PD is an incurable, progressive, neurodegenerative disease with motor dysfunction from the deterioration or loss of dopamine-producing neurons in the brain. About 60,000 new cases are diagnosed each year in the U.S. Average age of onset is 60 years old.

Hallmark symptoms include tremor, rigidity, slow movements (bradykinesia), and instability. Damage to dopamine-producing cells in the substantia nigra is thought to have started on average 6 years before motor symptoms develop. By the time symptoms appear. about 70-80% of dopaminergic neurons have been lost.

PD also causes damage to other areas of the brain that can cause non-motor symptoms 10 years or more before motor symptoms appear. These include changes in REM sleep (vivid, violent dreams), constipation, and loss of smell.

There are 5 classes of medications used to treat motor symptoms: carbidopa/levodopa, anticholinergic agents, dopamine agonists, monoamine oxidase type-B inhibitors, and amantadine. Both early drug therapy and a watch-and-wait approach have been used in the past. Newer therapies with improved long-term tolerability have lead to early treatment.

Carbidopa/levodopa — has been the standard of treatment. Levodopa is converted to dopamine. When given alone, it is converted quickly to dopamine which does not cross the blood-brain barrier and can cause GI discomfort. Carbidopa inhibits an enzyme that converts levodopa before it enters the brain which allows more levodopa to enter the brain where it can be converted to dopamine. This allows for much lower levodopa doses which reduces GI side effects such as nausea, loss of appetite, and vomiting.

Levodopa has a rapid effect and markedly reduces tremor, bradykinesia, and rigidity. Response is related to the dose, the higher the dose the stronger and more lasting the response. However, adverse effects are also related. Nausea, vomiting, postural hypotension, sedation, and restlessness are common early side effects. Long-term side effects can lead to confusion, delusions, hallucinations, paranoia, compulsive behaviors, and psychosis. Effectiveness and tolerability are best achieved when administration is begun at low doses and titrated slowly.

Dyskinesias (diminished voluntary and increased involuntary movements) and "on-off" fluctuations are the major motor adverse effects. Risk increases with duration of levodopa use. Over time, levodopa effectiveness diminishes. Dyskinesias and motor fluctuations develop in about 40% of patients treated for 4 to 6 years. The younger the age at onset of PD the greater the likelihood of motor complications from levodopa.

Anticholinergic agents — Reduced levels of dopamine in PD cause an imbalance between acetylcholine and dopamine levels. Acetylcholine provides excitatory signals to neurons, dopamine is inhibitory. Anticholinergics reduced acetylcholine levels to restore the acetylcholine/dopamine balance. Anticholinergics were once the standard of therapy but have been replaced by levodopa/carbidopa as the standard. The most commonly used are trihexylphenidyl, benztropine, and diphenydramine. They are most effective for tremor, rigidity, and salivation but least effective for bradykinesia or gait disturbances. Some guidelines indicate that anticholinergics may be more effective than levodopa to treat tremor. Adverse effects include dry mouth, constipation, urinary retention, and blurred vision. Higher doses may cause hallucinations and memory loss. These agents are usually better tolerated by younger patients.

Dopamine agents — These agents directly stimulate dopamine receptors. They have longer effects, which reduces their risk of motor complications. Products used include bromocriptine (Parlodel), pramipexole (Mirapex), ropinirole (Requip), and apomorphine (Apokyn). Pergolide (Permax) was withdrawn from the market because of heart-related side effects (valvular heart disease). Pramipexole and ropinirole are often used as alternatives to levodopa for initial monotherapy. Guidelines state that levodopa is more effective than these two; however, patients taking them have fewer motor complications than those on levodopa after 2.5 years.

Dopamine agonists may have significant adverse effects. Bromocriptine is associated with increased risk of pulmonary fibrosis. All may cause nausea, vomiting, orthostatic hypotension, hallucinations, confusion, drowsiness, and sleep attacks. Side effects can be reduced by careful titration of the dose. Recent studies have reported significant increased risk of impulse control disorders (compulsive shopping, binge eating, gambling, hypersexuality) in patients taking dopamine agonists alone in combination with levodopa. Higher doses and combination therapy increases the risk of compulsive disorders. These agents may interact with many other medications, so care must be taken if the patient is on other medications.

MAO-B inhibitors — Monamine oxidase type B is one of the enzymes responsible for the breakdown of dopamine. Selegiline (Eldepryl) and rasagiline (Azilect) inhibit this enzyme, raising dopamine levels. Rasagiline is approved for use as monotherapy. It has been show to slow functional decline, improve quality of life, and delay use of levodopa therapy. Side effects are flu-like symptoms, joint pain, depression and upset stomach. Drugs that inhibit both MAO-A and MAO-B require dietary restrictions to avoid tyramine-containing foods but MAO-B only inhibitors do not. MAO-B inhibitors interact with many antidepressants and other drugs that effect serotonin.

Amantadine — Amantadine is an anti-viral drug that was discovered to relieve symptoms of PD by chance. It increases dopamine production and release and blocks its reuptake and it has some cholinergic effects. Guidelines state that amantadine has modest effects on PD symptoms and the other treatment options are more effective. Adverse effects include nausea, dizziness, and insomnia. It has rarely been reported to cause depression, anxiety, hallucinations, peripheral edema, and orthostatic hypotension.

Other therapies are usually reserved to later-stage disease. These include catechol-O-methyltransferase inhibitors entacapone (Comtan) and tocapone (Tasmar). These agents block an enzyme that breaks down levodopa. This allows levodopa effects to last longer and are used with levodopa. Tocapone requires that liver function tests be normal before it can be initiated.

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