1. Parkinson's disease

2. 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

3. 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

4. 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

5. Pathophysiology
Acetylcholine V/s Dopamine

6. 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

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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

13. 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)

14. 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

15. 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.

16. 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

17. 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

18. 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

19. 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.

20. 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.

21. 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.

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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.

28. 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

30. THANK YOU