

is commonly due to drugs (such as diuretics, antihypertensive drugs, and neuroleptic drugs) and to neurocardiogenic or vasovagal syncope, which occurs at all ages, usually without any obvious triggers. Hypotension can also form part of autonomic neuropathies, such as those associated with diabetes and less commonly with amyloid. It is also associated with neurodegenerative diseases such as multiple system atrophy and can occur after spinal cord injury, during hemodialysis, and in astronauts. It has also been suggested that orthostatic hypotension is an essential element of the chronic fatigue syndrome in most or all affected individuals, but this is controversial. One relatively common cause of orthostatic hypotension is iatrogenic, in which case withdrawal of the causative drugs solves the problem. In other cases, or when hypotensive drugs cannot be withdrawn, a very wide range of therapies have been tried, reflecting their relative lack of efficacy. Extracellular fluid expansion, with salt and mineralocorticoids, such as fludrocortisone, is of low efficacy and considerable risk, and can lead to cardiac failure or supine hypertension. An alternative approach involves increasing peripheral resistance pharmacologically: ergot alkaloids are among the agents used for this, but their toxicity needs no elaboration. Midodrine is a potential alternative that has now been extensively tested in several of the orthostatic hypotension syndromes, including: neurogenic hypertension due to autonomic neuropathies (10~, 1 F ); neurocardiogenic syncope (12 c, 13 c, 14 ~, 15 M, 16c); the controversial syndrome of orthostatic hypotension and tachycardia that may be associated with chronic fatigue (17M, 18c); the hypotension seen during hemodialysis (19M); and hypotension due to neuroleptic drugs (20c). Midodrine is a prodrug, whose active metabolite is relatively selective for vascular post-junctional alphal-adrenoceptors and therefore increases peripheral resistance by arteriolar constriction, with some venoconstriction in capacitance vessels (21M). It has minimal activity in the central nervous system, since it does not cross the blood-brain barrier. It can be given orally and has a systemic availability of over 90% by this route. The half-life of the active deglycinated metabolite is relatively short (2-3 hours). The dosage range is 2.5-10 mg tds, and is usually towards the upper end of this range.

Chapter 13

Michael Schachter

Few of the above-mentioned studies have systematically addressed problems of safety and adverse effects, but on the whole the effects described are predictable from the adrenergic properties of the drug and are dose-related. The most common adverse effect, in up to 15% of patients, is piloerection, with or without paresthesia especially of the scalp and face, most commonly in the form of pruritus. Urinary urgency, increased frequency, and even retention have also been recorded; when they occur they constitute the single mostcommon reason for withdrawal. Less common but more serious is the problem of supine hypertension in up to 3% of subjects, although it is not clear how the underlying pathology of the hypotension influences the likelihood of this reaction. An unexpected reaction has been described in a 33year-old schizophrenic woman who took midodrine 4 mg/day because of postural hypotension due to risperidone 6 mg/day (22A). She developed an acute dystonic reaction, which recurred several times on rechallenge, and the dose of risperidone had to be halved to minimize the hypotension. Overall, midodrine is a relatively efficacious drug with good tolerability, but with some adverse effects that can usually be anticipated. Monitoring of supine blood pressure is essential.

Phenylpropanolamine N e r v o u s s y s t e m Cerebral hemorrhage has been attributed to p h e n y l p r o p a n o l a m i n e (23 A). A 37-year-old woman took an over-the-counter formulation containing phenylpropanolamine 100 mg. About 90 minutes later she developed very severe bilateral headache resistant to analgesics. Her blood pressure was 180/100 mmHg but fell rapidly to 110/70 mmHg. A CT scan showed multiple small frontal and parietal hemorrhages, and angiography showed extensive segmental vasospasm. She was treated with nimodipine and prednisolone, followed by verapamil. She made an uneventful recovery and there was angiographic resolution of the vascular lesions. The authors reviewed a n u m b e r o f other case reports of p h e n y l p r o p a n o l a m i n e - i n d u c e d cerebral v a s o s p a s m associated with h e m o r r h a g e s

Drugs that affect autonomic functions or the extrapyramidal system and drew a parallel with similar effects of amphetamines.

DRUGS THAT STIMULATE

PREDOMINANTLY BETA1-ADRENOCEPTORS (SED-14, 420; SEDA-23, 156; SEDA-24, 165; SEDA-25, 167) There are still some concerns about the safety of dobutamine stress testing, especially if an accelerated protocol is used. In 47 consecutive patients (mean age 64 years, 46 men) with three or more cardiovascular risk factors, intravenous dobutamine was given at a rate of 40 micrograms/kg/min until the target heart rate was achieved, which took a mean of 11.6 minutes (24c). Subjective sensations occurred in 49% of the patients (palpitation 21%, chestpain 6%, nausea 6%, headache 6%, dizziness 13%), while half the patients had abnormal cardiac rhythms (ventricular extra beats 38%, supraventricular tachycardia 10%, nonsustained ventricular tachycardia 2%). The authors concluded that the safety and tolerability of this procedure is comparable to that of standard dobutamine stress testing, although its specificity and selectivity are still uncertain.

Cardiovascular Even in the absence of overt clinical effects there might be concern that dobutamine may damage the myocardium. In 47 patients in Mannheim (mean age 61 years, 34 men) dobutamine echocardiography was carded out, with blood sampling immediately before and after the procedure and then at 1, 2, 4, 6, and 12 hours (25c). Assays were carried out for creatine kinase-MB, troponins I and T, myoglobin, and fibrin monomer antigen. There were no significant increases in these markers of myocardial damage and coagulation, regardless of the outcome of the stress test. These findings have confirmed those of an earlier study, although the data do not absolutely exclude abnormal findings in a minority of individuals (26c). Dobutamine does of course have therapeutic as well as diagnostic uses. Cardiac dysrhythmias have been reported.

Chapter 13

159

9 A 74-year-old man with idiopathic dilated cardiomyopathy was given dobutamine (5 mg/kg/min) to determine whether it would produce a positive inotropic effect (27A). After 14 minutes he developed asymptomatic pulsus alternans, which resolved with 20 minutes of withdrawal. A much more serious complication of dobutamine therapy is ventricular dysrhythmias. Of 305 patients with acutely decompensated congestive heart failure, 58 were given dobutamine (although it is difficult to ascertain the dose), 44 were given other standard inotropic drugs such as milrinone, and 203 were treated with brain natriuretic peptide (nesiritide, 0.015 or 0.03 ktg/kg/min) (28c). Of those given dobutamine 7% had sustained ventricular tachycardia, 17% had non-sustained ventricular tachycardia, and 5% had a cardiac arrest. In contrast, the figures for nesiritide were 1, 11, and 0% respectively. There was no analysis of other outcomes but these results certainly do not encourage the use of dobutamine in these very vulnerable patients.

DRUGS THAT ACT ON DOPAMINE RECEPTORS

(SED-14,

421; SEDA-23, 156; SEDA-24, 165; SEDA-25, 168)

Levodopa and dopamine receptor agonists Cardiovascular Dopamine receptor agonists can cause postural hypotension. The efficacy of domperidone in preventing this has been reported in patients taking a dopamine receptor agonist, CQA 206-291, that was never marketed but is said to be as effective as currently used agents (29c). Apomorphine, one of the oldest and most potent of dopamine receptor agonists, is being increasingly used in patients with severe motor fluctuations in Parkinson's disease. It is usually given by subcutaneous infusion, but this is associated with the development of persistent nodules, causing major problems in about 10% of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who

160 had responded well to subcutaneous apomorphine before nodules developed, had such cannulae inserted (30c). The apomorphine was given at a mean rate of 9.0 mg/hour to a total mean dose of 257 mg/day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished "off" periods, reduced oral antiparkinsonian drug dosages by 59%, and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of life. However, there were major problems. Two patients receiving high doses of apomorphine (450 and 290 mg/day, in the latter case a deliberate overdose) developed thromboembolic complications, following crystal formation, in one case to the right lung and in the other with obstruction to the superior vena cava. Both required surgical intervention. Both recovered fully, but the authors understandably commented that this therapeutic approach still needs further development. R e s p i r a t o r y Pleuropulmonary disease, especially with a fibrotic component, has been reported with all the ergot alkaloids after longterm use. 65-year-old man, who had been taking pergolide 3.5 mg/day for 3 years to treat restless legs syndrome, presented with progressive weight loss, fatigue, and dyspnea (31A). The history was of at least 2 years duration. A chest X-ray showed a loculated right hydropneumothorax, and a bloody pleural exudate was aspirated with no cytological evidence of malignancy. An open biopsy showed inflammatory changes and fibrosis. After withdrawal of pergolide and a short course of corticosteroids he made a full clinical and radiological recovery.

9 A

N e r v o u s system In the U S A bromocriptine has not been licensed for the suppression of lactation since 1994. Up to that time there had been no reports of intracranial hemorrhage associated with bromocriptine, but since the withdrawal of the license for this indication there have been 15 case reports of this disastrous adverse effect. 9 Three women aged 22, 24, and 40 years took bromocriptine 2.5 mg bd for 2-5 days post-partum and complained of headache; two lost consciousness (32~). One subsequently died and another had a residual neurological deficit. In all three cases intracerebral hemorrhage, confirmed by CT or MRI scans, occurred on the sixth day of administration. Maximal recorded blood pressures were 200/100, 173/120, and 180/118 mmHg.

Chapter 13

Michael Schachter

It hardly needs emphasis that the use of bromocriptine to suppress lactation is difficult to justify, given these potentially catastrophic, if rare, consequences. The successful use of ergot derivatives to shrink macroprolactinomas can have unwanted neurological consequences, and this has been described in two case reports. 9 Three Italian men aged 39, 42, and 53 years with invasive prolactinomas took cabergoline 1.0-3.0 mg/week and all developed CSF rhinorrhea after 2-7 months (33 A). This was clearly a consequence of loss of the "stopper" effect of the tumor, owing to shrinkage, and in each case was successfully treated by endoscopic trans-sphenoidal surgery. 9 A 42-year-old Spanish man took cabergoline (up to 3 mg/day) for a large prolactinoma causing hypopituitarism and symptomatic chiasmal compression (34A). After 18 months there was only a minimal tumor remnant on the floor of the sella turcica, but there was chiasmal herniation. However, there were no clinical effects of this, and in particular the visual fields were normal. A much less well-known adverse effect of levodopa and dopamine receptor agonists is impairment ofproprioception (35c). In 17 Parkinsonian patients three tests of proprioception were carded out 1 hour after the administration of levodopa or a dopamine receptor agonist. Although data were not provided for individual patients, there was an overall 11-31% deterioration in the mean scores in all three of the tests. There was no difference between patients with and without dyskinesias, but the authors suggested that abnormal proprioception may be a factor in drug-induced dyskinesia.

Sleep disorders with dopamine receptor agonists The apparent association of some newer dopamine agonists with "sleep attacks" continues to attract a great deal of interest. Some remarkable case reports have previously been published (SEDA-25, 169) and reports continue to appear, supplemented by prospective studies and other analyses. For instance, 11 studies involving ropinirole or pramipexole in a total of 2066 patients have been reviewed (36M). Four of these (two each with ropinirole and pramipexole) were placebo-controlled.

Drugs that affect autonomic functions or the extrapyramidal system The pooled relative risk o f somnolence was 4.98 compared with placebo: there was a nonsignificant trend for greater somnolence with ropinirole, but the confidence intervals were much wider than with pramipexole. In the other studies levodopa alone was compared with levodopa plus the newer drugs; the relative risk was 2.06 compared with levodopa alone. It must be borne in mind that somnolence and sleep attacks may be separate phenomena, although this is controversial. The whole field o f sleep disorders in Parkinson's disease has been reviewed in a consecutive series o f 320 patients from Houston, with analysable data from 303 (sex distribution unknown) (37c). The mean age was 67 years and the mean duration o f the disease was 9.1 years. All the patients completed the Epworth Sleepiness Scale and answered specific questions about falling asleep while driving and about the restless legs syndrome. The mean sleepiness score was 11.1, values greater than 10 being regarded as abnormal. As one would expect, just over half the patients had scores at that level. Higher scores correlated with longer duration and greater severity of the disease, with male sex, and with the use of dopamine receptor agonists. There was no.apparent difference in this regard between the three most commonly prescribed drugs in these patients (pergolide, ropinirole, and pramipexole, the last being the most frequent). Among those currently driving, 23% reported falling asleep in the car and nearly 20% had features of the restless legs syndrome. This study has therefore reinforced the view that sleep disorders are common in Parkinson's disease, especially in its advanced stages, and are exacerbated by dopamine agonists as a class. However, one can draw no conclusions about individual drugs from this review. The effects o f pramipexole, cabergoline, and levodopa on daytime sleepiness have been assessed in three groups o f patients with Parkinson's disease (38c). The first group was 19 patients taking pramipexole (mean age 60 years, mean dosage 4.5 mg/day, eight as monotherapy, the remainder with levodopa); the second group was 22 patients taking cabergoline (mean age 63 years, mean dosage 4.1 mg/day, 10 as monotherapy); the third group was 14 patients taking levodopa (mean age 69 years, mean dosage 789 mg/day) as monotherapy.

Chapter 13

161

The scores on the Epworth Sleepiness Scale were virtually identical (8.0, 8.1, 8.1). Scores o f greater than 16, indicating excessive daytime sleepiness, were also evenly distributed across the three groups, and were attributed to only four individuals; there were no reports of sleep attacks. These results have been supported by a study in 160 patients with Parkinson's disease (mean age 66 years) divided into four equal groups and taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, or levodopa with pramipexole (39c). They were compared with 40 healthy younger controls (mean age 58 years). All the subjects were evaluated using the Epworth sleepiness scales. All the drug regimens were associated with increased sleepiness compared with the controls but there were no distinct sleep attacks. The authors noted that all the drug regimens produced similar levels of sedation, although the data appeared to show a trend towards greater somnolence with ropinirole and more particularly pramipexole. However, these are not uncontested f n d ings. In a study that was described as prospective, but was strictly speaking not, 236 patients (106 men, 130 women, mean age 67years) were questioned (40c). All but one was in HoehnYahr stages II-IV. Sleep attacks were reported by 72patients, o f whom 70% were considered to have autonomic dysfunction. The authors concluded that the highest risk was attributable to ropinirole (OR = 7.35), followed by bromocriptine (5.78) and lisuride (5.68); f o r comparison, the figure f o r levodopa was 0.61. No patients took pramipexole. Again, it is uncertain whether sleep attacks can truly be distinguished from "ordinary" sleepiness, but the results emphasize the sedative potential o f dopamine receptor agonists. On the other hand, these results have been disputed in another report, with authors in common with the previous report. They presented four case studies, three men and one woman, aged 49-87 years, who had had Parkinson's disease f o r 8-17 years; the longest duration was in the youngest patient (41 a ). All four were taking levodopa (300-1500 mg/day) plus a decarboxylase inhibitor All four reported sudden irresistible sleep episodes, even during conversations: two also complained of sleepiness distinct from these attacks. Two ~f the patients

Chapter 13

162

also had definite autonomic disturbances. The authors concluded that sleep attacks do occur and may be associated with levodopa as well as with dopamine receptor agonists. The sedative potential o f levodopa has been examined in 16 healthy volunteers (mean age 25 years, eight men), although o f course this represents a very different neuropsychological context from Parkinson's disease (42c). They were given levodopa 200 mg or a placebo as a single dose, with domperidone to minimize peripheral adverse effects, followed by the active drug or control in a cross-over design. Sedation was assessed using a visual analogue scale and reaction time by the response to a light stimulus. There was no overall change in reaction time, but this concealed considerable interindividual variation. Four subjects complained o f nausea and one o f excitation after levodopa and all had slower reaction times without complaining o f sedation. However, seven subjects reported a greater level o f sedation with levodopa than placebo, and this correlated (r = O.7) with their reaction times. In other words, levodopa can cause sedation in normal young people but does not necessarily do so, at least after a single dose. The extent to which these results can be extrapolated to elderly Parkinsonian patients is debatable. Overall, therefore, the current evidence suggests that sedation is a class effect of all dopaminergic drugs, including levodopa. It may be more severe with the newer synthetic agents pramipexole and ropinirole, but this cannot yet be stated with certainty. The existence o f discrete sleep attacks also remains controversial although on balance one would conclude that they can occur. Psychiatric In a prospective study of 89 patients with Parkinson's disease, of whom 60 were free of hallucinations at entry, though most of these had disturbed sleep patterns, after 4 years 50% of the original non-hallucinators were experiencing hallucinations, while only 14% of those with hallucinations at entry were no longer affected by them (43c). Those classified as having severe hallucinations increased from 10% at entry to 35% after 4 years. The development or worsening of hallucinations was not associated with levodopa dosage but was strongly correlated with the use of dopamine receptor agonists in combination

Michael Schachter

with levodopa: some 59% of patients with hallucinations were taking agonists as against 33% of non-hallucinators.

Drug interactions Ropinirole has been reported to enhance the effects of warfarin (44 A). 9 A 63-year-old man taking co-careldopa and warfarin 4 mg/day (it is not entirely clear why) was also given ropinirole 0.75 mg/day to allow levodopa sparing. After 9 days of ropinirole his INR had increased to 4.6 from a previously stable value of 1.8-2.1, little changed in 2 years. There was no clinical evidence of bleeding. Warfarin was withheld for 4 days and then restarted at 25% of its previous dose. The ropinirole was then withdrawn because of gastrointestinal adverse effects and the warfarin dosage was restored to its previous level. The mechanism of this interaction has not been elucidated. Ropinirole is metabolized by CYP1A2, but that is not the major isoform involved in warfarin metabolism.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SED-14, 424; SEDA-24, 167; SEDA-25, 171)

Amantadine Nervous system The popularity of amantadine has waned in recent years, but it is still used in many Parkinsonian patients, especially the more elderly. A new adverse effect has been described in three Japanese women aged 78-87 years (45A). They had taken amantadine 100-200 mg/day for 1 month to 5 years, in two cases together with co-careldopa. All three developed multifocal myoclonus and two were confused. Amantadine concentrations were high in the two patients in whom they were measured, at over 3000 ng/ml; a concentration over 1000 ng/ml is regarded as toxic. Amantadine was withdrawn and the myoclonus disappeared within 1-2 weeks and did not recur. Cortical myoclonus has also been described with levodopa and bromocriptine, but the mechanism is not known.

Drugs that affect autonomic functions or the extrapyramidal system

Catechol-O-methyl transferase inhibitors Tolcapone was very effective but was withdrawn in 1998 because of liver toxicity. It has been replaced by entacapone, which appears to lack this serious adverse effect, although some neurologists also consider it to be less effective. In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3-7 months and were given entacapone in dosages titrated to 800-2000 mg/day after a transition period of 3 - 6 months with co-beneldopa, the improvements in "on" and "off" times were less impressive than they had been with tolcapone and there were more adverse effects (46c). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox: entacapone appears to be safer but overall causes more adverse effects. t The safety issue has been specifically addressed in a Finnish study in 326 patients (mean age 62 years, 217 men) taking levodopa plus a decarboxylase inhibitor (47c). Two-thirds were randomized to take entacapone 200 mg/day and the remainder to placebo. The withdrawal rate due to adverse events was 14% with entacapone compared to 11% with placebo. Dyskinesias were greatly increased in the former (29% vs 11%) and entacapone was also associated with increased incidences of diarrhea (9.2% vs 1.9%), dry mouth (6.0% vs 0), and discolored urine (6.9% vs 0). However, there was no evidence of liver toxicity with entacapone.

Chapter 13

163

Cardiovascular Vasospasm is a well-known adverse effect of ergot alkaloids. A 48-year-old woman developed a cold pulseless fight leg and no measurable blood pressure at the fight ankle (48At). She was a migraine sufferer and had been taking over-the-counter medications, some of which contained ergot derivatives, although the nature and quantity were not specified. Arteriography showed severe stenosis of the superficial femoral artery, with no identifiable tibial vessels. There was an initial improvement with intra-arterial glyceryl trinitrate infusion, and sustained normalization of the circulation in the leg after administration of sodium nitroprusside, nifedipine, prazosin, and heparin. She made a full recovery. The authors reviewed the pharmacology of the ergot alkaloids and the acute and subclinical ischemic syndromes that they can produce. They pointed out that in some countries, notably in Latin America, ergot-containing formulations are freely available without a prescription. A 34-year-old woman has a myocardial infarction after being given ergonovine for an atonic uterus after cesarean section (49 A). Within minutes she became unresponsive, with bradycardia and then asystole followed by ventricular fibrillation during cardiopulmonary resuscitation. An electrocardiogram showed an acute anterior infarct and coronary angiography showed diffuse spasm of the circumflex and left anterior descending arteries, with subtotal occlusion of the latter. The spasm was reversed with intracoronary glyceryl trinitrate but she required ventilation for another 2 days and was eventually discharged 11 days after the infarct, with a borderline left ventricular ejection fraction of 45%. The authors commented that the patient was of Asian origin and that such individuals are thought to have increased susceptibility to the vasoconstrictor effects of ergot derivatives. Any vascular bed is susceptible to the vasospastic effects of ergot alkaloids.

SEDA-23, 157; SEDA-24, 168; SEDA-25, 171)

9 A 50-year-old woman developed ischemic necrosis of the stomach wall after taking up to 5 rag/day of ergotamine tablets for 10 years because of daily headaches (50A). The necrosis was on the greater curvature and was about 10 cm in diameter. She required laparotomy because of peritonitis and there was a 4 cm area of full-thickness necrosis within the ischemic area. She made a full recovery.

Ergot-related adverse effects are still remarkably frequent and severe,

The authors noted that this is an extremely rare manifestation of ergot-induced ischemia.

T H E ERGOT ALKALOIDS A N D RELATED AGENTS (SED-14, 431;

164 i n t e r a c t i o n s It is important to remember that ergot derivatives are subject to metabolism by cytochrome P450 and hence to drug interactions. This has been highlighted by two cases of interactions, one with clarithromycin the other with ritonavir. Drug

9 A 41-year-old woman presented with pain and pallor in the leg and a sensation of coolness exacerbated by exercise (51A). For many years she had been taking a formulation containing ergotamine 1 mg plus caffeine 100 mg, at a dose of one or two tablets daily, for both prophylaxis and treatment of migraine. For 7 days she had also taken clarithromycin (dose is not stated) for a chest infection. Her legs were cool and cyanosed, with no palpable popliteal or foot pulses and an ankle-brachial index of only 0.6 (normal > 0.8). The authors concluded that her symptoms had been precipitated by the introduction of clarithromycin, a cytochrome P450 inhibitor like the other macrolide antibiotics. However, she was also taking omeprazole, another inhibitor, which may have contributed to the problem. All drugs were withdrawn and nifedipine was given, with full recovery within a couple of days. 9 A 37-year-old woman with AIDS who had been taking ritonavir developed acute dysphasia and right-sided weakness having taken a total of t0 mg of ergotamine in suppository form for severe headaches that were presumed to be migraine (52A). Transcranial Doppler and angiography showed multiple stenoses in vessels in the circle of Willis, and an MRI scan showed watershed infarcts in the right and left hemispheres. It was presumed that she had had ergotamine-induced vasospasm due to inhibition of ergotamine metabolism by ritonavir. She was treated with "hemodilution, hypertension and hypervolemia", and her cerebral flow velocities normalized over the next 18 days and the angiographic appearances by day 90. She was left with a slight right expressive dysphasia and weakness in the right leg.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SED-14, 436; SEDA-23, 158; SEDA-24, 168; SEDA-25,

172)

Acetycholinesterase inhibitors C a r d i o v a s c u l a r The cholinesterase inhibitors are potentially very dangerous drugs, as two American case reports of asystole have testified.

Chapter 13

MichaelSchachter

9 A 67-year-old man underwent left upper lobec-

tomy for a presumed malignancy 11 years after cardiac transplantation (53A). He had had no cardiac symptoms since his transplant. Succinylcholine was used as a muscle relaxant and was reversed with glycopyrrolate 0.8 mg and neostigmine 4 mg. Within a few minutes he developed asystole, which lasted for about 45 seconds. He subsequently made a full recovery. The authors speculated that some degree of cardiac re-innervation may have occurred; they recommended that this type of response should be anticipated in future anesthesia in such patients and that therapeutic measures, such as a beta-adrenoceptor agonist, should be available. Another case of asystole has been reported with the very short-acting cholinesterase inhibitor edrophonium (54 A). A 49-year-old woman was given intravenous edrophonium chloride 2 mg as part of the investigation of an acute myopathy following gastrointestinal surgery. She had also received a total of 60 mg of intravenous labetalol in the 14 hours before the edrophonium was given: presumably this was for a raised blood pressure, but that was not specified. Labetalol caused transient but severe bradycardia (heart rate about 20 beats/min). Immediately after the injection of edrophonium she developed asystole, which was treated immediately with atropine and recovered in 10 seconds. Such reactions are extremely rare, but in this case the risk was undoubtedly enhanced by previous beta-blockade.

Anticholinergic drugs The adverse effects of the antimuscarinic anticholinergic drugs in patients with incontinence and bladder overactivity has been emphasized in several recent reviews (55 M, 56 c, 57 M, 58c). The findings are not unexpected: dry mouth is by far the most c o m m o n l y reported adverse effect, with a frequency of about 40% in patients taking 2 mg of the immediate-release formulation bd. The next most common effects are consistently headache, constipation, and abdominal discomfort. Hallucinations and tachycardia have also been reported. It is agreed that higher doses should not be used because of the risk of urinary retention. About 5% of patients stopped taking tolterodine because of adverse effects and in about 10% the dosage

Drugs that affect autonomic functions or the extrapyramidal system was reduced. In 2 mg bd with 4 formulation the lower incidence efficacy (59r

one comparison of tolterodine mg od in an modified-release latter produced about a 23% of dry mouth, with increased

C a r d i o v a s c u l a r Non-sustained ventricular tachycardia has been attributed to orphenadrine (60A). 9 A 57-year-old woman had been taking a formulation containing orphenadrine 15 mg and paracetamol 450 mg bd for musculoskeletal pain. She was also taking propafenone 600 rag/day for paroxysmal atrial fibrillation. After 5 days she developed severe palpitation. Holter monitoring showed frequent brief episodes not only of atrial fibrillation but also of non-sustained ventricular tachycardia. After the orphenadrine was withdrawn the palpitation ceased. The authors pointed out the potential problems of anticholinergic drugs like orphenadrine in patients taking antidysrhythmic drugs. Possible precipitation of acute myocardial infarction has been discussed by two American emergency medicine specialists (61A). 9 A 62-year-old woman developed chest pain and sinus bradycardia (41 beats/min). She had thirddegree heart block and was given, atropine 1 mg intravenously. Three minutes later her chest pain increased and the electrocardiogram now showed

Chapter 13

165

an acute inferior myocmdial infarction, confirmed by serum markers. Angioplasty recanalized The right coronary artery. The authors discuss the possibility, suggested by others, that atropine can precipitate acute myocardial infarction in an ischemic setting. They concluded that while this may be true, on the whole the advantages of successfully correcting bradycardia outweigh the risks of this rare complication. S a l i v a r y glands The reference drug for tolterodine is oxybutynin, and there have been several comparisons of the two. All agree that the older drug, in its standard formulation at a dose of 5 mg bd, while of similar efficacy, produces significantly more adverse effects (62c). The incidence of dry mouth reached 60%, and over 75% in patients taking the highest dose of 5 mg tds. Direct measurements of saliva production confirmed that oxybutynin 5 rag/day reduces saliva output significantly more than tolterodine 2 mg or a modified-release formulation of oxybutynin 10 mg, all given as single doses (63c). In over 300 patients modifiedrelease oxybutynin once daily produced less dry mouth (28% vs 33%) than immediate-release tolterodine 2 mg bd (64 c).

REFERENCES

1. Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B, Peyron I, Diquet B, Lechat P. Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) dose of ephedrine in healthy subjects. Eur J Clin Pharmacol 2001; 57: 447-55. 2. Hutchins GM. Dietary supplements containing Ephedra alkaloids. New Engl J Med 2001; 344: 1095-6. 3. Haller CA, Benowitz NL. Dietary supplements containing Ephedra alkaloids. New Engl J Med 2001; 344: 1096-7. 4. Traub SJ, Hoyek W, Hoffman RS. Dietary supplements containing Ephedra alkaloids. New Engl J Med 2001; 344: 1096. 5. Flaherty ML, Infante M, Tinsley JA, Black JL. Factitious hypertension by pseudoephedrine. Psychosomatics 2001; 42: 150-2. 6. Taylor D, O'Toole K, Auble T, Ryan C, Sherman D. The psychometric and cardiac effects of pseudoephedrine and antihistamine in the hyper-

baric environment. S Pac Underw Med Soc J 2001; 31: 50-7. 7. Klestov A, Kubler R Meulet J. Recurrent ischaemic colitis associated with pseudoephedfine use. Intern Med J 2001; 31: 195-6. 8. Pederson KJ, Kuntz DH, Garbe GJ. Acute myocardial ischaemia associated with ingestion of bupropion and pseudoephedrine in a 21-year-old man. Can J Cardiol 2001; 17: 599-601. 9. Radley SC, Chapple CR, Bryan NP, Clarke DE, Craig DA. Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, doubleblind crossover study. Neurourol Urodyn 2001 ; 20: 43-52. 10. Low PA, Gilden JL, Freeman R, Sheng K-N, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. J Am Med Assoc 1997; 277: 1046-51.

166 Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995; 99: 604-10. 12. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998; 79: 45-9. 13. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a doubleblind, placebo-controlled study with midodrine. Am J Med 1993; 95: 38-48. 14. Sra J, Maglio C, Biehl M, Dhala A, Blanck Z, Deshpande S, Jazayeri MR, Akhtar M. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997; 8: 42~5. 15. Calkins H. Pharmacologic approaches to therapy for vasovagal syncope. Am J Cardiol 1999; 84: 20Q-25Q. 16. Perez-Lugones A, Schweikert R, Pavia S, Sra J, Akhtar M, Jaeger F, Tomassoni GF, Saliba W, Leonelli FM, Bash D, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12: 935-8. 17. Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med 1998; 105: 14S-21S. 18. Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance and cognitive impairment in adolescents. PACE 2000; 23:344-51. 19. Perazella MA. Pharmacologic options available to treat symptomatic intradialytic hypotension. Am J Kidney Dis 2001; 38 Suppl 4: $26-$36. 20. Gairard A-C, Cordonnier A-L, Charles A, Viala A, Patti E, Germain C, Lafay N, Gury C. Recherche de la dose efficace de la midodrine dans l'hypertension orthostatique iatrog~ne h partir d'une Etude pilote. J Pharm Clin 2000; 19: 256-9. 21. Mauro VF. Focus on midodrine: an oral peripheral-acting alpha-agonist for the treatment of orthostatic hypotension. Formulary 1997; 32: 225-31. 22. Takahashi H. Acute dystonia induced by adding midodrine, a selective alpha 1 agonist, to tisperidone in a patient with catatonic schizophrenia. J Neuropsychiatry Clin Neurosci 2000; 12: 285~. 23. Yeyrac G, Huguenin H, Guillon B, Chiffoleau A, Thajte N, Bourin M, Jolliet E HEmorragie cErEbromEningEe et angiopathie cErEbrale aiguE associEes h la prise de phEnylopropanolamine: un noveau cas. ThErapie 2001; 56: 321-7. 24. Lu D, Greenberg MD, Little R, Malik Q, Fernicola DJ. Accelerated dobutamine stress testing: safety and feasibility in patients with known or suspected coronary artery disease. Clin CardioI 2001; 24: 141-5. 25. Pfleger S, Scherhag A, Latsch A, Dempfle CE, Simonis B, Haux P, Voelker W, Gaudron P. Safety of dobutamine echocardiography: no signs of myocardial cell damage or activation of the coag11.

Chapter 13

Michael Schachter

ulation system. Dis Manage Clin Outcomes 2001; 3: 15-19. 26. Beckmann S, Bocksch W, Muller C, Schartl M. Does dobutamine stress echocardiography induce damage during viability diagnosis of patients with chronic regional dysfunction after myocardial infarction? J Am Soc Echocardiogr 1998; 11: 181-7. 27. Kahn JHL, Starling MR, Supiano MA. Transient dobutamine-mediated pulsus altemans. Can J Cardiol 2001; 17: 203-5. 28. Burger A J, Elkayam U, Neibaur MT, Haught H, Ghali J, Horton DP, Aronson D. Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy. Am J Cardiol 2001; 88: 35-9. 29. Lang AE. Acute orthostatic hypotension when starting dopamine agonist therapy in Parkinson disease: the role of domperidone therapy. Arch Neurol 2001; 58: 835. 30. Manson A J, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous diamorphine therapy in Parkinson's disease. Clinical and pharmacokinetic observations. Brain 2001; 124: 331-40. 31. Danoff SK, Grasso ME, Terry PB, Flynn JA. Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001; 120: 313-16. 32. Kirsch C, Iffy L, Zito GE, McArdle JJ. The role of hypertension in bromocriptine-related puerperal intracranial hemorrhage. Neuroradiology 2001; 43: 302-4. 33. Cappabianca P, Lodrini S, Felisati G, Peca C, Cozzi R, Di Samo A, Cavallo LM, Giombini S, Colao A. Cabergoline-induced CSF rhinorrhea in patients with macroprolactinoma. J Endocrinol Invest 2001; 24: 183-7. 34. Marcos L, De Luis DA, Botella I, Hurtado A. Tumour shrinkage and chiasmal herniation after successful cabergoline treatment for a macroprolactinoma. Clin Endocrinol 2001; 54: 126-7. 35. O'Suilleabhain P, Bullard J, Dewey RB. Proprioception in Parl~inson's disease is acutely depressed by dopaminergic medications. J Neurol Neurosurg Psychiatry 2001; 71: 607-10. 36. Etminan M, Samii A, Takkouche B, Rochon PA. Increased risk of somnolence with the new dopamine agonists in patients with Parkinson's disease. A meta-analysis of randomised controlled trials. Drug Saf 2001; 24: 863-8. 37. Ondo WG, Vuong KD, Khan H, Atassi E Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson's disease. Neurology 2001; 57:1392~5. 38. Pal S, Bhattacharya KF, Agapito C, Chaudhuri KR. A study of excessive daytime sleepiness and its clinical significance in three groups of Parkinson's disease patients taking pramipexole, cabergoline and levodopa mono and combination therapy. J Neural Transm 2001; 108: 71-7. 39. Sanjiv CC, Schulzer M, Mak E, Fleming J, Martin WRW, Brown T, Calne SM, Tsui J, Stoessl AJ, Lee CS, Calne DB. Daytime somnolence in patients with Parkinson's disease. Parkinsonism Relat Disord 2001; 7: 283~.

Drugs that affect autonomic functions or the extrapyramidal system 40. Montastruc J-L, Brefel-Courbon C, Senard J-M, Bagheri H, Ferreira J, Rascol O, Lapeyre-Mestre M. Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study. Clin Neuropharmacol 2001; 24: 181-3. 41. Ferreira JJ, Thalamas C, Monastruc JL, CastroCaldas A, Rascol O. Levodopa monotherapy can induce "sleep attacks" in Parkinson's disease patients. J Neurol 2001; 248: 426-7. 42. Micallef-Roll J, Rihet P, Hasbroucq T, Possama'/ C, Blin O. Levodopa-induced drowsiness in healthy volunteers: results of a choice reaction time test combined with a subjective evaluation of sedation. Clin Neuropharmacol 2001; 24: 91-4. 43. Goetz CG, Leurgans S, Pappert EJ, Raman R, Sterner AB. Prospective longitudinal assessment of hallucinations in Parkinson's disease. Neurology 2001 ; 57: 2078-82. 44. Bair JD, Oppelt TF. Warfarin and ropinirole interaction. Ann Pharmacother 2001; 35: 1202~4. 45. Matunaga K, Uozomi T, Qingrui L, Hashimoto T, Tsuji S. Amantadine-induced cortical myoclonus. Neurology 2001; 56: 279-80. 46. Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L. Switch-over from tolcapone to entacapone in severe Parkinson's disease patients. Eur Neurol 2001; 46: 11-16. 47. Myllyla VV, Kultalahti E-R, Haapaniemi H, Leinonen M. Twelve-month safety of entacapone in patients with Parkinson's disease. Eur J Neurol 2001; 8: 53~60. 48. Zavaleta EG, Fernandez BB, Grove MK, Kaye MD. St Anthony's fire (ergotamine induced leg ischemia). A case report and review ~?fthe literature. Angiology 2001; 52: 349-56. 49. Tsui BCH, Stewart B, Fitzmaurice A, Williams R. Cardiac arrest and myocardial infarction induced by postpartum intravenous ergonovine administration. Anesthesiology 2001; 94: 363-4. 50. Papalampros EL, Salakou SG, Felekouras ES, Scopa C, Tsamandas AC, Bastounis E. lschemic necrosis of gastric wall after long-term ergotamine pill abuse. Case report and review of the literature. Dig Dis Sci 2001; 46: 981-4. 51. Ausband SC, Goodman PE. An unusual case of clarithromycin associated ergotism. J Emerg Med 2001; 21 : 411-13. 52. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral ergotism under treatment

Chapter 13

167

with ergotamine and ritonavir. Neurology 2001 ; 57: 743-4. 53. Bjerke RJ, Mangione MR Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anesth 2001; 48: 305-7. 54. Okun MS, Charriez CM, Bhatti MT, Watson RT, Swift TR. Asystole induced by edrophonium following beta blockade. Neurology 2001; 57: 739. 55. Clemett D, Jarvis B. Tolterodine. A review of its use in the treatment of the overactive bladder. Drugs Aging 2001; 18: 277-304. 56. Abrams R Malone-Lee J, Jacquetin B, Wyndaele J-J, Tammela T, Jonas U, Wein A. Twelvemonth treatment of overactive bladder. Efficacy and tolerability of tolterodine. Drugs Aging 2001; 18: 551--60. 57. Crandall C. Tolterodine: a clinical review. J Women's Health Gender Med 2001 ; 10: 735-43. 58. Layton D, Pearce GL, Shakir SAW. Safety profile of tolterodine as used in general practice in England. Drug Saf 2001; 24:703 13. 59. Van Kerrebroeck R Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001; 57: 414-21. 60. Dilaversi R Pantazis A, Vlasseros J, Gialafos J. Non-sustained ventricular tachycardia due to lowdose orphenadrine. Am J Med 2001; 111:418-19. 61. Brady WJ, Perron AD. Administration of atropine in the setting of acute myocardial infarction: potentiation of the ischaemic process? Am J Emerg Med 2001; 19: 81-3. 62. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001; 165: 1452~i. 63. Chancellor MB, Appell RA, Sathyan G, Gupta SK. A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate. Clin Ther 2001; 23: 753~i0. 64. Appell RA, Sand R Dmochowski R, Anderson R, Zinner N, Lama D, Roach M, Miklos J, Saltzstein D, Boone T, Staskin DR, Albrecht D. Prospective randomized controlled trial of extended-release oxybutynin chloride and torerodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin Proc 2001; 76: 358~53.