Antiparkinson agents

Anticholinergics
Example: Benzhexol

These drugs have a mild antiparkinsonian effect and are said to be more effective for tremor. These drugs should always be stopped slowly to avoid a rebound worsening of Parkinsonian symptoms.
Potential side effects:

• Neuropsychiatric
• Visual hallucinations, poor concentration/memory, organic confusional state.
• Patients with dementia or the elderly are particularly prone to developing these sorts of problems with anticholinergics.
• Blurred near vision
• due to mydriasis. Therefore these drugs are contraindicated in narrow-angle glaucoma.
• Dry mouth
• Acute urinary retention in males with prostatic enlargement
• Constipation
• Dyskinesia

Amantadine
This is a mild antiparkinsonian drug . The dose should be reduced with renal impairment.

Side effects:

• livedo reticularis
• ankle oedema
• confusion

Selegiline (Deprenyl)
Selegiline is a selective inhibitor of monoamine oxidase type B which metabolises dopamine.

There was considerable interest in the use of Selegiline as a neuroprotective agent given the results of the DATATOP study (NEJM 1989;321:1364-1371). However, there has been considerable controversy over the interpretation of the results of this and other studies in that was Selegiline truly neuroprotective or does it have some kind of symptomatic effect. Most neurologists now tend to favour the latter.
Secondly, there has been some suggestion that the use of Selegiline is associated with increased mortality (BMJ 1995;311:1602-1607). This has been shown in one study, however, the causes of death are unknown at present. Nonetheless it would seem to lay to rest the neuroprotective argument for Selegiline. Since we do not have data from any other studies or details on the causes of death in the Selegiline group in the BMJ paper, at present we do not know whether the reported increased mortality in the BMJ paper is causally linked with Selegiline or not.

Levodopa
Example: Sinemet, Madopar

Since dopamine does not cross the blood brain barrier, but its precursor Levodopa does, L-Dopa is given in an effort to replace the striatal dopamine deficiency. However, since L-dopa has significant peripheral metabolism, resulting in untoward side effects (nausea and vomiting) and decreased brain delivery of L-dopa, it is combined with a peripheral decarboxylase inhibitor.

Side effects:

• nausea or vomiting
• postural hypotension
• worsening of peptic ulcer symptoms
• sweating
• discoloration of urine/sweat
• with long-term use: Motor fluctuations and dyskinesias. These probably represent the biggest single problem in the long-term management of a patient with Parkinson's disease. It is estimated that at least 50% of patients with Parkinson's develop these complications within the first 5 years of treatment. As such, for reasons of brevity the reader is referred to the references below as a starting point.
• Neuropsychiatric problems. Confusion, hallucinations, psychosis.

Dopamine agonists

Examples: Bromocriptine; Pergolide; Lisuride.

These 3 drugs vary both in their duration of action and the degree to which they are D1 or D2 agonists. Thus:
Lisuride - short duration of action, mainly a D2 agonist

Pergolide- longest duration of action, acts on both D1 and D2 receptors.

There is evidence that patients who can tolerate monotherapy with a dopamine agonist for a prolonged time that the incidence of dyskinesias and motor fluctuations in the long term is reduced. The downside of this is that the dose needs to be gradually increased very slowly and side effects are more common than L-dopa.

These act directly on the dopamine D1 and D2 receptors. Since they also act in the periphery on the dopamine receptors of the vomiting centre, they can also cause nausea and vomiting.

Side effects:

• nausea or vomiting
• postural hypotension
• neuropsychiatric side effects (as for L-dopa but occur more frequently)
• vasospasm
• ankle swelling
• retroperitoneal fibrosis (rare)

Apomorphine

Apomorphine is also a D1 and D2 agonist, but since it is given parentally via subcutaneous injection, its use is generally witheld until problems with motor fluctuations and 'on-off' fluctuations occur which are not being easily controlled via other drugs. As a result of this, initiation of therapy is best instituted in the context of a specialist Parkinson's clinic.

Side effects:

• nausea or vomiting.-on account of this, the patient needs to be given Domperidone as an anti-emetic prior to the use of Apomorphine.
• postural hypotension
• sweating
• yawning
• drowsiness
• local skin reactions at injection site
• motor fluctuations and dyskinesias
• confusion and hallucinations

COMT inhibitors

Examples: Tolcapone, Entacapone

These are relatively new drugs and Tolcapone is no longer licensed in the UK due to some deaths due to liver failure. They are COMT inhibitors (catechol-O-methyltransferase inhibitors) and as such slow down break down of L-dopa either in the periphery alone (Entacapone) or centrally as well (Tolcapone). Results from studies suggest that they have a role in reducing on-off fluctuations and dyskinesias. Trial have shown alterations in liver function tests (LFTs), the exact mechanism for this is unknown, but for the first 6 months, LFTs need to be checked. Some patients develop diarrhoea but this is reversible. The main problems with COMT inhibitors are worsening of peak-dose dyskinesias, but it is relatively easy to treat this by reducing the amount of L-dopa.

ABSTRACT Aim This study tested three dopaminergic medications against a common unmatched placebo condition: hydergine 1 mg three times daily (n = 15); levodopa/carbidopa 25/100 mg three times daily (n = 15); cabergoline 0.5 mg per week (n = 15); and placebo three times daily (n = 15) as potential pharmacotherapies for cocaine dependence. Design The four-parallel group, Cocaine Rapid Efficacy Screening Trial (CREST) design featured a 2-week baseline period followed by randomization to an 8-week medication condition that included 1 hour per week of cognitive behavioral drug counseling. A safety evaluation was conducted 4 weeks after termination. Measures Outcomes included cocaine metabolites measured in urine, retention and self-reports for drug use, cocaine craving, clinical improvement, mood and HIV risk behaviors. Results Participants assigned to receive cabergoline provided more urine samples negative for cocaine metabolites (42.4%) than those assigned to receive placebo (25.0%), a statistically significant difference after controlling for baseline differences in self-reported cocaine use (F = 2.95, df = 3; P = 0.05). Cabergoline-treated participants demonstrated a significant improvement over placebo from baseline to week 8 when measured using the Addiction Severity Index (ASI) employment subscale (overall change = - 0.09, SD = 0.10, t = 2.36, P < 0.05). Safety and adverse event measures showed similar rates and types of complaints by treatment condition. Conclusions These results, combined with the apparent safety of cabergoline when used with this population, provide empirical support for conducting a larger study of the medication.

Expert Opin Investig Drugs. 2003 Aug;12(8):1335-52.
Recent developments in the pharmacological treatment of Parkinson's disease.
Tuite P, Riss J.
University of Minnesota, Department of Neurology, MMC 295, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Parkinson's disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.

INTRODUCTION. In recent years new anti Parkinson drugs have been marketed and there has been controversy over the safety of some drugs. OBJECTIVE. To analyze the evolution of the consumption of anti Parkinson drugs and the effect of the newer drugs. PATIENTS AND METHODS. A study of the consumption of anti Parkinson drugs (1989 1998). Data were obtained from the ECOM database of the Ministry of Health and TEMPUS of the National Statistics Institute. The drugs were classified using the Anatomo Therapeutic Clinical Classification (ATC). Consumption was expressed in defined daily dosage (DDD) and the costs in euros. The drugs marketed since 1990 were classified as new drugs and the others as classical drugs. RESULTS. The total consumption of drugs increased from 1.92 DDD/1,000 inhabitants/day in 1989 to 3.64 DDD/1,000 inhabitants/day in 1998. The drugs showing the greatest increase were selegiline, pergolide and levodopa. The total pharmaceutical expenses tripled. There was a smaller increase in the consumption of new drugs (1.2% of the total in 1991 and 6.6% in 1998) than in their costs (6.7% of the total in 1991 and 38.8% in 1998). The cost per DDD of the new drugs increased five times (1989: 2.55 euros and 1998: 13.59 euros) and that of the classical drugs was similar (1989: 0.54 euros and 1998: 0.62 euros). CONCLUSIONS. The total consumption of anti Parkinson drugs has progressively increased. The consumption of selegiline has also increased in spite of controversy over its safety. The new drugs have a major economic effect.

The data obtained during the past decade in experimental and clinical pharmacology show that the GABAergic drugs, with central activity, do not ameliorate the symptoms of the Parkinson's disease (PD), but would worsen the akineto-rigid syndrome, the dyskinesias and the deteriorating mental status in the later stages of the PD. On the other hand, recent data of experimental pharmacology suggest the possibility that glycinergic or glutamatergic derivatives, with central activity, would have a beneficial effect on the syndromes of the later stages of PD (declining efficacy of L-DOPA, dyskinesias, deteriorating mental status), which constitute, with the fluctuation of the response to L-DOPA, ("on-off" effects), the major problems of the PD's treatment. Some theoretical and experimental data also suggest the possibility of a beneficial effect of the glutamatergic drugs in the treatment of the "on-off" effects.

JAMA 2000 Oct 18;284(15):1931-8
Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group
Parkinson Study Group

CONTEXT: Pramipexole and levodopa both ameliorate the motor symptoms of early Parkinson disease (PD), but no controlled studies have compared long-term outcomes after initiating dopaminergic therapy with pramipexole vs levodopa. OBJECTIVE: To compare the development of dopaminergic motor complications after initial treatment of early PD with pramipexole vs levodopa. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Three hundred one patients with early PD who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997. INTERVENTIONS: Subjects were randomly assigned to receive pramipexole, 0.5 mg 3 times per day, with levodopa placebo (n = 151); or carbidopa/levodopa, 25/100 mg 3 times per day, with pramipexole placebo (n = 150). For patients with residual disability, the dosage was escalated during the first 10 weeks. From week 11 to month 23.5, investigators were permitted to add open-label levodopa to treat continuing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of any of 3 dopaminergic complications: wearing off, dyskinesias, or on-off motor fluctuations; changes in scores on the Unified Parkinson's Disease Rating Scale (UPDRS), assessed at baseline and follow-up evaluations; and, in a subgroup of 82 subjects evaluated at baseline and 23.5 months, ratio of specific to nondisplaceable striatal iodine 123 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane (beta-CIT) uptake on single photon emission computed tomography imaging of the dopamine transporter. RESULTS: Initial pramipexole treatment resulted in significantly less development of wearing off, dyskinesias, or on-off motor fluctuations (28%) compared with levodopa (51%) (hazard ratio, 0.45; 95% confidence interval [CI], 0. 30-0.66; P<.001). The mean improvement in total UPDRS score from baseline to 23.5 months was greater in the levodopa group than in the pramipexole group (9.2 vs 4.5 points; P<.001). Somnolence was more common in pramipexole-treated patients than in levodopa-treated patients (32.4% vs 17.3%; P =.003), and the difference was seen during the escalation phase of treatment. In the subgroup study, patients treated initially with pramipexole (n = 39) showed a mean (SD) decline of 20.0% (14.2%) in striatal beta-CIT uptake compared with a 24.8% (14.4%) decline in subjects treated initially with levodopa (n = 39; P =.15). CONCLUSIONS: Fewer patients receiving initial treatment for PD with pramipexole developed dopaminergic motor complications than with levodopa therapy. Despite supplementation with open-label levodopa in both groups, the levodopa-treated group had a greater improvement in total UPDRS compared with the pramipexole group.