DOPAMINE AGONISTS

Dopamine agonists offer the theoretic advantage of exerting a direct action
on striatal dopamine receptors, which does not require presynaptic uptake
and synaptic release by degenerating dopaminergic nerve terminals. In
addition, they do not require metabolic conversion to exert their effects,
and their absorption and transport into the brain are not influenced by
circulating plasma amino acids.

Traditionally, dopamine agonists have been developed and used largely for
the treatment of patients with declining response to levodopa, motor
fluctuations, dyskinesias, or other adverse levodopa effects. The early use
of dopamine agonists as a levodopa-sparing strategy - to reduce or delay
long-term levodopa complications - recently has been suggested.

In a widely cited, uncontrolled, retrospective study, patients treated with
bromocriptine and levodopa showed equivalent therapeutic benefit with fewer
motor fluctuations and dyskinesias than patients treated with levodopa
alone. A prospective trial from the same center, comparing patients treated
with lisuride, lisuride plus levodopa, or levodopa also showed fewer
fluctuations in lisuride-treated patients than patients receiving levodopa
alone.

However, a double-blind, randomized, prospective study of a small number of
patients - comparing early combination therapy with levodopa monotherapy -
showed no significant differences in frequency of long-term levodopa
fluctuations after 4 years of treatment. Results of a similar but larger
prospective study comparing levodopa with combination therapy have not yet
been published.

Despite the lack of definitive data on the comparative advantages of
levodopa and combination therapy, the early use of dopamine agonists is
increasingly advocated as a levodopa-sparing strategy, to delay or reduce
the incidence and severity of long-term levodopa fluctuations and
dyskinesias, and possibly to reduce oxidative stress from free radicals
generated by high-dose levodopa replacement therapy.

Bromocriptine and pergolide are the only dopamine agonists currently
available for use in the United States.

Bromocriptine has both presynaptic and postsynaptic effects and stimulates
D2 receptors. It is started in low doses with close monitoring for such
side effects as hypotension, nausea, vomiting, hallucinations, peripheral
vasoconstriction, and erythromelalgia. Bromocriptine is initiated at 1.25
mg daily and titrated slowly, according to response, to a level of 10 to 25
mg daily. Some patients, however, might require dosages as high as 50 to 75
mg daily. As bromocriptine is titrated upward, the dosage of levodopa is
usually lowered to reduce dopaminergic toxicity.

Pergolide does not have presynaptic effects and stimulates both D1 and D2
receptors. It is more potent than bromocriptine by a factor of 10 and has a
longer duration of action. It is initiated with 0.05 mg daily and titrated
slowly over several weeks to a dose of 2 to 3 mg daily. Further increases
in dosage might be considered, if needed, to a maximum of 5 mg daily.
Although pergolide's therapeutic efficacy is similar to that of
bromocriptine, pergolide may be beneficial for some patients in whom
bromocriptine therapy fails because it does not produce a clinical response
or cause intolerable side effects.

Patients under 60 years of age.

Dopamine agonist monotherapy may be considered for mild parkinsonian
symptoms in patients aged 60 years and below, but it produces suboptimal
benefit in many patients. Even when it is effective, its benefit might wane
after several months. We therefore recommend that in most cases, dopamine
agonists be held in reserve until after initiation of levodopa, when they
can be used instead of increasing levodopa dosages for management of
increased parkinsonian disability. It is not yet known whether this
approach will reduce or delay the incidence of long-term levodopa
fluctuations, but the issue is expected to be resolved by studies currently
in progress.

Patients over 60 years of age.

The rationale for dopamine agonists in patients over age 60 is similar to
that for its use in younger patients. The aim is to reduce cumulative
exposure to levodopa and thereby possibly reduce long-term side effects.
Controversy remains, however, as to whether cumulative levodopa exposure
over the long term has any adverse consequences. It is recommended that
levodopa be initiated first and that when the levodopa requirement exceeds
600 mg daily, a dopamine agonist be added according to the regimen
described previously.


LEVODOPA

Levodopa is the most effective drug available for the treatment of early
PD, and patients who fail to respond to it are highly unlikely to respond
to dopamine agonists.
Despite a good initial response, however, approximately 50% of patients
experience motor fluctuations, such as "wearing-off" effect, unpredictable
"on-off" effects, dyskinesias, and dystonias within 6 years of levodopa's
initiation.

Patients under 60 years of age.

The treatment of patients with young-onset PD, who show earlier and more
frequent appearance of severe motor fluctuations and involuntary movements,
is particularly problematic with regard to the adverse effects of long-term
levodopa use.

Some practitioners have expressed the concern that levodopa fluctuations
and dyskinesias are related more to the duration of levodopa treatment than
to the duration and severity of the disease, Therefore, proponents of this
theory have recommended that levodopa treatment be withheld until the
appearance of significant limitations in activities of daily living and job
performance.

Other clinicians, however, contend that because no evidence proves that
levodopa therapy is directly responsible for these late effects, delay of
treatment unnecessarily deprives patients of improved function during the
early phase of the disease.

Despite this unresolved controversy, most practitioners agree that
treatment with levodopa should be initiated when the disease markedly
impairs job performance or activities of daily living.

Another possibility is that the form of levodopa delivery plays a role in
the development of fluctuations and dyskinesias. In experimental animals,
continuous and intermittent administration of dopamine agonists exert
different and frequently opposite effects on dopamine-mediated behavior. In
several recent studies, chronic, intermittent levodopa administration
produced greater dopamine-mediated behavioral supersensitivity than
continuous treatment, although this has not been confirmed by all studies.

Some research has suggested that chronic intermittent therapy is less
physiologic than continuous treatment and might result in postsynaptic
changes that affect the response to levodopa treatment. These dopamine
receptor changes might then cause a narrowing of the therapeutic window and
steepening of the dose-response curve, resulting in a fluctuating levodopa
response.

Dopamine replacement treatments that provide stable stimulation of dopamine
receptors might possibly avoid the appearance of motor fluctuations. For
this reason, the use of sustained-release formulations of levodopa for
initiation of therapy has been advocated increasingly, although their
ability to produce predictably smooth plasma levodopa levels and prevent
motor fluctuations has not been proven.

In Europe, the sustained-release benserazide-levodopa formulation utilizes
the decarboxylase inhibitor benserazide rather than carbidopa. The drug is
sold under the trade name Madopar.

One randomized, double-blind study comparing sustained-release
benserazide-levodopa with standard benserazide-levodopa in a relatively
small number of patients showed fewer fluctuations and dyskinesias in
patients on the sustained-release preparation 2 years after treatment began.

More definitive information on the potential advantage of the early use of
sustained-release carbidopa-levodopa should emerge from an ongoing clinical
trial, in which patients are randomized to either immediate, or sustained-
release carbidopa-levodopa.

We typically introduce levodopa therapy in the form of sustained-release
carbidopa-levodopa in patients who are beginning to experience significant
disability in activities of daily living or professional activities.
Determination of what constitutes significant disability must be made on a
case- by-case basis.

Once this decision has been reached, the issue of dosage must be addressed.
No available prospective, controlled studies have compared low-dose with
higher-dose levodopa treatment, and uncontrolled studies have yielded
conflicting results regarding the effect of dosage on incidence of
fluctuations.

Experimental studies of alternate-day and oral-pulse levodopa therapy in
early PD have been carried out in an effort to reduce total levodopa
exposure. These approaches, however, are of unproven long-term benefit arid
expose the patient to the potential adverse effects of intermittent rather
than continuous treatment, which might be less desirable.

Sustained-release carbidopa-levodopa should be initiated at 25/100 mg or
50/200 mg twice daily given early morning and early to midafternoon. If
delayed onset of effect ("kick-in" time) and lack of sufficient peak effect
are problematic, then standard carbidopa-levodopa may be introduced.

A relatively low dose of 200 to 400 mg of levodopa should be maintained
until progressively disabling symptoms require an increase in dosage or
dosing frequency.

When a daily dose of 500 to 800 mg of levodopa is reached, the addition of
a dopamine agonist is favored over further increases in the levodopa dosage.

Patients over 60 years of age.

The concern for long-term adverse effects of levodopa are not as great for
patients above age 60, in whom the incidence and severity of motor
fluctuations and dyskinesias appears to be diminished. Since
anticholinergic drugs are discouraged in patients older than age 60 and
dopamine agonist monotherapy is unlikely to be of sufficient long-term
benefit, carbidopa-levodopa is likely to be required earlier in this age
group.

As in patients 60 years or younger, sustained-release carbidopa-levodopa is
recommended, but an early trial with standard carbidopa-levodopa should be
considered if the response to the sustained-release preparation is suboptimal.

The incidence of CNS side effects, such as hallucinations, confusion, and
psychosis, is higher among patients in this age group, and appropriate
caution should be exercised in determining dosage and in combining
carbidopa-levodopa with other medications that exert CNS effects.


ADVANCING PARKINSON'S DISEASE


DYSAUTONOMIAS

CONSTIPATION

Pfeiffer and his colleagues have emphasized the importance of considering
two distinct processes responsible for normal stool expulsion. First, stool
moves through the colon by the sequential contraction of muscles within the
intestinal wall. Intrinsic enteric neurons regulate this muscular activity.
Second, parasympathetic afferent and efferent fibers mediate the excitatory
and inhibitory input to the colon.

In patients with PD, Lewy bodies have been found within degenerating
colonic neurons (myenteric plexus); the primary clinical correlate is
slowed stool transit time related to impaired colonic muscle contraction.
In a second syndrome, colonic transit time may or may not be normal, but
the primary abnormality is in defecation. Parkinsonian patients are unable
to straighten the anorectal angle on straining, accentuating its flap valve
action and resulting in an obstruction to the passage of stool.

It has been suggested that this paradoxical contraction of the pelvic
musculature is dystonic in nature and correlates with the progression of
PD. In support of this argument, apomorphine has been shown to alleviate
this defecatory problem in some patients with PD. Other disorders
associated with constipation in patients with PD include megacolon and
sigmoid volvulus.

Management.

Dietary modification aimed at increasing bulk and softening the stool
should be the first strategy for constipation, and ultimately the most
efficacious, in patients with PD. They must be encouraged to drink at least
eight glasses of water each day. Low-fiber foods, such as many breads and
cakes need to be reduced, and bananas must be eliminated from the diet.

At least two meals per day should include high-fiber raw vegetables.
Carrots, cauliflower, and broccoli are good choices. Oat bran as a hot
cereal (Quaker Oats bran) adds significant fiber to the diet, especially
when one-fourth to one-third cup is used in the morning. As a morning meal,
it reduces the amount of protein, adds bulk, and helps stimulate the
gastrocolic reflex.

Increasing physical activity is also helpful. Although vigorous exercise is
not necessary, just doing a few pushups, situps, or isometric exercises is
not enough. Patients must be encouraged to walk as much as several miles a
day, if possible, or swim regularly.

If stools remain hard despite the measures outlined above, stool softeners
such as docusate, given with each meal can be useful. Lactulose, 10 to 20 g
per day, may benefit some patients. Patients are warned that the results
with any method of softening stool will not be immediate and that
persistence with dietary and pharmacologic measures is necessary.

Since anticholinergic agents decrease bowel motility, stopping such drugs
can be useful for alleviating constipation, but this is often at the price
of increased parkinsonism.
The next step is a trial of cisapride (a cholinomimetic agent) which
increases intestinal motility. Even at the usual dosage of 5 mg bid, it is
important to watch for occasional worsening of Parkinson's signs and symptoms.

Mild laxatives such as milk of magnesia or enemas should be a last resort
and used sparingly - perhaps no more than once a week as part of an overall
bowel regimen - but in some patients enemas may be necessary. Apomorphine
injection may provide enough benefit to permit successful defecation.


URINARY PROBLEMS

The neuro-anatomic substrate for normal voiding is widespread. The detrusor
motor area in the frontal lobes connects with a similar functional region
in the pontomesencephalic reticular formation. Input from the basal ganglia
to this cortico-mesencephalic loop depresses detrusor contraction;
hypothalamic input increases detrusor contraction. Peripherally the
detrusor is innervated via sacral parasympathetic neurons, a pathway that
is facilitated by noradrenergic neurons in the locus ceruleus.

Seemingly more important for patients with PD, however, is the loss of
dopaminergic output from the substantia nigra, which appears to increase
detrusor hyperreflexia. Most patients with PD suffer from detrusor
hyperactivity. Relatively few have detrusor hypoactivity or urethral
sphincter dysfunction.

Common symptoms in PD patients that result from detrusor hyperactivity
include urgency, frequency, and nocturia. Nocturia is the most common and
usually the earliest complaint, only much later followed by daytime
symptoms. In fact, if daytime frequency or urgency occurs as an initial
complaint, causes from mechanical outlet obstructions, such as prostatic
hypertrophy, must be considered.

Management.

Many patients can reduce nighttime frequency by the simple expedient of
reducing liquid intake in the evening (no liquids after supper). If this
nonpharmacologic intervention is ineffective, peripherally acting
anticholinergics, such as oxybutynin or propantheline, can be tried.
Oxybutynin, 5 to 10 mg, can be administered at bedtime only or on a tid
basis. Propantheline, 7.5 to 15 mg, may also work well at bedtime or on a
tid schedule.

If anticholinergics prove ineffective, hyoscyamine, a parasympatholytic
agent, may work on a qid regimen or at night only (0.15 to 0.30 mg). A
trial of desmopressin, administered at night in escalating doses (usually
10 to 20 micro g) as an intranasal spray, may work for otherwise refractory
cases.

Anticholinergic agents, used in the treatment of detrusor hyperactivity,
reduce detrusor contractions, an effect that may worsen voiding problems in
patients with detrusor hypoactivity or outlet obstruction. Detrusor
hyporeflexia, producing incomplete bladder emptying and urinary frequency,
may respond to a reduction in the dosage of an anticholinergic
antiparkinsonian medication when that is the cause.

It is therefore essential that PD patients with urinary dysfunction have
urologic evaluations that include recording of bladder and sphincter
pressure, sphincter electromyography, and fluoroscopy and that these tests
be performed only by a urologist familiar with their interpretation.

When cystometric studies reveal a hypoactive detrusor, benefit may be
obtained from alpha adrenergic-blocking agents such as phenoxybenzamine or
prazosin, which decrease tone in the bladder neck. Unfortunately, these
agents can exacerbate or cause orthostatic hypotension and cardiac
arrhythmias and should be used with caution in patients with PD.

Drugs that relax striated muscle -- such as diazepam, baclofen, or
dantrolene -- can ocasionally be effective when the external sphincter is
hyperreflexic. Intermittent catheterization is necessary with myogenic
overdystension. Any deterioration in voiding pattern (even in the absence
of dysuria) should raise the concern of infection, which should be treated
promptly.


SEXUAL PROBLEMS

Little attention has been paid to the sexual dysfunction common in patients
with PD. Most treatment is aimed at impotence in men, with virtually
nothing being known about the sexual function of women with PD. In men, the
most common problem is achieving or sustaining an erection.

Management.

Propranolol or other beta-adrenergic blockers, sometimes used to control
postural or action tremor in patients with PD, are common offenders. Other
possible problem drugs include antihypertensives (alpha-adrenergic blockers
such as clonidine, methyldopa, and guanfacine). Guanethidine, although less
frequently used, is a potential offender, as are thiazide diuretics,
anxiolytics, digoxin, and cimetidine.

Looking for depression is often rewarding; medical evaluation is mandatory
but rarely helpful. Although depression is a frequent cause of sexual
dysfunction, it is noteworthy that antidepressant drugs (particularly the
serotonin uptake inhibitors fluoxetine, paroxetine, sertraline) can cause
impotence. Tricyclics also have been implicated as a less frequent cause of
impotence.

Depressed patients should be treated with either tricyclic antidepressants
or serotonin uptake inhibitors, despite the problems described above.
Tricyclics (with anticholinergic properties) have the added advantage of
alleviating some of the parkinsonian symptoms, but the best approach is to
use the most efficacious drug to lift depression in a given patient. Some
patients with anxiety- or stress- associated sexual dysfunction benefit
from low-dose anxiolytics.

Endocrine function can be ascertained with serum levels of prolactin
testosterone, and luteinizing hormone and studies of thyroid function. If
no medical or psychologic reasons seem to be causing impotence, one can try
yohimbine, 5 mg tid for 1 month.
Further treatment, under consultation with an expert urologist, can include
local injection of phentolamine(an alpha- adrenergic blocker) and
papaverine. This combination provides a short-term vasodilator effect by
acting on smooth muscle. More invasive approaches, such as implants, are
less easily accepted by patients and treating physicians.

Previously untreated patients may find that starting treatment with
levodopa can help sexual dysfunction, probably by alleviating bradykinesia
and increasing desire. In fact, some patients on high doses of
antiparkinsonian agents become hypersexual, even in the face of inability
to perform.


ORTHOSTATIC HYPOTENSION

The anatomic site responsible for orthostatic hypotension (OH) patients
with PD are probably heterogeneous, since no consistency in abnormalities
has been reported. Sympathetic efferent dysfunction in some patients can be
inferred from a failure to increase heart rate with falling blood pressure
and the lack of blood pressure overshoot with Valsalva. Abnormalities of
renin and inadequate increases in serum norepinephrine on standing may be
contributory factors.

A central autonomic defect may be involved, as suggested by an increased
pressor response to norepinephuine patients with PD. The finding of Lewy
bodies in the hypothalamus of these patients support such an etiology in
some. More likely in most patients however, is a generalized sympathetic
degeneration from Lewy body disease causing cell loss in the sympathetic
ganglia.

Management.

OH, although not uncommon in patients with PD, should be treated only in
those who are symptomatic. Levodopa or dopamine receptor agonists
exacerbate OH, the latter especially during the first weeks of treatment.

Many patients who have been on antihypertensive drugs begin to experience
OH with progression of PD. They often can tolerate a reduction in or
cessation of their antihypertensive medications. In those patients who are
not taking antihypertensives, the first step in treating OH should be the
addition of salt and fluids to the diet. Higher salt intake can be achieved
by deliberately adding salt to food at the table (as opposed to adding it
in the cooking process) so that other family members do not get additional
unnecessary salt. Salt tablets, up to 2 g per day, are another alternative.
Compressive stockings and behavior modification should be used in
conjunction with increased salt and fluid intake. Knee-high stockings are
less effective than thigh-high ones, but the former are preferable because
of increased compliance. Practitioners can teach patients behavior
modification that reduces OH, such as getting up slowly and sleeping with
the head tilted.

For parkinsonian patients with OH, fludrocortisone (a salt-retaining
steroid) can be started in doses of 0.1 rug per day and titrated upwards in
0.1 mg increments up to 0.3 mg tid. Patients taking it should be monitored
for possible congestive heart failure and supine hypertension, however
Indomethacin, 25 mg tid is not as effective as fludrocortisone but is more
easily tolerated. It probably works by inhibiting vasodilating
prostaglandins. Midodrine, 5 to 10 mg qid, is an investigational
alpha-adrenergic agonist that is particularly effective in some patients.

In evaluating patients with "dizziness" OH should be distinguished from
complaints caused by postural instabilityvisualmotor dysfunction, or
multiple sensory deficits.


THERMOREGULATION

The neurochemical and anatomic regulation of temperature is complex and
poorly understood. Preoptic and hypothalamic areas appear to have
thermoregulatory function. Noradrenergic, serotonergic, and cholinergic
systems have an incompletely understood role in thermal homeostatais.

Sweating is mediated by efferent sympathetic cholinergic fibers, which may
be damaged in PD. Lewy bodies and cell loss in the hypothalamus have been
implicated in PD-associated sweating abnormalities.

Management.

Abnormal sensations of heat or cold, impaired sweating responses, and
hypothermia all can occur in the untreated patient. Excessive sweating of
the head and neck in response to external heat has been associated with
poor heat dissipation. Some of these phenomena disappear with levodopa
treatment, which suggests a role for central dopaminergic systems in
thermoregulation.

Severe drenching sweats occur as an end-of-dose "off" phenomenon in
patients with motor fluctuations, further supporting a role for dopamine
systems in vasomotor tone and heat regulation. Dopamine agonist therapy may
be of benefit to such patients.

Although peak-dose chorea can cause sweating, it is rarely if ever as
severe as that seen in the "off' state. For patients who experience it,
however, a reduction in the dopaminergic medications may help but often at
the price of more "off" time. These patients are more likely to respond to
beta-adrenergic blockers than are patients with "off"-period sweating.

Severe hyperpyrexia after levodopa withdrawal resembles the neureleptic
malignant syndrome and needs to be treated promptly with reinstitution of
dopaminergic agents.

Other causes of excessive sweating must not be neglected simply because the
patient has PD. Benign sweating can occur with either a visual, olfactory
or gustatory stimulus. Ethanol and aspirin in high doses also can cause
increased intermittent sweats. Therefore, taking a thorough history usually
will clarify these situations.
Thyrotoxicosis and postmenopausal states need to be considered and
appropriate endocrine evaluation initiated. Finally, chronic infections
such as tuberculosis must not be forgotten in the differential diagnosis.


PAIN

The mechanisms responsible for pain in PD are unclear and probably not the
same in all patients. It can be mediated via peripheral somatic or
autonomic afferent nerves. Selective autonomic block, however, does not
seem to reduce the pain in PD, and signs of autonomic disturbance are not
usually present. Since many of these syndromes are associated with
dystonia, one possible site for the origin of PD-associated pain is
afferent nerve fibers within the dystonic muscles. A spinal cord or
cerebral origin for some pains is suggested by the pseudoradicular pattern
seen in some patients.

Many pain syndromes occur in the "off" state only, suggesting a role for
dopamine-containing cells in the diencephalon, which terminate on receptors
in the dorsal horn and intermediolateral column. Sensory symptoms often
appear neuritic in character, including paresthesias, burning dysesthsisa,
coldness or numbness, and deep aching.

The legs are more often involved than the arms; face and neck are rarely
involved. Akathisia sometimes is present. Pain is often, but not always,
worse on the side of worse parkinsonism.

Management.

Pain related to parkinsonism often responds to adjustment of
antiparkinsonian medications. Most often, it is linked to levodopa "off"
states or insufficient levodopa dosage; thus, optimizing medications (as
described later) can be gratifying.

Other causes for radicular pain and neuropathy need to be evaluated when
appropriate. Pain related to arthritis is not uncommon in elderly patients
with PD.


DYSPHAGIA

Significant dysphagia in patients with PD is usually; But not always,
related to the severity of disease and occurs in up to 40% of patients.
direct involvement of oropharangeal muscles is suggested by the observance
that many patients suffer severe dysphagia only when "off," a situation
that improves dramatically as soon as a dose of levodopa becomes effective.

Swallowing abnormalities include abnormal lingual control and inability to
pass a bolus of food backward into the pharynx. Silent aspiration with
repetitive reflux of food from the vallecula and pyriform sinuses into the
oral cavity are a significant problem.
Retention of food and pills in the vallecula are another contributory cause
of erratic levodopa absorption, and therefore, a secondary cause of
dysphagia. Esophageal dysmotility occurs in as many as 70% of patients but
also is present in a significant number of controls.

Management.

Soft diets help most types of dysphagia by making It easier to move food in
the mouth and esophagus. Soft food also decreases aspiration by reducing
the need for separate liquid intake, since liquids often cause more
aspiration than solids. Since dysphagia is usually decreased dramatically
during "on" times, the best strategy is to increase "on" time with
additional dopaminergic medications, if possible. Increased "off" time,
however; is not a realistic goal for many patients.

All patients should eat only during an "on" period. Feeding gastrostomies
or jejunostomies are a last resort and are rarely necessary in patients
with idiopathic PD; but when needed, these procedures provide the benefit
of allowing more normal intake of food and medication.

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