swallowing. The patient may have a shuffling and unsteady gait, and the upper part of the body is bent for-ward. Fine tremors begin in the fingers with a pill-rolling movement, increase with stress, and decrease with pur-poseful movement. Depression or dementia may occur,causing memory impairment and alterations in thinking.
Parkinson’s disease has no cure, but the antiparkinsonism drugs are used to relieve the symptoms and assist in maintaining the patient’s mobility and functioning capability as long as possible. For years, levodopa was the drug that provided the mainstay of treatment. Now, there are new drugs that are used either alone or in combina-tion with levodopa. Entacapone (Comtan), pramipexole (Mirapex), and ropinirole (Requip) are newer drugs used in the treatment of Parkinson’s disease. Drug-induced parkinsonism is treated with the anticholinergics benz-tropine (Cogentin) and trihexyphenidyl (Artane).
Parkinsonismis a term that refers to the symptoms of
Parkinson’s disease, as well as the Parkinson-like symp-toms that may be seen with the use of certain drugs, head injuries, and encephalitis. Drugs used to treat the symp-toms associated with parkinsonism are called antiparkinsonism drugs. As with some other types of drugs, it may be necessary to change from one antiparkinsonism drug to another or to increase or decrease the dosage until maximum response is obtained.Antiparkinsonism Drugs provides a listing of the drugs used to treat Parkinson’s disease. Antiparkinsonism drugs discussed in the chapter are classified as dopaminergic agents, anticholinergic drugs, COMT inhibitors, and dopamine receptor agonists (non-ergot)
DOPAMINERGIC DRUGS
Dopaminergic drugs are drugs that affect the dopamine content of the brain. These drugs include levodopa (Larodopa), carbidopa (Ladosyn), amantadine (Symmetrel), and pergolide mesylate (Permax).
ACTIONS
The symptoms of parkinsonism are caused by a depletion of dopamine in the CNS. Dopamine, when given orally,does not cross the blood–brain barrier and therefore is ineffective. The body’s blood–brain barrier is a meshwork of tightly packed cells in the walls of the brain’s capillaries that screen out certain substances. This unique meshwork of cells in the CNS prohibits large and poten-tially harmful molecules from crossing into the brain.This ability to screen out certain substances has important implications for drug therapy because some drugs are able to pass through the blood–brain barrier more easily than others.Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross the blood–brain barrier, and a small amount is then converted to dopamine. This allows the drug to have a pharmacologic effect in patients with Parkinson’s disease Combining levodopa with another drug (carbidopa)causes more levodopa to reach the brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone.Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa; Sinemet CR is a time-released version of the combined drugs). The mechanism of action of amantadine (Symmetrel) and selegiline (Eldepryl) in the treatment of parkinsonism is not fully understood.
USES
The dopaminergic drugs are used to treat the signs and symptoms of parkinsonism. As with some other types of drugs, it may be necessary to change from one antiparkinsonism drug to another or to increase or decrease the dosage until maximum response is obtained.
Levodopa has been considered the gold standard drug therapy for Parkinson’s disease since it was first used in the 1960s. Carbidopa is always given with levodopa, combined either as one drug or as two separate drugs. When it is necessary to titrate the dose of car-bidopa, both carbidopa and levodopa may be given at
the same time, but as separate drugs. Sometimes the response with these two drugs can be enhanced by the addition of another drug. For example, selegiline or pergolide may be added to the drug regimen of those being treated with carbidopa and levodopa but who have had a decreased response to therapy with these
two drugs.Amantadine is less effective than levodopa in the treatment of Parkinson’s disease but more effective than the anticholinergics. Amantadine may be given alone or
in combination with an antiparkinsonism drug with anticholinergic activity. Amantadine is also used as an antiviral drug
ADVERSE REACTIONS
During early treatment with levodopa and carbidopa,adverse reactions are usually not a problem. But as the disease progresses, the response to the drug may becomeless, and the period of time that each dose is effectivebegins to decrease, leading to more frequent doses, and more adverse reactions.The most serious and frequent adverse reactions seen with levodopa include choreiform movements(involuntary muscular twitching of the limbs or facial muscles) and dystonic movements (muscular spasms most often affecting the tongue, jaw, eyes, and neck). Less common but serious reactions include mental changes, such as depression, psychotic episodes, paranoia, and sui-cidal tendencies. Common and less serious adverse reac-tions include anorexia, nausea, vomiting, abdominal pain, dry mouth, difficulty in swallowing, increased hand tremor, headache, and dizziness. Carbidopa is used with levodopa and has no effect when given alone.
The most common serious adverse reactions to aman-tadine are orthostatic hypotension, depression, congestive heart failure, psychosis, urinary retention, convulsions,leukopenia, and neutropenia. Less serious reactionsinclude hallucinations, confusion, anxiety, anorexia, nau-sea, and constipation. Adverse reactions with selegiline include nausea, hallucinations, confusion, depression,loss of balance, and dizziness.
AND INTERACTIONS
The dopaminergic drugs are contraindicated in patients with known hypersensitivity to the drugs. Levodopa is
contraindicated in patients with narrow-angle glaucoma,those receiving a monoamine oxidase inhibitor, and during lactation. Levodopa is used cau-tiously in patients with cardiovascular disease, bronchial
asthma, emphysema, peptic ulcer disease, renal or hepatic disease, and psychosis. Levodopa and combina-tion antiparkinsonism drugs (eg, carbidopa/levodopa) are classified as Pregnancy Category C and are used with caution during pregnancy and lactation.
Levodopa interacts with many different drugs. When levodopa is used with phenytoin, reserpine, and papaverine, there is a decrease in response to levodopa.
The risk of a hypertensive crisis increases when lev-odopa is used with the monoamine oxidase inhibitors . Foods high in pyridoxine (vitamin B6) or vitamin B6 preparations reverse the effect of levodopa.However, when carbidopa is used with levodopa, pyri-doxine has no effect on the action of levodopa. In fact,
when levodopa and carbidopa are given together, pyri-doxine may be prescribed to decrease the adverse effects associated with levodopa.
Selegiline is used cautiously in patients with psy-chosis, dementia, or excessive tremor. When selegiline is administered with levodopa, the effectiveness of levodopa increases. This effect allows for a decrease in the dosage of levodopa. If selegiline is given in doses greater than 10 mg/d there is an increased risk of hypertension,particularly if tyramine-containing foods (eg, beer, wine, aged cheese, yeast products, chicken livers, and pickled herring) are ingested. A potentially serious reaction(confusion, agitation, hypertension, and seizures) can occur when fluoxetine is administered with selegiline.Fluoxetine therapy is discontinued for a least 1 weekbefore treatment with selegiline is initiated.
Amantadine is used cautiously in patients with seizure disorders, hepatic disease, psychosis, cardiac dis-ease, and renal disease. The antihistamines, phenothiazines, disopyramide, and alcohol increase the risk of adverse reactions when administered with amantadine.
ANTICHOLINERGIC DRUGS
ACTIONS
Drugs with anticholinergic activity inhibit acetylcholine (a neurohormone produced in excess in Parkinson’s dis-ease) in the CNS. Drugs with anticholinergic activity are generally less effective than levodopa.
USES
Drugs with anticholinergic activity are used as adjunc-tive therapy in all forms of parkinsonism and in the con-trol of drug-induced extrapyramidal disorders. Examples of drugs with anticholinergic activity include benz-tropine mesylate (Cogentin), biperiden (Akineton),diphenhydramine, procyclidine (Kemadrin), and trihexyphenidyl (Artane).Antiparkinsonism Drugs for specific uses of these drugs.
ADVERSE REACTIONS
Frequently seen adverse reactions to drugs with anti-cholinergic activity include dry mouth, blurred vision,dizziness, mild nausea, and nervousness. These may become less pronounced as therapy progresses. Other adverse reactions may include skin rash, urticaria (hives), urinary retention, dysuria, tachycardia, muscle
weakness, disorientation, and confusion. If any of these reactions are severe, the drug may be discontinued for several days and restarted at a lower dosage, or a differ-ent antiparkinsonism drug may be prescribed.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
These drugs are contraindicated in those with a hyper-sensitivity to the anticholinergic drugs, those with glau-coma (angle-closure), pyloric or duodenal obstruction,peptic ulcers, prostatic hypertrophy, achalasia (failure ofthe muscles of the lower esophagus to relax causing dif ficulty swallowing), myasthenia gravis, and megacolon.These drugs are used with caution in patients with tachycardia, cardiac arrhythmias, hypertension, hypoten sion, those with a tendency toward urinary retention those with decreased liver or kidney function, and those with obstructive disease of the urinary system or gastro intestinal tract. The anticholinergic drugs are given with caution to the older adult.
When the anticholinergic drugs are administered with amantadine, there is an increased anticholinergic
effect. When digoxin is administered with an anticholinergic drug, digoxin blood levels may be increased, leading to an increased risk for digitalis toxicity. Haloperidol and anticholinergic co-administration may result in worsening of schizophrenic symptoms, decreased haloperidol blood levels, and development of tardive dyskinesia When the anticholinergic drugs are adminis-tered with the phenothiazines, there is a decrease in the therapeutic effects of the phenothiazines and an increase in anticholinergic adverse reactions.
COMT INHIBITORS
A newer classification of antiparkinson drugs is thecatechol-O-methyltransferase (COMT) inhibitors.Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar).
ACTIONS
These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catecholOmethyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa.
USES
The COMT inhibitors are used as adjuncts to levodopa/carbidopa in Parkinson’s disease. Tolcapone is a potent COMT inhibitor that easily crosses the blood–brain barrier. However, the drug is associated with liver damageand liver failure. Because of the danger to the liver, tol-capone is reserved for people who are not responding to other therapies. Entacapone is a milder COMT inhibitor and is used to help manage fluctuations in the response to levodopa in individuals with Parkinson’s disease.
ADVERSE REACTIONS
The adverse reactions most often associated with the administration of the COMT inhibitors include disorientation, confusion, light-headedness, dizziness, dyski-nesias, hyperkinesias, nausea, vomiting, hallucinations,and fever. Other adverse reactions are orthostatic hypotension, sleep disorders, excessive dreaming, som-nolence, and muscle cramps. A serious and possibly fatal adverse reaction that can occur with the adminis-tration of tolcapone is liver failure.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
These drugs are contraindicated in patients with a hypersensitivity to the drugs and during pregnancy (Category C) and lactation. Tolcapone is contraindicated in patients with liver dysfunction. The COMT inhibitors are used with caution in patients with hypertension,hypotension, and decreased hepatic or renal function. The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors because there is an increased risk of toxicity If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epi-nephrine, there is a risk of increased heart rate, arrhyth-mias, and excessive blood pressure changes.
DOPAMINE RECEPTOR AGONISTS
(NON-ERGOT)
ACTIONS
The exact mechanism of action of these drugs is not understood. It is thought that these drugs act directly on postsynaptic dopamine receptors of nerve cells in the brain, mimicking the effects of dopamine in the brain.
USES
The dopamine receptor agonists, such as pramipexole (Mirapex) and ropinirole (Requip), are used for the treat-ment of the signs and symptoms of Parkinson’s disease.
ADVERSE REACTIONS
The most common adverse reactions seen with pramipexole and ropinirole include nausea, dizziness,postural hypotension, hallucinations, somnolence, vomiting, confusion, visual disturbances, abnormal involun-tary movements, and headache.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
The dopamine receptor agonists are contraindicated in patients with known hypersensitivity to the drugs, severe ischemic heart disease, or peripheral vascular disease.
The dopamine receptor agonists are used with caution in patients with dyskinesia, orthostatic hypotension, and hepatic or renal impairment. The dopamine receptor agonists are used cautiously in patients with a history of hallucinations or psychosis, cardiovascular disease, and renal impairment. Both ropinirole and pramipexole are Pregnancy Category C drugs, and safety during preg-nancy has not been established.There is an increased risk of CNS depression when the dopamine receptor agonists are administered with
other CNS depressants. When administered with lev-odopa, the dopamine receptor agonists increase the effects of levodopa (a lower dosage of levodopa may be required). In addition, when the dopamine receptor agonists are administered with levodopa, there is an increased risk of hallucinations. When administered with ciprofloxacin, there is an increased effect of the dopamine receptor agonist.
The phenothiazines may decrease the effectiveness of the dopamine receptor agonists. When pramipexole is
administered concurrently with cimetidine, ranitidine,verapamil, and quinidine, there is an increased effect of pramipexole. When ropinirole is administered with the estrogens, particularly estradiol, there may be an increased effect of ropinirole.
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