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What are the drugs available in Malaysia?

The list of old and new drugs is shown on Table 1. Levodopa is the most effective among all the drugs while all others only have only mild to moderate effect.

Table 1. Medications used in the treatment of PD.

Medications (pharmaceutical name) Daily dosage
Levodopa (Madopar / Sinemet) Levodopa 150 mg to 1000 mg daily in divided doses.
Benzhexol (Artane) 1mg to 4 mg twice daily.
Amantadine (PK-Merz) 100 mg to 300 mg daily in one to three divided doses.
Selegiline (Jumex) 5 mg once to twice daily.
Bromocriptine (Parlodel) 10 to 40 mg daily in two to three divided doses.
Pergolide (Celance) 0.5 mg to 4 mg once daily.
Cabergoline 0.5 to 5 mg daily
Pramipexole (Sifrol) 1.5 to 4.5 mg daily in three divided doses
Ropinirole (Requip) 0.75 to 24 mg daily in three divided doses
Piribedil (Trivastal) 50 mg once to thrice daily.
Entacapone (Comtan) Each dose of 200 mg is taken with each dose of levodopa, up to 2000 mg daily.
Stalevo (50, 100, 150) three to eight tablets per day.

a) Levodopa

Levodopa relieves all the three major symptoms of PD (bradykinesia,
rigidity and tremor). It acts by replacing the depleted dopamine in the brain – once taken up by the body, it is converted to dopamine. The way the brain of PD patients needs levodopa is similar to the way a car needs petrol – a car can only move when there is petrol. PD patients need regular doses of levodopa throughout the day to keep “going” everyday – a car’s petrol tank needs to be filled up regularly to keep moving everyday.

In order to reduce the degradation of levodopa by dopa decarboxylase (an enzyme) in the bloodstream, levodopa is usually given together with dopa decarboxylase inhibitors (benserazide, carbidopa). The various preparations of levodopa are shown on Table 2.

Sinemet CR (Controlled-Release) and Madopar HBS (Hydrodyna-mically Balanced System) have longer duration of effect but are less powerful than Madopar or Sinemet. They are meant for patients who have short-lasting response to Madopar or Sinemet. Madopar (dispersible) is dissolvable in water and suitable for patients who have difficulty swallowing tablets.

Table 2. The various preparations of levodopa.

 

Pharmaceutical name Preparations
Madopar Levodopa / benserazide – 200 / 50 mg
Sinemet Levodopa / carbidopa – 100 / 10 mg, 100 / 25 mg, 200 / 50 mg
Madopar (dispersible) Levodopa / benserazide – 100 / 25 mg
Madopar HBS Levodopa / benserazide – 100 / 25 mg
Sinemet CR Levodopa / carbidopa – 200 / 50 mg

 

Short-term side effects – nausea, vomiting, confusion, hallucination, psychosis, postural hypotension (lowering of blood pressure when moving from lying to standing position). Levodopa must not be stopped suddenly without doctor’s advice because it may lead to complications (neuroleptic malignant syndrome).

The long-term side effect is development of motor complications, which seen in 50% of patients who have been treated with levodopa for three to five years.

b) Anticholinergic drugs (Benzhexol)

These drugs reduce the acetylcholine activity in the brain. It is useful for patients who have tremor as the predominant symptom.

Side effects – dry mouth, blurring of vision, constipation, difficulty in urination, confusion and postural hypotension.

c) Amantadine

It acts by increasing the dopamine level in the brain. It is useful for treating bradykinesia, rigidity and tremor. In addition, Amantadine has direct effect in reducing dyskinesia. Previously, Amantadine was thought to have short-lasting response – only for several months. However, subsequent studies showed that its effect lasted up to several years.

Side effects – confusion, hallucinations, insomnia (difficulty in sleeping), nightmares and ankle swelling.

d) Selegiline

It acts by reducing the degradation of dopamine in the brain. Its role of “brain protection” (neuroprotection) is debatable. It is usually well tolerated.

Side effects – nausea, vomiting, confusion, insomnia (the second dose should be given at noon to avoid insomnia).

e) Dopamine agonists

These drugs act by enhancing the activity of dopamine in the brain. The commonly used drugs are Bromocriptine, Piribedil and Pergolide. Others are Cabergoline and the newer drugs, Pramipexole and Ropinirole. Studies have shown that initial treatment with most dopamine agonists alone is associated with lower incidence of motor complications. When levodopa and dopamine agonists are combined, the total daily dose of levodopa can be reduced. Failure to respond to a dopamine agonist does not mean that patients will not respond to other drugs in the same group.

Side effects – nausea, vomiting, confusion and postural hypotension.

f) COMT inhibitor / Stalevo

COMT inhibitor (Entacapone, Comtan) act by reducing the degradation of dopamine and enhancing the effect of levodopa. The daily dose of levodopa can be reduced when combined with COMT inhibitors. These drugs have been proven to improve the patients’ mobility, daily activities and quality of life.

Stalevo is a combination of Entacapone, levodopa and carbidopa (“3-in-1” pill). As such, it is more convenient to be taken everyday. Stalevo is available in three different strengths; levodopa 50 mgs, 100 mgs and 150 mgs.

Side effects – dyskinesia, diarrhea, nausea, abdominal pain, constipation, hallucination, confusion, insomnia (difficulty in sleeping) and change in urine colour (reddish).

Drug treatment – some commonly asked questions.

a) How do medications help Parkinson’s patients?

All the available drugs can merely reduce the symptoms of PD but do not cure the illness.

There is strong evidence that dopamine agonists may be able to slow down the disease progression of PD but this is not proven or confirmed yet. The results of the latest studies showed that Parkinson’s patients who received Ropinirole or Pramipexole had slower loss of brain cells compared to others who received levodopa. This observation was encouraging but further research work should be carried out in order to confirm that these two drugs can indeed offer some “protection” to brain cells.

One previous study had revealed that Selegiline also might be able to slow down the disease progression in PD. However, another follow-up study had contradicted the earlier finding – Selegiline could not slow down the disease progression. Thus, the ability of Selegiline to offer “protection” to brain cells of Parkinson’s patients is still debatable.

b) Does every patient need to take medications?

This decision should be individualized and depends on how much the patients’ daily activities are affected. Doctors are inclined to treat someone whose career or daily work is affected (such as difficulty handling computers, writing, cooking, and traveling). In contrast, people who live sedentary life (such as retirees) may be able to delay taking drugs until their daily activities are impaired.

c) To what extent do drugs relieve the patient’s symptoms?

Drugs cannot completely relieve the symptoms and this is particularly so at the later stage of illness. This is because the administration of even the most optimal dose of levodopa to a patient with PD cannot adequately replace the depleted dopamine in the brain. With optimal medications, the percentage of recovery ranges from 50-90%, and not 100%. Therefore, it is important that patients understand this limitation of drug treatment.

Unrealistic expectation may cause patients to take excessive drug dosage, which may cause unnecessary side effects. Patients are advised to consult doctors before increasing the drug dosage.

d) Which medication should be used first?

This depends on several factors such as ;

i)patient’s age – as younger patients (< 65 years old) are more prone to develop motor complications with levodopa treatment, it is best to avoid using levodopa as the first drug in younger patients. Studies have shown that newly diagnosed patients who were treated with dopamine agonist alone had a lower risk of developing motor complications compared with those patients taking levodopa. Therefore, younger patients should receive dopamine agonists first, and levodopa should be used only in the later stage of illness as a last resort (when the symptoms become more severe).

In older patients (> 65 years old), levodopa is the preferred drug of first choice. This is because the risk of developing motor complications with levodopa treatment is lower in older patients. In addition, levodopa is less likely to cause mental side effects (confusion, hallucination) compared with other drugs in older patients.

ii)severity of patient’s disability – being the most effective drug, levodopa should be given to severely disabled patients.
iii)individual drug tolerance – the preferred drug will be the one that causes either no or least side effects.
iv)doctor’s belief – doctors who believe in the protective effect of dopamine agonists (Ropinirole, Pramipexole) on the brain cells would be inclined to use it as the first drug.

e) Does long-term levodopa treatment hasten the disease progression of PD?

This has been debated for at least twenty years by neurologists but until now there is no convincing evidence that levodopa accelerates the loss of brain cells in PD. The worsening of symptoms in the later stage of illness is either due to the natural progression of disease or development of motor complications due to levodopa.

f) Does vitamin C and E help in PD?

It has been speculated that the anti-oxidant effect of these vitamins may protect the brain cells from damage in PD. This is because certain oxidative chemicals have been shown to play an important role in the disease process in PD. However, there is no convincing evidence that vitamins can slow down the disease progression. Therefore, I usually do not encourage patients to take vitamins except when they are malnourished.

g) Does alternative medicine helps?

There is no firm scientific evidence that alternative medicine (such as sinseh drugs, acupuncture) help in PD. On the other hand, there is also no evidence that alternative medicine do any harm in PD. As such, I do not discourage Parkinson’s patients from seeking alternative medicine as long as they continue taking my medications.

 

Conclusions

The happy news is that there is currently a long list of drugs available for treatment of PD. The sad news is that there is still no “best” or “ideal” drug, which is defined as a highly efficacious drug that does not lead to long-term motor complications. The selection of the most suitable drug for any patient should be individualized.

Various factors such as age, daily activities, severity of illness and potential side effects should be taken into consideration. Despite their limitations and adverse effects, drug treatment has significantly improved the quality of life of Parkinsons’ patients and remains the cornerstone in the management of PD.