parkes1981

Review Articles
Drugs 21: 341-353 (1981)
00 12/6667/81/0005-0341/$03.25/0
© ADIS Press Australasia Pty Ltd . All rights reserved.
Adverse Effects of Antiparkinsonian Drugs
J.D . Parkes
University Department of Neurology, King's College Hospital and Institute of Psychiatry, London
Summary
In the last decade neurohormone replacement therapy with levodopa has revolutionised the
treatment of Parkin son's disease. At the same time the use of amantadine and dopamine-like
ergot drugs has developed, although there is still a place for anticholinergic drugs, now in use
for a century. These advances have resulted in the availability of many different drugs to treat
Parkinsonism with different pharmacological actions. It is now usually possible to control disability, at least in the .initial stages of disease, although sometimes at the expense offrequent
and disabling side effects , In most cases these result from the widespread distribution of
cholinergic and dopaminergic systems inside and outside the brain and the non-selective action
of therapeutic agents on these different systems. Despite the recent division of dopamine receptors into DI and D2 classes. no selective dopamine-like antiporkinsonian drugs are known.
The pract ical treatment of Parkinsonism depends on accurate knowledge of the side effects
as well as therapeutic effects of many different drugs, and requires titration of individually
determined dosages in different patients to achieve the optimum response . This iIJ usually deter mined by dose-limiting side effects as well as by improvement. The possibility that the eventual
de velopm ent of response fluctuation and failure may result from the sustained use of large
doses of dopamine-like drugs must be considered. and it is probably wise at present to give low
rather than high doses of these agents. No presently available treatment appears to influence
the natural progression of Parkinsonism.
Many untreated patients with Parkinson's disease
are elderly and frail, and in addition to their extrapyramidal disturbance often have joint disease,
poor vision, ill-fitting dentures and a variety of respiratory, cardiac or renal disorders. These patients often
live alone or are cared for by relatives who are themselves disabled. This review highlights the additional
problems which are often caused by antiparkinsonian
drugs.
The diagnosis of idiopathic Parkinson 's disease
can be difficult, and subjects with cerebro-arteriosclerosis, senile dementia or familial tremor may have
apparently similar clinical features. Such patients
often do not respond to antiparkinsonian drugs and
neuropsychiatric complications are common.
Drugs used to treat Parkinson 's disease belong to
different chemical groups with different pharmacological characteristics. They include: (I) anti-
342
Adverse Effects of Antiparkinsonian Drugs
cholinergic drugs which are thought to act centrally
and reduce excess cholinergic activity in the basal
ganglia; (2) levodopa which is metabolised by the
enzyme dopa decarboxylase to dopamine both inside
and outside the brain. Dopamine is then thought to
act as a neurohormone or neurotransmitter in the
basal ganglia; (3) decarboxylase inhibitors which do
not penetrate the brain and have no separate antiparkinsonian effect, but combined with levodopa
reduce or abolish the peripheral decarboxylation of
this substance in the gut, liver and other extracerebral
organs without altering the central decarboxylation of
levodopa to dopamine in the brain. The commercialIy
available decarboxylase inhibitors include benserazide
and carbidopa, (4) amantadine, which may act by
causing an increase in presynaptic dopamine release
in response to nerve stimulus and also prevents
presynaptic dopamine reuptake (the structure of
amantadine is unrelated to that of any other antiparkinsonian drug); (5) ergot derivatives which have
similar actions to dopamine, although often different
side effects to levodopa, and (6) muscle relaxants,
tranquillisers, central stimulants, antihistamines and
the monoamine oxidase B inhibitor deprenyl. All of
these drugs are effectiveto a greater or lesser extent in
Parkinsonism, but adverse drug reactions are frequent.
The treatment of choice in Parkinsonism is
usually determined by the degree of disability. In
patients with mild disability anticholinergics alone or
combined with amantadine may be used. Both drugs
are usually given in fixed dosages. In patients with
moderate disability levodopa, usual1y combined with
benserazide or carbidopa, is the most effective treatment available. Treatment must be given in individual1y determined doses and may, if necessary, be
combined with anticholinergics or amantadine . In
patients with severe disability, which is often accompanied by disease progression, levodopa failure and
fluctuation in disability, the addition of deprenyl or
bromocriptine to previous regimens occasionally produces improvement.
Because of polypharmacy in the treatment of
Parkinsonism, it is often difficult to attribute side
effects in individual patients to one drug . An attempt
should always be made to prescribe the simplest regimen that is consistent with an adequate degree of improvement. No antiparkinsonian drug should be
stopped abruptly as this often results in a severe increase in disability which may last several days. Overall, antiparkinsonian drugs cause few serious biochemical problems, and adverse reactions, although
frequent, are rarely life-threatening. All effective antiparkinsonian drugs may cause changes in mood or
behaviour and should be avoided in patients with a
history of severe neuropsychiatric disorders.
Table I is a summary of the important facts that
patients should know about Parkinson's disease and
the possible side effectsof drug treatment. It is essential that both patients and their relatives are warned
of the possibility of side effects and specifical1y of the
consequences of autonomic blockade with anticholinergics, sickness and faintness with levodopa
and related compounds, ankle oedema with amantadine, and uncommon but severe 'first-dose' reactions with bromocriptine. Decarboxylase inhibitors
and deprenyl have not been reported to cause any
serious adverse reactions.
This review concentrates on the most common adverse reactions seen in clinical practice. The reported
incidence of side effects of antiparkinsonian drugs
varies widely and is dependent on the intensity with
which they are sought and that with which patients
are warned of them . Thus, figures in the text are at
best approximate and refer to experience in the King's
College Hospital extrapyramidal clinic. Detailed information on toxic effects and uncommon side effects
of levodopa and bromocriptine has appeared in
various articles in the Journal [see Drugs 2: 262
(I 97 I) ; 4: 49 (I972); 6: 364 (I 973); II: 61 (I 976);
II: 329 (I 976) and 17: 365 (I 979»).
J. Anticholinergic Drugs
Anticholinergics are usual1y not very potent antiparkinsonian drugs although the various preparations
commercially available (see table II) all reduce
Adverse Effects of Antiparkinsonian Drugs
343
Table I . Summary of important facts that pat ients should know about Parkinson's disease
Cause
This is unknown, but Parkinson's disease is not due to any 'softening' of the brain or failure of blood
flow. A few cases followed sleeping sickness in 1916 to 1926, but there have been no recent epidemics
of this illness
Progress
In about 40% of people the severity of Parkinson's disease does not progress rapidly, and overall the
condition is unlikely to shorten life
Mind and senses
The intellect and the senses are not affected by Parkinson's disease, at least for many years
Cure
As the cause is not known, there is no present cure. However, Parkinson's disease can be treated
Drugs
Most people will need levodopa in some form and at some stage of the illness. Levodopa is converted
to the naturally occurring compound dopamine which is reduced in concentration in Parkinsonism.
Levodopa will probably have to be given for life . All drugs used to treat Parkinson's disease may cause
neuropsychiatric disturbance as well as other specific side effects
Surgery
Done previously to abolish tremor, but now largely if not entirely replaced by levodopa
Diet and weight
A low protein diet is possibly sometimes helpful in increasing immediate response to levodopa . Weight
should be restricted
Exercise
May increase patient morale and reduce stiffness, but does not fundamentally alter disease
tremor, rigidity and akinesia by approximately 20 % .
They differ in potency, duration of action and sedative
effect. All probably act centrally to prevent acetylcholine having its usual effect at receptor sites; quartenary ammonium compounds which are fully
ionisedand do not penetrate the brain have little or no
antiparkinsonian effect. The adverse effects of these
compounds are well known and easily recognised,
being mainly due to peripheral cholinergic receptor
blockade.
Treatment with anticholinergic drugs is usually
started in fixed dosages with slow increase until an
extrapyramidal effect is obvious or side effects are intolerable. Patients with postencephalitic Parkinsonism may tolerate very high dosages.
Central effects of anticholinergic drugs include
mild vagal and respiratory stimulation, but peripheral
vagal depression usually results in a slight increase in
heart rate. Changes in awareness and behaviour are
of more clinical importance, Benztropine, biperiden
and procyclidine all cause drowsiness, and benztropine may have a prolonged and cumulative effect. In
contrast, orphenadrine occasionally causes euphoria.
All centrally acting anticholinergics will cause
changes in awareness, slow cerebration, inattention,
restlessness, aggressive or paranoid behaviour or
ideas, visual or, less commonly, tactile hallucinations
or changes in mood, Intercurrent infection, concomitant administration of other drugs with anticholinergic properties such as antihistamines,
butyrophenones, phenothiazines, tricyclics or other
antiparkinsonian drugs, may precipitate these side
effects. Mental symptoms usually recover without incident within 2 to 7 days of anticholinergic withdrawal, although physostigmine 2mg subcutaneously
has been given to speed recovery (El-Yousef et al.,
1972). Although phenothiazines may enhance the
toxic effectsof anticholinergics, and should if possible
be avoided in subjects with Parkinsonism,
chlorpromazine has been used in cases of atropine
poisoning (Wood and Haq, 1971). Approximately 19
to 30 % of patients with Parkinsonism given anticholinergics develop depression, confusion, delusions
or hallucinations (Editorial, 1974).
Toxic doses of anticholinergic drugs result in a
severe mental disturbance with excitement, confusion, widely dilated pupils, flushed dry skin and fever.
Increased intraocular pressure with tachycardia, pal-
Adverse Effects of Antiparkinsonian Drugs
Table II . Some anticholinergic drugs used in Parkinsonism
Drug
Benapryzine
Benzhexol
Benztropine
Biperiden
Chlorphenoxamine
Cycrimine
Usual daily dose (mgl
150-200
2-20
0.5-6
2-12
344
required. Neostigmine, which unlike physostigmine
does not penetrate the brain or increase disability in
Parkinsonism, will reverse peripheral but not central
side effects of anticholinergic drugs. Eczema (Cant,
1969), retrosternal pain due to increased oesophageal
reflux (Piper and Heep, 1972) and cardiac infarction
(Scherf, 1973) have all been attributed to anticholinergic drugs.
150-400
5-20
Ethopropazine
40-500
Meth ixine
7.5-15
Orphenadrine
150-400
Procyclidine
7.5-30
pitations and arrhythmias, urinary retention and constipation and rapid respirations result from peripheral
cholinergic blockade. Treatment is with physostigmine 1 to 2mg subcutaneously (Duvoisin and Katz,
1968), sodium thiopentone if excitement predominates and if necessary oxygen and assisted respiration.
Atropine has long lasting mydriatic and
cycloplegic effects. Most anticholinergics used in the
treatment of Parkinsonism have less prolonged ocular
effects than atropine, but difficulty in focussing is
common . Dilatation of the pupil with photophobia
may occur, and very rarely precipitation of angle
closure glaucoma results in loss of vision (Friedman
and Neumann, 1972). Reversal of anticholinergic-induced mydriasis can be achieved with thymoxamine
0.5% (Smith, 1971).
Decreased salivation with anticholinergic drugs
may be of value in Parkinsonism, although extreme
dryness of the mouth can lead to almost total loss of
teeth (Winer and Bahn, 1967). Increase in heart rate,
decreased production of sweat, bronchial, lacrimal,
nasal, gastric and intestinal secretions with decreased
gut motility and inhibition of micturition requiring
catheterisation are not uncommon. Change in diet,
addition of roughage, lactulose 5 to 30ml daily,
ispaghula husk 3 to 5g daily or other laxatives may be
1.1 Precautions and SpecialNotes
Anticholinergics should be avoided in the presence
of prostatic enlargement, pyloric stenosis or paralytic
ileus, and should not be given to patients with closed
angle glaucoma or a narrow angle between the iris
and the cornea.
Individual tolerance to anticholinergic-induced
side effects differs greatly. Deaths have occurred
following atropine 100mg whilst recovery has occurred after Ig. The sudden withdrawal of anticholinergics should not be attempted in patients with
Parkinsonism as this may cause a considerable increase in disability.
Elderly patients may require only small doses of
anticholinergic drugs. Benzhexolcan be given in conventional doses to patients with impaired renal function (Bennett et al., 1973).
2. Amphetamines
Amphetamines were widely used to treat patients
with postencephalitic Parkinsonism in the 1930s, and
often caused a considerable subjective improvement
in mood or energy, but had little objective effect on
extrapyramidal symptoms (Davis and Stewart, 1938).
Side effects were relatively common, including dry
mouth , nausea, difficulty in micturition , agitation and
restlessness, insomnia and dizziness, headache,
tremor and anorexia, with increasing systolic and
diastolic blood pressure, tachycardia and cardiac arrhythmia in high doses. Because of the very slight
therapeutic effect, frequent side effects and the possi-
345
Adverse Effects of Antiparkinsonian Drugs
bility of drug misuse, leading to aggressive, antisocial
or psychotic behaviour with a risk to public health,
amphetamines are best avoided in the treatment of
Parkinson's disease.
3. Amantadine
The incidence of adverse drug reactions with
amantadine 100 to 300mg daily in Parkinsonism is
relatively low (Hacohen and Gurtner, 1972; table III;
Rao and Pearce, 1971). Central nervous system
stimulant effects which are produced by high dosages
in animals occur rarely with therapeutic doses in
man, and although amantadine shares pharmacological properties with amphetamine, addiction to amantadine has not been reported . Amantadine overdosage
may produce an acute toxic psychosis. At very high
doses (4 times the recommended dosage) convulsions
have occurred (Schwab et al., 1969).
Amantadine has little or no anticholinergic effect,
but will potentiate neuropsychiatric disorders due to
anticholinergic drugs . Disorders in awareness and
hallucinations occur in 2 to 10 % of subjects treated
with amantadine alone and are increasingly common
with amantadine dosages higher than 200mg daily.
Visual hallucinations and nocturnal confusion
usually stop within a few days of amantadine withdrawal. Harper and Knothe (1973) described coloured
Lilliputian hallucinations in a woman with
Breughel's syndrome (orornandibular dystonia) , and a
patient with cerebrovascular disease given amantadine.
Symptoms of central nervous system stimulation
with restlessness, nervousness and irritability occur
in up to one-fifth of Parkinsonian patients treated
with amantadine 100 to 300mg daily, and may account for the increase rather than decrease in tremor
that occurs in some patients . Amantadine has a slight
but definite alerting effect and may cause insomnia
(Vitetta, 1971).
Amantadine, unlike levodopa, does not usually
cause dyskinesias, and the addition of amantadine to
levodopa does not increase the severity of levodopa-
induced involuntary movements (Godwin-Austen et
aI., 1970), although Pearce (I 97 I) described a 68year-old woman who developed orofacial dyskinesias
whilst taking amantadine 200mg daily.
Livedo reticularis was first described in Parkinsonian patients treated with amantadine by Shealy et al.
(I 970). This marbled fish net-like appearance of the
skin had previously been described in collagen disorders , although not attributed to drugs . Livedo with
amantadine appears to result from a pharmacological
response, rather than a pathological change in blood
vessels. Livedo may be more severe in cold climates
than in warm surroundings and occurs to some extent in untreated normal subjects. Livedo usually
resolves within 2 to 4 weeks of amantadine withdrawal. Approximately 10% of subjects treated with
amantadine develop ankle oedema accompanying
livedo. Oedema is usually mild in severity and first
appears within 6 to 8 weeks of starting treatment.
Oedema may result from changes in vascular permeability in skin blood vessels, and is usually unaccompanied by signs of heart , liver or kidney disease.
It responds to diuretics but occasionally necessitates
amantadine dose reduction or withdrawal.
Table III . Common adverse reactions to amantadine in
Parkinsonism
Effect'
CNS stimulation
(insomnia, excitement.
agitation)
Approximate frequency
(%)
5 to 20
Mental disturbance
hallucination
nocturnal confusion
15
5
Livedo
up to 80
Oedema
5 to 15
1 Additionally. anorexia. dizziness. myalgia . shivering. abdominal pain and orthostatic hypotension have all been
described in subjects on amantadine.
Adverse Effects of Antiparkinsonian Drugs
346
Table IV. Adverse reactions to levodopa in patients with Parkinsonism
Effect
Approximate frequency (%)'
without
decarboxylase
inhibitor
with
decarboxylase
inhibitor
50
80
10
Rare
Rare
90
5
40
Rare
Rare
Neuropsychiatric
Agitation, anxiety
Aggression , delusions, hallucinations, etc .
Changes in mood, awareness
20
20
20
25
25
25
Involuntary movements
Restlessness, chorea
Dystonia
70
10
80
15
Gasrrointestinal
Anore xia
Nausea
Abdominal pain, constipation, diarrhoea , GI bleeding
Cardiovascular
Postural hypotension
asymptomatic
symptomatic
Palpitations, flushing, arrhythmia
1
15
5
Based on reports of subjects with Parkinson's disease attending the King's College Hospita l extrapyramidal disease clinic.
Fahn et al. (1971) described the effects of an overdosage of amantadine (2.8g) which resulted in an
acute toxic confusional state with hyperpyrexia. The
patient recovered after a few days.
combining it with peripherally acting dopamine
decarboxylase inhibitors (vide infra).
4.1 Gastrointestinal Symptoms
Vomiting, with or without nausea, occurs 20 to
90 minutes after a dose of levodopa in about 80 % of
all subjects. After several months of treatment,
The many adverse effects of levodopa (table IV) tolerance to the emetic effect occurs in the majority,
are attributable to dopamine receptor stimulation at but not in all subjects. Nausea may sometimes be
different sites inside and outside the central nervous avoided by giving low single doses of levodopa (125
system (table V). A characteristic of receptors is to 250mg), increasing daily dosage very slowly <increspecificity, but at present there is no definite clinical ments of 250 to 500mg weekly), and by always takevidence of a distinction between different types of ing levodopa with food. Although there appear to be
dopamine receptors at different sites inside or outside gastric dopamine receptors, vomiting with levodopa
the brain. Despite this, some progress has been made is attributable to stimulation of the medullary emetic
in preventing adverse reactions to levodopa without centre, situated in the brain stem, but outside the
seriously impairing the drug's therapeutic effect, by blood-brain barrier to dopamine.
4. Levodopa
347
Adverse Effects of Antiparkinsonian Drugs
Gastrointestinal symptoms from levodopa may be
lessened by concomitant administration of anticholinergic drugs. However, the combination of levodopa with decarboxylase inhibitors which penetrate
the vomiting centre but not extrapyramidal areas of
the brain, and hence prevent dopamine stimulation of
medullary chernoceptors, reduces the incidence of
vomiting from approximately 80 % to 15 % . To
achieve adequate inhibition of peripheral decarboxylation , a minimum dose of carbidopa (75mg daily) or
benserazide (I OOmg) is required. Patients taking
small amounts of levodopa-decarboxylase inhibitor in
fixed dose combinations may not achieve an adequate
degree of inhibition of decarboxylation to prevent
nausea. In addition, or alternatively, to decarboxylase
inhibitors, metoclopramide 10 to 20mg, domperidone 10 to 20mg, or antacids may be given 30 to
60 minutes before levodopa. Metoclopramide 20mg
penetrates the brain and will partially block the therapeutic response to levodopa, but domperidone 10 to
20mg penetrates the brain poorly if at .all and thus
probably does not alter the therapeutic effects of
levodopa. Despite all these measures, levodopa still
occasionally may cause severe gastrointestinal disturbance.
Other gastrointestinal symptoms attributable to
levodopa include constipation, although this probably
results from concomitant anticholinergic medication,
diarrhoea, flatulence and heartburn. Gastrointestinal
Table V. Distribution of dopamine-regulated systems in
the body
Intracerebral
Nigrostriatum (motor controll
Hypothalamus
(growth hormone regulation)
Extracerebral
Pituitary
(prolactin controll
Autonomic ganglia
limbic system (? motor con troll
Pancreas
Cortex (?)
Spinal cord
Medulla (vomiting. blood pressur e)
Renal artery
(renal blood flow )
bleeding has occurred in subjects with a history of
peptic ulceration given levodopa.
4.2 Cardiovascular Effects
Levodopa causes a fall in systolic and diastolic
blood pressure because dopamine stimulates blood
vessels , peripheral nerve terminals and the central
nervous system (Clark et al ., 1978). Hypotension,
with an average fall of systolic blood pressure of
20mm Hg occurs in the majority of subjects given
levodopa, but is usually asymptomatic. However,
faintness and dizziness are not uncommon at the start
of treatment and may first occur in certain sensitive,
disabled and hypo kinetic subjects 2 to 3 years after
commencing therapy. When severe, hypotension
with syncope may prevent levodopa therapy. An
upright posture at night may partially reduce this side
effect, and postural hypotension may be occasionally
sat isfactorily controlled with elastic stockings, oral
ephedrine 30 to 120mg, fludrocortisone 0.1 mg or
propranolol (Duvoisin, 1970).
A wide range of cardiac dysrhythmias has been
described in Parkinsonian patients taking levodopa,
although the incidence of transient sinus tachycardia,
and atrial and ventricular extrasystoles is low and
may be reduced still further by the addition of decarboxylase inhi bitors . The benefits of levodopa in practical therapy usually outweigh any risk of cardiac
dysrhythmia in Parkinsonian subjects with heart
disease, although such patients should be given
'Madopar' or 'Sinemet' rather than levodopa alone .
Patients with Parkinson's disease are usually in an
age group with a relatively high incidence of coronary
artery disease, and not all dysrhythmias that appear
whilst on levodopa can be necessarily attributed to the
drug.
4.3 Neuropsychiatric Disorders
Agitation, anxiety , elation, insom nia, drowsiness,
depression, aggression, paranoid ideas, hallucina-
Adverse Effects of Antiparkinsonian Drugs
tions, delusions, or unmasking of dementia may occur within a few days or several years after starting
levodopa, and usually present at the time of levodopa
dose increase or pyrexia, or on the addition of another
antiparkinsonian drug . These neuropsychiatric disorders are common with some degree of nocturnal confusion in 20 to 30 % of all Parkinsonian patients on
levodopa. Improvement usually occurs 1 to 2 weeks
after levodopa withdrawal , but severe psychotic
symptoms may require hospitalisation. The addition
of decarboxylase inhibitors to levodopa, if this permits an effective increase in levodopa dosage, will
tend to increase the frequency and severity of mental
disturbances.
Mild psychotic symptoms, with change in mood
or awareness, may be acceptable as the price of improved mobility. Levodopa-induced neuropsychiatric
disorders may be treated if necessary with a psychotropic drug or non-phenothiazine derivative such
as chlormethiazole.
Insomnia, changes in sleep pattern or daytime narcolepsy may rarely occur in patients on levodopa
(Muenter, 1970), although usually the drug has little
or no effect on awareness. Elevation or depression of
mood has been recorded on levodopa, although this
may be a secondary effect due to alteration in severity
of Parkinsonism.
348
voluntary movements. Damage to the motor system
is a major determinant of levodopa dyskinesias which
are unusual in subjects without motor disorders given
large doses of levodopa.
In some patients with Parkinson 's disease,
dyskinesias first appear as treatment progresses and
at dosages that have been well tolerated previously,
and in other subjects dyskinesias recur at progressively lower levodopa doses.
Levodopa dyskinesias vary in severity with the
level of arousal and the degree of motor activation.
Dyskinesias may not be troublesome to the patient
and some degree of mobility accompanied by
dyskinesias may be preferable to a lower degree of
benefit unaccompanied by involuntary movements.
However, in view of the possibility of long term
levodopa response failure or response fluctuation,
levodopa dosages that result in severe dyskinesias in
the early years of treatment should be avoided.
Indeed, the only satisfactory way to avoid levodopa dyskinesias is to reduce levodopa dosage or give
small but frequent (2-hourly) oral doses oflevodopa if
response fluctuation occurs with more widely separated doses. The possibility of preventing dyskinesias
with the selective blockade of a 'dyskinesia-generating' population of dopamine receptors (Costall and
Naylor, 1975) is of theoretical interest. Several different neuroleptic drugs will block levodopa dyskinesias
to a greater or lesser extent, although usually at the
expense of increased Parkinsonism (Barbeau, 1969;
4.4 Dyskinesias
Bedard et al., 1978; Klawans and Weiner , 1974;
Restlessness, chorea or dystonia occur in 60 to Lbermitte et al., 1977; Tarsy et al., 1975). Thus, with
90 % of all subjects with Parkinson's disease on neuroleptic treatment there is usually a reduction in
otherwise optimum doses of levodopa. Dyskinesias the severity of levodopa dyskinesias as well as a
are usually dose-related and of maximum severity at reduction in the therapeutic effect of levodopa. Howthe time of optimum clinical improvement from ever, with careful titration of the dosage of the neurolevodopa, although many different patterns of leptic drugs tiapride and oxiperomide, it is sometimes
dyskinesia and therapeutic improvement have been possible to achieve a neuroleptic dosage that will inreported. The central origin of dyskinesias is shown hibit dyskinesias without impairment of the theraby the finding that the addition of peripherally acting peutic response (Bedard et al., 1978; Price et al.,
decarboxylase inhibitors to levodopa, which permits 1978). Both tiapride and oxiperomide may induce
the use of large centrally effective doses of levodopa drowsiness.
An alternative approach to abolish levodopa
without the occurrence of nausea or vomiting, results
in an increase in the frequency and severity of in- dyskinesias has been the use of low doses of
349
Adverse Effects of A ntiparkinsonian Drugs
dopamine agonists rather than antagonists in an attempt to produce feedback-mediated reduction in
dopamine turnover and release (Carlsson et al.,
1976). However, despite the occasional report of apparently paradoxical effects of the dopamine agonists
apomorphine and lergotrile in Parkinsonism (Tolosa,
1974; Weiner et al., 1978), there is insufficient evidence to conclude that low doses of dopamine-like
drugs have opposite pharmacological effects to high
doses in man, or that these drugs are of clinical value
in the prevention of levodopa dyskinesias.
4.5 Response Fluctuation
Fluctuation in disability is common in untreated
Parkinsonian patients. The amplitude of Parkinsonian tremor may vary 7-fold during an hour , sudden
'freezing' episodes are common in severely disabled
patients and exercise, anxiety, exhaustion, changes in
arousal or motor effort all may alter the severity of
akinesia. With the addition of levodopa treatment,
further dose-related response swings may appear
whilst involuntary levodopa dyskinesias will also interfere with voluntary movement. Response fluctuations usually increase in severity and frequency with
the progression of disease and the period of levodopa
treatment. Some, but not all, types of 'on-off
response may be avoided by drug manipulation .
Following a single oral dose of levodopa, plasma
dopa reaches peak concentration after 30 minutes to 3
hours, with a mean plasma half-life of 1.08 hours
without decarboxylase inhibitor and 1.6 hours with
inhibitor (Dunner et al., 1971). The clinical response
usually follows this time course. Attempts to delay
the absorption of levodopa by administering it with
food , or to increase brain penetration of levodopa by
reducing dietary intake of those amino acids which
compete with levodopa for transport mechanisms
into the brain , may alter the duration of clinical
response (Morgan et al., 1971). If despite 2-hourly
administration, alone or with decarboxylase inhibitor,
a steady response is not obtained, it may be necessary
to consider the addition of bromocriptine or deprenyl
(see below). 25 to 50 % of all Parkinsonian patients
treated with levodopa for 5 years or more develop
an unpredictable pattern of response or response
failure.
4.6 Response Failure
The disease process of Parkinson's disease is
unaltered by dopamine replacement, and there is a
progressive loss of dopamine receptors in the caudate
nucleus which may explain the decreasing loss of
response to levodopa and the shrinking period of
benefit from each separate dose. It is not certain
whether levodopa treatment per se may be responsible for the common appearance 2 or more years after
starting treatment of response fluctuation and apparent response failure, or whether these changes are
due to the unchecked progressive melanin-neurone
loss in the basal ganglia. However, it is probably wise
to limit levodopa early in treatment and avoid doses
causing severe dyskinesias.
4.7 Other Adverse Reactions
Reported urinary effects of levodopa including
polyuria, incontinence, difficulty in micturition and
retention may in fact result from infection, other
genitourinary disease or concomitant anticholinergic
drugs rather than levodopa. Patients with chronic
wide angle glaucoma may be treated cautiously with
levodopa, but this is contraindicated in patients with
narrow angle glaucoma. The hormonal consequences
of levodopa treatment (increase in growth hormone
and suppression of prolactin) are usually of no clinical
importance in elderly Parkinsonian subjects.
Biochemical and haematological changes reported
in subjects on levodopa have been reviewed in the
Journal previously (Brogden et al., 1971). These
changes are usually minor and include slight and
usually transient rises in blood urea and nitrogen, increased serum transaminases (SGOT and SGPT>,
alkaline phosphatase and bilirubin , and the occur-
350
Adverse Effects of Ant iparkinsonian Drugs
renee of a positive direct Coomb's test with evidence
of haemolysis.
The safety of levodopa has now been demonstrated over a decade of use. No separate reactions attributable to the use of decarboxylase inhibitors have
been reported in man, and their availability has made
it possible to partially revise previous recommendations, precautions and contraindications to levodopa
treatment.
4.8 Precautions and Special Notes
Levodopa remains contraindicated in patients with
severe psychoneurosis or closed angle glaucoma. It
should not be given within 2 weeks of monoamine
oxidase A inhibitors. Vitamin preparations which
contain pyridoxine interfere with the action of
levodopa, but not when this is combined with decarboxylase inhibitors.
If indicated in the treatment of severe Parkinsonism, levodopa combined with a decarboxylase inhibitor can be given to patients with cardiac or renal
disease, although there is a slight possibility of provoking atrial, nodal or ventricular dysrhythmias, particularly following myocardial infarction. Some caution is needed in the treatment of patients with active
peptic ulcers. Periodic biochemical evaluation is unnecessary.
4.9 Drug Interactions with Levodopa
Levodopa can be safely combined with other antiparkinsonian drugs and also with analgesics, tricyclic
antidepressants , antidiabetic and antihypertensive
drugs . Patients with Parkinsonism tolerate surgery
poorly and if possible this should be done under
regional or local anaesthesia. Serious adverse reactions of levodopa in combination with anaesthetics
have not been reported, but if a general anaesthetic is
unavoidable levodopa should be discontinued 6 hours
prior to surgery .
The motor effects of levodopa are diminished by
phenothiazines, butyrophenones, reserpine, pyridoxine and papaverine, and enhanced by anticholinergics,
amphetamine, amantadine and decarboxylase inhibitors .
5. Benserazide and Carbidopa
These decarboxylase inhibitors prevent the
enzymatic conversion of levodopa to dopamine . Carbidopa (l-o-methyldopa hydrazine) does not penetrate
into the brain. It is usually given with levodopa in a
ratio of I part carbidopa to 10 parts levodopa. The
usual dose range of carbidopa is 75 to 150mg daily,
given in divided doses. Benserazidewill penetrate into
the brain in extremely high dosage, but at a dose of
100 to 200mg daily it causes peripheral but not
central decarboxylase inhibition, The usual dose ratio
of benserazide to levodopa is I to 4. No clinically obvious untoward effects have been attributed to these
decarboxylase inhibitors given in these dosages with
levodopa, but their use is not recommended in
patients under 25 years of age or during pregnancy.
6. Ergot Derivatives
Several ergot derivatives (bromocriptine, lergotrile, lisuride and pergolide)have been used in Parkinsonism, but bromocriptine is the only one of these
compounds at present in widespread use. Lergotrile,
but not the other compounds, has been shown to
cause liver damage (Teychenne, 1979).
Adverse reactions to bromocriptine and other
dopamine-like ergot derivatives fall into 2 classes:
first, those due to widespread and non-selective
dopamine receptor stimulation; and second, those
common to a number of ergot drugs , with particular
reference to vascular effects (Caine et al., 1978).
The dopamine stimulant actions of bromocriptine
are similar in nature to those of levodopa, although
the frequency of specific adverse effects with each
compound is different. Tolerance to the emetic and
hypotensive effect of both compounds may develop
Adverse Effects of Antiparkinsonian Drugs
over I to 2 months of treatment, but the therapeutic
effect is undiminished .
6.1 Dopamine-like Adverse Effects of
Ergot Drugs
Nausea, vomiting or faintness occur in a minority
of subjects (approximately 5 to 15 % ) given bromocriptine and are less troublesome than with levodopa.
The incidence of these side effects depends on the care
and speed with which bromocriptine is introduced:
the drug should be started with a 1.25mg dose, taken
with food and in bed to minimise the risk of fainting,
and dose increases should not be greater than 2.5 to
5mg on alternate days. (Different patient groups
allegedly show a different sensitivity to these side
effects of bromocriptine , which rarely if ever causes
vomiting when used to suppress postpartum lactation). If precautions are not taken a few sensitive subjects may collapse for 15 to 60 minutes after a first
dose of bromocriptine, but usually recover without
incident and tolerate further treatment well.
Bromocriptine lowers blood pressure because it
stimulates dopamine receptors on blood vessels, peripheral nerve terminals and the central nervous
system. The incidence of asymptomatic hypotension
with bromocriptine is comparable with that produced
by levodopa in equivalent therapeutic dosages. Severe
symptomatic hypotension is uncommon . 22 of over
10,000 subjects given bromocriptine have had hypotension and collapse, mainly on starting treatment,
with less severe symptoms in 1.8 % of subjects with
both endocrine and motor disorders (data on file, Sandoz Pharmaceuticals). Factors affecting the liability to
develop serious hypotension with bromocriptine have
not been definitely identified, although previous tendency to faint, presence of peripheral vascular disease,
vasodilator drugs and high altitudes may all be risk
factors (Parkes, 1980).
Neuropsychiatric symptoms with bromocriptine
are similar to those caused by levodopa alone,
although with bromocriptine they may be more
severe, more frequent and of longer duration, lasting
351
2 to 6 weeks after drug withdrawal. These symptoms
are more common in elderly frail subjects with
Parkinson's disease than in young subjects given bromocriptine to reduce hyperprolactinaemia or treat
acromegaly (drug dosages in the different groups are
not usually comparable).
Bromocriptine causes an increased incidence of
uterine tumours in rats, but apparently not in human
beings. At present it may be wise to recommend that
all women on bromocriptine have an annual
gynaecological examination (Besser et al., 1977),
although this will probably eventually prove unnecessary. Women with Parkinsonism are seldom of
childbearing age: although it is recommended that
bromocriptine should not be given to pregnant
women , the incidenceof abortion and fetal malformation is similar in subjects who have taken bromocriptine throughout pregnancy and in the general population (Griffith et al., 1978).
6.2 Other Adverse Effects of Ergot Drugs
Vascular toxicity with bromocriptine appears to
be less common than with some other ergot derivatives; Raynaud's phenomenon, erythromelalgia and
Livedo reticularis sometimes occur in parkinsonian
patients given bromocriptine , but serious vascular or
endothelial damage is very rare.
7. Deprenyl
Retarding the breakdown of dopamine should
prolong the antiparkinsonian effect of separate doses
of levodopa and reduce symptom fluctuations when
this results from rapid changes in brain dopamine
levels. This can be achieved by monoamine oxidase
(MAO) inhibitors, but the combination of levodopa
with most available MAO inhibitors is liable to cause
hypertensive crises as well as requiring rigid dietary
restrictions . 2 types of MAO inhibitors are now
recognised, and I-deprenyl selectively inhibits MAO
type B, the predominant type in the human brain
Adverse Effects of Antiparkinson ian Drugs
(Glover et al., 1977). The addition of deprenyl IOmg
daily to levodopa appears to enhance and prolong the
antiparkinsonian effect of levodopa (Birkmayer et al.,
1977; Lees et al., 1977). Although I-deprenyl is converted to I-amphetamine in the brain , and possibly
the liver, the drug appears to have little or no
amphetamine-like properties or side effects, and addiction or tolerance to I-deprenyl has not yet been
reported . Despite the absence of side effects, if 1deprenyl does achieve a permanent place in the
management of Parkinsonism, the minimal dose
causing central MAO inhibition should be used. This
dosage has not been defined, but may be as low as 2
to 5mg daily.
References
Barbeau . A.: L-dopa therap y in Park inson 's disease: a critical
review of nine years' experience. Jou rnal of the Canadia n
Medical Association 101: 59-68 (1969 ).
Bedard . P; Parkes. J.D. and Marsden . C. D.: Effect of new
dopamine-block ing agent (oxiperom ide) on drug -induced
dyskinesias in Parkinson's disease and spontaneous
dyskinesias, British Medical Journal I: 954-956 (197 8).
Bennett. W .M.; Singer. I. and Coggins. C.H .: Gu ide to drug usage
in adult patients with impaired renal function . Journal of the
American Medical Association 223: 991-997 (1973 ).
Besser. G .M.; Thorner. M.O.; Wass. J.A.H. ; Doniach. I.; Cant i,
G .; Curling. M.; Grudziniskas, J.G . and Setchell, M.E.: Absence of uterine neoplasms in patients on bromocriptine. British Medical Journal 2: 868 (1977 ).
Birkmayer, W .; Riederer, P.; Ambrozi , L. and Youdirn, M.B.H.:
Implications of combined treatment with Madopar and Ideprenil in Parkinson's disease. Lancet I : 439-443 (1977) .
Caine . D.B.; Williams, C .; Neoph ytides, A.; Plotkin . C, Nutt ,
J.G. and Teychenne , P.F.: Long-term treatment of parkinsonism with bromocriptine. Lancet I: 735-73 8 (197 8).
Cant . J.S.: Iatrogen ic eye disease. Practitioner 202: 787-795
(1969).
Carlsson. A.; Kehr, W. and Lindqvist, M.: The role of intraneuron al amine levels in the feedback control of dopamine.
noradrenaline and 5-hydroxy-tryptamine synthesis in rat
brain. Journal of Neural Tran sm ission 39: 1-19 (1976 ).
Brogden . R.N.; Speight. T.M . and Avery, G.S .: Levodopa, A
review of its pharmacological propert ies and therapeu tic uses
with particular reference to park insonism. Drugs 2: 262-400
(197)).
352
Clark . BJ.; Scholtysik, G. and Fluckiger , E.: Cardio vascular actions of bromocriptine. Acta Endocrinologia (Suppl.) 216 :
78-81 (1978).
Costall, B. and Naylor. RJ .: Neuroleptic antagoni sm of dyskinetic
phenomena. European Journal of Pharmacology 33: 30 1-312
(1975 ).
Davis, P.L. and Stewart . W.B.: The use of benzedrine sulfate in
post-encephal itic parkinson ism. Journal of the American
Medical Association 110: 1890-1892 (1938) .
Dunner. D.L.; Brodie. H.K.H. and Goodwin, F.K.: Plasma
DOPA response to levodopa administration in man : Effects of
a peripheral decarboxylase inhibitor . Clinical Pharmacology
and Therapeutic s 12: 212-217 (197)).
Duvoisin , R.C.: Hypotension caused by levodopa . British Medical
Journal 3: 47 (1970).
Duvoisin , R.C. and Katz. R.: Reversal of central ant icholinergic
syndrome in man by physostigmine. Journal of the American
Medical Association 206: 1963-1965 (1968) .
Editorial. Mental changes in Parkinsonism. British Medical Journal 2: 1-2 (1974).
EI·Yousef, M.K.; Janowsk y, D.S.; David. J.M. and Sekerk e, HJ .
Reversal of benztrop ine toxicity by physostigmine . Journ al of
the Amer ican Medical Association 220 : 125 (1972) .
Fahn , S.; Cradd ock. G. and Kumin, G.: Acute toxic psychosis
from suicidal overdosage of amantadine. Archives of Neurology 25: 45-48 (1971).
Friedman. Z. and Neumann. E.: Benzhexol-induced blindn ess in
Parkinson's disease. British Medical Journal I : 60 5 () 972 ).
Glover . V.; Sandler. M.; Owen. F. and Riley. GJ .: Dopamine is a
monoamin e oxidase B substrate in man . Nature 265 : 80-8 1
(1977).
Godwin-Austen , R.B.; Frears, c.c.; Bergmann . S.; Parkes. J .D.
and Knill-Jones, R.P.: Comb ined treatment of par kinsonism
with l-dopa and amantadine. Lancet 2: 383-385 (970).
Griffith, R.W .; Turk alj, I. and Braun . P.: Outcome of pregnancy
in mothers given bromocriptine. British Journal of Clinical
Pharmacology 5: 227-231 (1978).
Hacohen, H. and Gurtner. B.: Klinische pru fung des
therapieseffektes von Amantadin -HCI bei morbu s parkin son.
Schweizerische Medizinische Wochenschrift 102: 583-58 6
(972).
Harper . R.W . and Knothe, B.: Coloured Lilliputian hallucination s
with amantadine . Medical Journal of Australia I: 444-445
(1973) .
Klawans, H.L. and Weiner, WJ .: Attemp ted use of haloperidol in
the treatment of I-dopa induced dyskinesias. Journ al of Neurology, Neurosurgery and PSYChiatr y 37: 427-4 30 (1974).
Lees. AJ .; Shaw . K.M.; Kohout, L.J.; Stern . G .M.; Elsworth .
J.D.; Sandler . M. and Youdim , M.B.H.: Depren yl in Park inson's disease. Lancet 2: 791 -796 (1977) .
Lherm itte, F.; Agid, Y.; Signoret, J. L. and Studler , J-M.: Les
dyskinesies de 'debut et fin de dose' provoquees par la I-dopa.
Revue Neuro logique 133: 297-308 (1977>.
Adverse Effects of Antiparkinsonian Drugs
Morgan, J.P .; Bianchine, J .R .; Spiegel, H.E .; Rivera -Calimlim, L.
and Hersey, R.M.: Metabolism of levodopa in patients with
Parkinson's disease. Radioactive and fluorometric assays .
Archives of Neurology 25: 39-44 (1971).
Muenter, M.D.: Double-blind, placebo controlled study of
levodopa therapy in Parkinson's disease . Neurology 20
(Suppl .). 673 <1970>.
Parkes , J .D .: Side effects of bromocriptine. New England Journal
of Medicine 302 : 749 -750 (1980).
Pearce, J .: Mechani sm of action of amantadine. British Medical
Journal 3: 529 (1971>.
Piper , D.W. and Heap , T .R .: Medical management of peptic ulcer
with reference to anti-ulcer agents in other gastro-intestinal
diseases. Drugs 3: 366 -403 (1972).
Price, P.; Parkes, J .D . and Marsden, C.D.: Tiapride in Parkinson's
disease . Lancet 2: 1106 (1978).
Rao, N.S . and Pearce , J.: Amantadine in parkinsonism. An extended prospective trial . Practitioner 206 : 241-245 <1971>.
Scherf, D.: Atropine in acute myocardial infarctions. American
Heart Journal 86: 284 (1973).
Schwab , R.S.; England , A.C .; Poskanzer, D.C. and Young , R.R .:
American Medical Association 208 : 1168 (1969).
Shealy , C.N .; Weeth, J .B. and Mercier, D.: Livedo reticularis in
patients with parkinsonism receiving amantadine. Journal of
the American Medical Association 212 : 1522-1523 (1970).
Smith, S.E .: Mydriatic drugs for routine fundal infection . Lancet
2: 837-839 (1971>.
353
Tarsy, D.; Parkes , J.D . and Marsden, C.D. : Metoclopramide and
pimozide in Parkinson's disease and levodopa-induced
dyskinesias. Journal of Neurology, Neurosurgery and Psychiatry 38: 331-335 (1975).
Teychenne, P.F.: Hepatocellular injury with distinctive
metochondrial change s induced by lergotrile mesylate: A
dopaminergic ergot derivative. Gastroenterology 76: 575-583
(1979).
Tolosa, E.S.: Paradoxical suppression of chorea by apomorphine.
Journal of the American Medical Assoc iation 229 : 1579-1580
(1974).
Vitetta, M.: Effetti dell'amantadina sullo stato di viglanza nelle
psicosindromi cerebrali diffuse vasculopatiche. Minerva
Medica 62: 3984-3986 (1971>.
Weiner, W,J .; Kramer, J.; Nausieda, P.A. and Klawans, H.L.:
Paradoxical response to dopaminergic agents in Parkinsonism.
Archives of Neurology 35: 453-455 (1978).
Winer, J .A. and Bahn, S.: Loss of teeth with antidepressant drug
therapy. Archives of General Psychiatry 16: 239-240 (1967) .
Wood, B. and Haq , E.U.: An unusual case of atropine poisoning.
British Journal of Clinical Practice 25: 469-470 (1971>.
Author's address: Dr J.D. Parkes. University Department of
Neurology, King's College Hospital, London SE5 (Eng1and).