Drugs
Used to Treat PD
Five
classes of drugs are used to treat the motor symptoms of PD:
Dopaminergic
Agents
Levodopa
(precursor to dopamine)
Carbidopa/levodopa (Sinemet, Parcopa)
Dopamine
Agonists
Apomorphine
(Apokyn)
Bromocriptine
(Parlodel)
Pergolide (Permax)
Pramipexole
(Mirapex)
Ropinirole (Requip)
COMT
Inhibitors
Entacapone (Comtan)
Tolcapone (Tasmar)
Entacapone/levodopa/carbidopa (Stalevo)
MAO-B
Inhibitors
Rasagiline
(Azilect)
Selegiline
(Eldepryl and Zelapar)
Anticholinergics
Trihexyphenidyl (Artane)
Benztropine
Ethopropazine
Amantadine
Levodopa
Levodopa is converted in the brain into dopamine, the same
chemical created by cells in a part of the brain known as the substantia nigra.
Dopamine is a chemical that allows nerve cells to talk to each other and is
involved in controlling movement. Levodopa was introduced as a treatment of PD
in the 1960s and remains the most effective treatment for motor symptoms. It
lessens and helps to control all the major motor symptoms of PD, including the
slowness of movements (bradykinesia), which is generally the most disabling
feature of the disease. Levodopa cant be taken by itself because the medicine
breaks down too quickly in the body before it gets to its targetthe brain.
Therefore, levodopa is combined into one pill with carbidopa, which allows more
levodopa to get to the brain and minimizes side effects such as nausea and
vomiting.
If
enough levodopa doesnt get into the bloodstream and ultimately to the brain,
then the dose of medicine that your doctor has told you to take may not be
effective in treating the symptoms of PD. There are a few key steps to getting
levodopa into the brain that effect how much of the dose of levodopa your body
can actually use. Amino acids are the building blocks of proteins. Protein in
the food that you eat is made up of amino acids. Levodopa is another type of
amino acid. When you eat foods that contain protein, the amino acids are
transported through the wall of your intestines into your bloodstream. In this
same way, when you take your levodopa, the medicine must be transported through
the wall of your intestines into your bloodstream. Amino acids from both food
and levodopa require the action of a specific transporter or amino acid vehicle
in the lining of the intestine. Because this transporter can only work so fast,
if you eat too much protein, the transporter is busy transporting the food-based
amino acids into your bloodstream and cant transport all of the levodopa into
your bloodstream. The medicine simply passes through your system without being
absorbed and used. In a similar process, once levodopa is in the bloodstream,
it must then cross into the brain, where it becomes active in controlling the
symptoms of PD. However, levodopa has to cross from the bloodstream into the
brain, just as it did from the intestines into the bloodstream. To be able to
get the most out of the medication that they are taking, people with more
advanced PD may need to time when they take their levodopa so that they dont
take it near mealtime or they may need to eat less protein-containing food at
certain meals.
Side effects
Nausea and vomiting are the most common side effects of
levodopa and are due to a build up of dopamine in the bloodstream. Orthostatic hypotension (low blood pressure upon standing)
also occurs. The risk of hallucinations and paranoia increases the longer that a person takes levodopa.
Compulsive behavior, including gambling and hypersexuality, is another risk.
Drowsiness
is a common side effect of levodopa and of other dopamine-like medicines, and
sudden sleep onset is possible. People who take these medicines may not have
any warning signs of sudden sleep onset. It is important to understand this
possibility, especially when you first start taking levodopa, when you increase
the amount of the medicine that youre taking, or when you switch to another
dopamine-like medicine.
The
most troubling effect that might happen when you take levodopa for a long time
is dyskinesias. Dyskinesias are uncontrolled movements, including writhing,
twitching, and shaking. Dyskinesias result from the combination of the use of
levodopa over a long period of time and the fact that PD becomes worse over
time as the dopamine-producing cells in the brain continue to decrease in
number. Mild dyskinesias usually begin to develop after 3 to 5 years of
treatment but are more severe after 5 to 10 years of treatment with levodopa.
As
the PD gets worse, it usually takes more and more levodopa to control the
symptoms of the disease until the person reaches the point that the dyskinesias are intolerable. This limits the continuing
usefulness of levodopa. At this point, surgery may be the only effective
option. Because of this potential, many doctors recommend starting a younger
patient (younger than 70 years old) on a dopamine agonist instead of levodopa, which delays the
onset of dyskinesias.
Immediate-release
carbidopa/levodopa is available in pills that contain of 10/100, 25/100, and
25/250 milligrams of the carbidopa/levodopa. The effects of the medicine
usually start in 20 to 40 minutes and usually last about 2 to 4 hours in people
who have more advanced stages of PD.
Some
people dissolve the tablets in orange juice as a way to speed up the effects of
the medicine. People must be sure to consult with their doctor before trying
this because the effects of the medicine usually dont last as long when the
levodopa is taken this way.
In
2006, a new medicine was approved that delivers levodopa in a different way.
Parcopa is a tablet that dissolves on the tongue and does not need
to be taken with water. The effects of Parcopa usually start within 30 minutes.
The side effects with the use of Parcopa are the same as those for other forms
of carbidopa/levodopa. Unlike other forms of carbidopa/levodopa, however,
Parcopa contains phenylalanine, which may restrict the use in some people.
Parcopa is available in tablets that contain of 10/100, 25/100, and 25/250
milligrams of carbidopa/levodopa. The tablets should not be taken out of the
bottle until just before they are used. They should only be handled by someone
with dry hands because the tablets start breaking down when they touch
moisture.
COMT Inhibitors
COMT inhibitors prolong the effects of levodopa by
preventing its breakdown. Two medicines are approved in the United States,
entacapone (Comtan) and tolcapone (Tasmar). Both have
been shown to decrease the amount of time when PD symptoms are present (off time) in people who have a lot of off time. Tolcapone is more effective than entacapone. In
research studies, tolcapone has been shown to reduce off time by 2 to 3
hours, versus 1 to 2 hours for entacapone. Both medicines usually allow people
to take about 20% to 25% less levodopa than they took without the COMT
inhibitor.
People
with PD usually take 200 mg of entacapone with each dose of levodopa. Diarrhea
is the most common side effect, which may require stopping treatment. Severe
diarrhea occurs in about 5% of patients.
People
with PD usually take 100 or 200 mg of tolcapone three times per day. Side
effects include diarrhea, which may be severe enough in up to 15% of people
that they cant continue taking tolcapone. Four cases of severe liver disease
(acute fulminant hepatic necrosis), with three deaths, were reported in 1998,
and led the FDA to issue a black box warning on tolcapone. This warning
recommends that physicians only prescribe tolcapone for patients whose symptoms
cannot be controlled without this medicine. The warning states that patients should
have a blood test to check for liver function on a regular basis. The blood
should be tested before the medicine is started and every two to four weeks for
the first six months after the medicine is started. After the first six months,
these blood tests should be performed as the doctor feels is clinically
necessary.
A
combination of levodopa, carbidopa, and entacapone in a single tablet (Stalevo)
is also available. Stalevo has the same type of side effects as the other forms
of COMT inhibitors and carbidopa/levodopa.
Dopamine Agonists
Dopamine agonists are drugs that act like or mimic the
action of levodopa in the brain by directly stimulating dopamine receptors.
These are the same receptors that dopamine itself stimulates. Although they are
not quite as effective as levodopa, they provide excellent relief of symptoms
and delay the onset of motor complications.
A
variety of dopamine agonists are available that differ in how long
their effects last, their chemical makeup, in what form they are delivered, and
side effects. The currently available agonists (generic name followed by trade
name) are:
Apomorphine (Apokyn)
Bromocriptine (Parlodel)
Pergolide (Permax)
Pramipexole (Mirapex)
Ropinirole (Requip)
Studies
of several of the agonists (pergolide, pramipexole, ropinirole) have shown that
these medicines delay motor complications when they are used as the only drug
(monotherapy) given early in the disease. Dopamine agonists tend to produce
more edema and psychosis than does levodopa. These effects may be more
significant than mild dyskinesias, especially in older patients. Because of this,
doctors often give patients who are younger (younger than age 70) and otherwise
healthy a dopamine agonist first and wait to start treatment with levodopa
until the symptoms of PD become worse. People who are older than 70 (especially
those who have problems with thinking and memory) are most often given levodopa
and not a dopamine agonist.
Side Effects
Drowsiness is a common side effect of dopamine agonists and levodopa, and sudden sleep onset is
possible. People who are taking dopamine agonists may not experience any
warning signs of sudden sleep onset. It is important to understand this
possibility, which is especially likely when you first start taking a dopamine
agonist, when increasing the amount of a dopamine agonist that youre taking,
or when you switch to a different dopamine agonist or levodopa. Other significant side
effects of dopamine agonists include nausea and vomiting, orthostatic hypotension, edema, and psychosis.
Some
people who have taken a specific type of dopamine agonist called an
ergot-derived dopamine agonists (pergolide
and bromocriptine) have developed a condition known as fibrosis. Fibrosis may occur in the space around the lungs or in the
heart valves. Although some people may not notice any changes in their health
when they have fibrosis, this condition may be medically significant,
especially when it affects the heart valves. The fibrosis usually gets better
when people stop taking the ergot-derived dopamine
agonists and switch to one of the other dopamine agonists such as
pramipexole or ropinirole.
Apomorphine
Apomorphine (Apokyn) is the dopamine agonist that has effects on the symptoms of PD
that are most like those of dopamine. However, it cannot be taken in pill form.
Apomorphine must be given as a shot beneath the skin (injected subcutaneously).
Also, the effect of apomorphine doesnt last as long as that of levodopa.
Subcutaneously
injected apomorphine is used as a rescue therapy for patients with off
episodes. This means that it is not used as the main method of treatment but,
rather, is used when the person with PD is having an off
episode. The effects of apomorphine usually start about 10 minutes after the
shot is given and usually last about 90 minutes. Apomorphine can be used
whenever the person feels an off episode coming on before the next dose of levodopa
takes effect, such as early in the morning or during that day when wearing off occurs. It can be used up to 10 times per day. If
someone needs apomorphine more than that, the doctor will usually look into
other forms of treatment. People who
use apomorphine may have reactions at the spot where the shot is given, but
this is usually not a problem.
Nausea
and vomiting are the main side effects with the use of apomorphine. People who
use apomorphine have to take a medicine to treat nausea and vomiting (an antiemetic) before they start using the apomorphine.
Trimethobenzamide is the medicine that doctors usually prescribe. Many people
are able to stop taking the antiemetic after several weeks.
MAO-B Inhibitors
Monoamine oxidase (MAO-B)
inhibitors slow the breakdown of dopamine in the brain. Two of these medicines
are available in the Unites States: selegiline and rasagiline.
Selegiline offers mild relief of
symptoms of PD. People who are just beginning to have symptoms of PD may take
selegiline as the only medicine for the relief of symptoms, or people who are
in the later stages of PD may take selegiline and levodopa, selegiline and a
dopamine agonist, or all three medicines.
Selegiline is available in two forms. Both forms of selegiline are usually
taken once each day. The first form of selegiline is a traditional pill and is
called Eldepryl or various generic forms of the medicine. These
pills are swallowed. In 2006, a new form of selegiline was approved by the US
Food and Drug Administration, called Zelapar. Zelapar
is a tablet that contains selegiline, but this tablet doesnt need to be
swallowedit dissolves on the tongue. People who have trouble swallowing pills
or who do not wish to swallow their medicine may prefer to take Zelapar.
People should not eat or drink anything for five minutes before or after taking
Zelapar.
Rasagiline (Azilect) offers mild relief of symptoms of PD.
People who are just beginning to have symptoms of PD may take rasagiline as the
only medicine for the relief of symptoms, or people who are in the later stages
of PD may take rasagiline and levodopa, rasagiline and a dopamine agonist, or
all three medicines.
Side Effects, Contraindications,
and Warnings
People who take MAO-B inhibitors
need to be very aware of a problem known as a hypertensive crisis that can
occur when they eat foods that contain tyramine or take medicines that contain
amines. These warnings apply to people taking any of the swallowed forms of
selegiline (that is, Eldepryl or the generic forms of the drug),
more than 2.5 mg per day of Zelapar, or rasagiline. Tyramine
restrictions do not apply to people who take up to 2.5 mg per day of
Zelapar (which is considered to be the therapeutic dose of the medicine).
Hypertensive crisis (also called the cheese effect) happens when blood
pressure goes up to dangerous levels. Symptoms of hypertensive crisis include severe headache, blurred vision/visual
disturbances, difficulty thinking, stupor/coma, seizures, chest pain, unexplained nausea or vomiting,
or signs or symptoms of a stroke. People should seek immediate medical
attention if they have these symptoms.
Foods to avoid include air-dried or fermented meats, pickled herring, fava
beans, soy beans and soy products (including soy sauce), aged cheeses, red
wine, non-pasteurized beer, sauerkraut, and yeast extracts. Drugs to avoid
include pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine.
People should also not take meperidine, tramadol, methadone, propoxyphene,
dextromethorphan, or St. Johns wort. People who are taking antidepressants
should talk to their doctors before starting to take either MAO-B inhibitors.
MAO-B inhibitors and
neuroprotection
The term neuroprotection refers to the ability to prevent or slow the death
of nerve cells or neurons. Researchers studied the neuroprotective effects of
selegiline in a study called the DATATOP trial. When the results of the study
were first analyzed, they appeared to show that selegiline slowed the rate of
PD, that is, that selegiline was neuroprotective. However, when researchers
analyzed the results more carefully, they found that the benefit could also
be explained by the effect that the medicine had on the symptoms of PD. Thus,
the results of this study were not clear.
In 2004, a preliminary study of rasagiline that used a different study
design suggested that rasagiline may change the course of PD in a positive way.
This study will need to be repeated and more people will have to take part in
it before firm conclusions can be drawn.
Anticholinergic Medicines
Anticholinergic medicines have a limited role in the
treatment of PD. They are primarily effective in relieving tremor and rigidity.
There may be significant side effects, especially in elderly patients, with the
use of these medicines. Typical doses for common anticholinergic medicines are:
Trihexyphenidyl
(Artane): 2 to 15 mg/day
Benztropine:
1.0 to 4.5 mg/day
Ethopropazine:
10 to 200 mg/day
Common
side effects with the use of anticholinergic medicines are memory loss, dry
mouth, trouble emptying the bladder, constipation, sedation, delirium, and hallucinations.
Amantadine
Amantadine (Symmetrel) has some effect on the motor symptoms
of PD, but a greater effect on the dyskinesias. The usual dose is 100 mg two to four times
each day. Side effects include hallucinations, difficulty falling asleep or staying asleep
(insomnia), agitation, and difficulty concentrating. Dry mouth, ankle swelling,
and skin mottling (uneven color tones) may also be present. Amantadine may not
be effective for treating dyskinesias in up to one third of people with PD who take this
medicine.
Updated
10/26/06
