Parkinson's disease

Parkinson's disease A chronic CNS disorder characterized by slowness and poverty of purposeful movements, muscular rigidity and tremor Tremor at rest Rigidity Hyperkinesias Bradykinesia Postural Instability Difficulty in stopping, starting and turning while walking

Epidemiology Incidence increases with age Approximately affects 1% world wide Age of onset for men and women and incidence is equal Prevalence increases with age

Etiology Cause of Parkinson’s is not known Characterized by neuronal cell loss and associated presence of inclusion bodies (Lewy bodies) in degenerate neurons In PKD there is progressive degeneration of Substantia nigra neurons that have dopaminergic neurons

Pathophysiology Acetylcholine V/s Dopamine

Stages of Parkinson’s Based on the severity of the disease Stage I – Unilateral involvement Stage II – Bilateral or midline; no impairment of balance stage III – Bilateral involvement Stage IV – Fully developed, severely disabled Stage V – Confined bed or chair unless aided

Diagnosis is based on the presence of tremor, rigidity and bradykinesia, either together or alone. Many factors influence therapeutic decision-making, including the degree of confidence in the diagnosis, functional and social disability, age and the psychological and neurological condition of the patient.

Rationale for drug use Provide symptomatic relief. No agent has been proven to slow progression of disease. Treatment does not alter progression and individual response can be variable, such as in benign tremulous Parkinson’s disease where the tremor may respond poorly, but usually progresses very slowly.

Pharmacological Management Early Parkinson’s disease It might be appropriate not to treat mild disease if symptoms are not causing disability or handicap. While levodopa is the most efficacious treatment, a dopamine agonist may sometimes be given alone in young patients (less than 50 years of age). Anticholinergic agents can also be the initial treatment in young patients with tremor-dominant disease.

levodopa+benserazide 50mg/12  levodopa+benserazide 50mg/12.5mg orally, 3 times daily, after meals, increase to 100mg/25mg 3 times daily over 1 to 2 weeks, depending on response     OR      levodopa+carbidopa 50mg/12.5mg orally, 3 times daily, after meals, increase to 100mg/25mg 3 times daily over 1 to 2 weeks, depending on response.

An increase in the total daily dose and the frequency of dosing is eventually necessary in most patients. In some patients, higher doses are necessary to control symptoms adequately. Dietary factors such as a high protein meal can impair the response to an individual dose. Levodopa taken without food often the response to each dose is more rapid.

Additional therapy The dopamine agonists, bromocriptine, cabergoline and pergolide, are not as effective as levodopa and are usually used in conjunction with levodopa. They may help reduce motor fluctuations and have the advantage of enabling the dose of levodopa to be lowered with a consequent lessening of the drug-induced dyskinesias. They should be used cautiously in the elderly because of possible acute psychotic reactions

bromocriptine 2.5mg orally, twice daily, up to 15mg twice daily OR     bromocriptine 2.5mg orally, twice daily, up to 15mg twice daily   OR cabergoline 0.5mg orally, daily, up to 5mg once daily. Increase in increments of 0.5 to 1mg weekly up to optimal dose OR       pergolide 0.05mg orally, twice daily, up to 1.5mg 3 times daily. Entacapone 200mg orally initially, with each dose of levodopa. (Usual effective daily dose is 800 to 1400mg)

Tremor In young patients, an anticholinergic agent may be added to produce better control of tremor. benztropine 1 to 2mg orally, daily, up to 2mg twice daily    OR    benzhexol 2mg orally, 2 or 3 times daily, up to 5mg 3 times daily    OR  biperiden 1mg orally, 2 times daily, up to 2mg, 3 to 4 times daily Very occasionally higher doses are beneficial hallucinations and confusion, especially in the elderly, so restrict their use

Advanced Parkinson’s disease Management is often difficult in these patients and clinical experience is helpful with choice of medication, dose and frequency of administration most develop new symptoms as a result of disease progression and complications of therapy new symptoms as a result of disease progression and complications of therapy isolated dose failures, delayed effect of a particular dose, end of dose failure, rapid fluctuations not necessarily related to dose, dyskinesias (peak dose or off time), dystonia and freezing.

Drug Usual dosage Adverse effects Dopaminergic levodopa+benserazide 100/25 to 250mg/62.5mg 3 times daily ·        nausea and vomiting (initially), involuntary movements, psychosis, postural hypotension, constipation levodopa+carbidopa 100/25 to 250mg/50mg 3 times daily Dopamine agonists bromocriptine 5 to 15mg 2 times daily ·        neuropsychiatric, postural hypotension, erythromelalgia, fibrosis (pleuro, pulmonary, retroperitoneal) cabergoline 0.5 to 5mg daily pergolide 0.05 to 1.5mg 3 times daily

200mg with each dose of levodopa COMT inhibitors entacapone 200mg with each dose of levodopa ·        potentiation of levodopa adverse effects, diarrhoea Anticholinergics benztropine 1 to 2mg 2 times daily ·        neuropsychiatric, dry mouth, urinary retention, constipation, blurred vision, postural hypotension benzhexol 2mg 2 or 3 times daily biperiden 1 to 2mg 1 to 4 times daily Others apomorphine complex individualized schedule, see Pharmacological management of advanced Parkinson’s disease ·        nausea, neuropsychiatric, injection site reaction selegiline 2.5 to 5mg 1 or 2 times daily ·        insomnia, neuropsychiatric amantadine 100mg 2 times daily ·        neuropsychiatric, nightmares, livedo reticularis, ankle oedema  

Levodopa Improves bradykinesia and rigidity more consistently than tremor First line treatment for most people, especially the elderly and people with cognitive impairment Long term use is associated with increased motor fluctuations (end-of-dose failure and on-off effect), dyskinesias and dystonias

Bromocriptine, Cabergoline and Pergolide Improve bradykinesia and rigidity, but are less effective than levodopa May cause confusion and hallucinations more commonly than levodopa, especially in elderly or demented people, and in high doses Combination of dopamine agonists with levodopa allows a reduction in levodopa dosage and improves motor fluctuations.

Bromocriptine, Cabergoline and Pergolide Cabergoline or bromocriptine used as monotherapy in early disease may delay the onset of motor fluctuations and dyskinesias and may be preferred as first line treatment in younger patients Cabergoline or bromocriptine used as monotherapy in early disease may delay the onset of motor fluctuations and dyskinesias and may be preferred as first line treatment in younger patients.

Bromocriptine, Cabergoline and Pergolide Long term use as monotherapy is limited as adverse effects associated with the high doses needed risk of retroperitoneal and pleuropulmonary fibrosis gradual loss of efficacy Pergolide is marketed for use only as an adjunct to levodopa Efficacy and safety of dopamine agonists seem broadly similar. Cabergoline has a longer duration of action than bromocriptine and pergolide and can be given once daily.

Selegeline Selectively inhibits monoamine oxidase type B May be used as monotherapy in early disease to delay the need for levodopa and as adjunct to levodopa in later disease to reduce motor fluctuations Evidence for its effectiveness is inconclusive TWO previous studies found an increased mortality associated with selegiline use But not confirmed in a recent meta-analysis of the use of monoamine oxidase type B inhibitors in early Parkinson's disease

Amantadine Antiviral drug with dopaminergic and anticholinergic activity and also acts as a N-methyl-D-aspartate (NMDA) antagonist More effective than anticholinergic drugs for akinesia and rigidity, but less effective for tremor Some loss of efficacy after 3–6 months May be used as monotherapy in early disease or later as adjunctive treatment to alleviate drug-induced dyskinesias

Apomorphine Dopamine agonist Start treatment in hospital under specialist supervision Administer by SC injection or continuous infusion Useful in people severely disabled by motor fluctuations refractory to conventional treatment May allow a reduction in levodopa dosage Highly emetogenic and requires pretreatment with domperidone to reduce nausea

Entacapone Inhibits catechol-O-methyltransferase (COMT) in peripheral tissues and prolongs the clinical response to levodopa May be used as an adjunct to levodopa in patients with motor fluctuations It increases duration of motor improvement ('on' time), but also increases levodopa-induced dyskinesias and GI adverse effects The dose of levodopa may need reduction

Entacapone There are limited data available for treatment with controlled release formulations of levodopa The first COMT inhibitor to be licensed (tolcapone) was deregistered because of severe hepatic reactions There is no evidence to date of any hepatic adverse effects of entacapone

Anticholinergics Include benzhexol, benztropine, biperiden and orphenadrine Modest effect on tremor, but little effect on rigidity and bradykinesia May be used as monotherapy in early disease when tremor is predominant, or as adjunctive treatment in patients inadequately controlled by levodopa Used infrequently because of the incidence of adverse effects and relatively poor efficacy.

Anticholinergics Avoid use in the elderly and those with cognitive impairment Adverse effects include dry mouth, constipation, urinary retention, blurred vision, aggravation of glaucoma and psychiatric adverse effects (confusion, memory loss, hallucinations) Withdraw slowly to avoid precipitating a cholinergic crisis

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