1. Parkinson s disease
Niazy Burhan aldin

2. What is Parkinson’s Disease?
Parkinson's disease (PD) is a movement disorder that is chronic and progressive, meaning that symptoms continue and worsen over time. Nearly one million people in the US are living with Parkinson's disease. The cause is unknown, and although there is presently no cure, there are treatment options such as medication and surgery to manage its symptoms

3. Epidemiology 2nd common neurodegenerative disease,
. After Alzheimer s disease
PD affect 1% of the population over 65 years of age ,rising to 2% over the age of 80
Although it my be less common in china and west Africa. Most epidemiological studies have indicated a small male- to – female predominance .

4. Aetiology
Parkinson's disease occurs when a group of cells in an area of the brain called the substantia nigra begin to malfunction and die. These cells in the substantia nigra produce a chemical called dopamine. Dopamine is a neurotransmitter, or chemical messenger, that sends information to the parts of the brain that control movement and coordination.
When a person has Parkinson's disease, their dopamine-producing cells begin to die and the amount of dopamine produced in the brain decreases. Messages from the brain telling the body how and when to move are therefore delivered more slowly, leaving a person incapable of initiating and controlling movements in a normal way.

5. Aetiology
Both genetic and environmental factor have been implicated as a cause of parkinson s disease
The discovery of a mutation in the gene coding for a synaptic protein called alpha-synuclein provided tremendous impetus to research .
Environmental – chronic systemic exposure to the pesticide rotenone can reproduce the clinical and pathological features of parkinson s

6. pathophysiology
Neuronal loss in pigmented brainstem nuclei, together with the presence of esinophilic inclusion bodies, called Lewy bodies;in surviving cell .loss of 80% of nigral neurons before symptoms appear
Host of other nuclei and neurotransmitter systems are involved. For example, cholinergic neurons. Swallowing difficulty (dysphagia) and sleep disturbance (REM disterbance)

7. Pathophysiology
The loss of noradrenergic and serotogenic neurones wthin the locus coeroleus and raphe nucleus , respectively , may provide a pathophysiological basis for depression which is common in PD.

8. Drug induced parkinsonism
(DIP) is potentially reversible upon cessation of the offending agent.
Chlorpromazine
Fluphenazine as neuroleptic drugs
Prochlorperazine and cinnarzine
The pathogenesis of drug-induced parkinsonism due to dopamine receptor blocked.
Non – neuroleptic drugs associated with drug induced parkinsonism see table 32.3 page 466

9. Investigations Clinically Should be based
Copper studies and DNA testing to exclude wilsons disease and Huntingtons disease respectively .
Brian imaging by computed tomography (CT) or magnetic resonance image (MRI) to exclude hydrocephalus , cerebrovascular disease or basal ganglia abnormalties .
SPECT test imaging to identify loss of nigrostriatal dopaminergic terminals in striatum

10. Clinical features Bradykinesia is general in parkinsonism
Rest tremor, extra pyramidal rigidity (so called lead pipe –and/or cog- wheel) rhythmic movement it some times described as pill-rolling in nature from movement of thumb across the fingers.
Postural instability is a late feature of parkinson s disease and loss of arm swing in walking . There is reduced blink frequency and facial expression .
60% of people with PD may have a dominant postural tremor .

11. Clinical features

12. Clinical features Postural instability is a late feature of PD
There is reduced blink frequency and facial expression with reduced volume (hypophonic) .
Autonomic dysfunction may occur in parkinson disease ,urogenitial difficulties ,with erectile dysfunction in males and urinary urgency in both sexes.
Depression affects approximately 40% of patients .
Occurrence of dementia related to the age in PK

13. Treatment (General approach )
All currently available drugs for PD are symptomatic .
A number of factors including age , severity and type of disease ( tremor-dominant versus bradykinesia-dominant )
The limitation of levodopa treatment (levodopa syndrome)

14. Treatment Drug treatment 1-Levodopa preparations
A/Immediate- release Levodopa remain the most effective oral symptomatic treatment for PD . It is administered with the peripheral dopa-decarboxylase inhibitors carbidopa or benserazide, 50 mg per day increasing every 3-4 days take with food to minimize nausea
B/Controlled –release Levodopaving both sinemet and madopar simplifying drug regimens , relieve fluctuation.
Duodopa a highly soluble form of levodopa is administered directly into small bowel .

15. Co-careldopa intestinal gel
. An intestinal gel preparation
of levodopa and carbidopa (Duodopa®) is available that is administered directly into the small bowel (specifically, the jejunum) via a percutaneous route, using a portable electronic pump. Through continuous delivery in this way, motor fluctuations may be significantly reduced. Although effective, this treatment modality requires careful patient selection

17. Co-careldopa intestinal gel

18. Treatment
2- Dopamine agonists – Bromocriptine Cabergoline ,Ropinirol pramipexole and pergoide
3-Catechol-O- methyl transferase inhibitors (COMT) Entacapone Tolcapone(Hepatotoxic)
4-Monoamine oxidase inhibitors type B inhibitors propargylamines Selegiline and rasagiline
5- Amantadine blocking dopamine reuptake An anticholinergic effect.
6- Anti cholinergic drugs (trihexyphenidyl & orphenadrine modret effect in reducing tremor

19. 2- Dopamine agonists
Dopamine agonists differ in their affinity for a number of receptors, including the dopamine receptor family. It is not known whether these differences are clinically significant, but experience to date would suggest not. Cabergoline is an ergot dopamine agonist with a much longer plasma half-life of 63–68 h than other agents in this class. This means that once-daily dosing is possible. Ropinirole and pramipexole are non-ergot derivatives that originally had to be administered three times daily. Slow release preparations of ropinirole
(XL) and pramipexole (PR) are now available for once-daily dosing. A transdermally administered non-ergot dopamine agonist, rotigotine, is also available as a 24-h adhesive
patch.

20. Dopamin Agonist

21. Dopamine agonists have also been associated with impulse control disorders (ICDs). These disorders include pathological gambling, hypersexuality and excessive shopping. The onset may relate to dopamine D2/3 receptor stimulation in
predisposed individuals.

22. Catechol-O-methyl transferase inhibitors

23. 3-Catechol-O-methyl transferase inhibitors
Inhibitors of the enzyme catechol-O-methyl transferase (COMT) represent a novel addition to the range of therapies available for Parkinson's disease (Schrag, 2005). Use of the first agent in this class, tolcapone, was originally suspended in Europe because of fears over hepatotoxicity, although the drug became available again in 2005, accompanied by strictprescribing and monitoring guidelines. Entacapone is also available and studies have not shown derangement of liver
function with this drug

25. Monoamine oxidase type B inhibitors
The propargylamines selegiline andrasagiline are inhibitors of monoamine oxidase type B. Inhibition of this enzyme slows the breakdown of dopamine in the striatum. These agents effectively have a ‘levodopa-sparing’ effect and may delay the onset of, or reduce existing, motor complications. Both drugs may also have an antiapoptotic effect (apoptosis is a form of programmed cell death thought to be important in several neurodegenerative conditions, including Parkinson's disease).

26. buccal selegiline.

27. A single daily dose of 5 or 10 mg of selegiline is prescribed.
Higher doses are associated with only minimal additional inhibition of monoamine oxidase. Selegiline may also be
administered as a lyophilised freeze-dried buccal preparation.The dose of rasagiline is 1 mg daily.Both selegiline and rasagiline may be used as de novo or adjunctive treatments in Parkinson's disease, although trial data for the latter indication are strongest for rasagiline and buccal selegiline.

28. Amantadine
Amantadine was introduced as an anti-Parkinsonian treatment in the late 1960s. It has a number of possible modes of action, including facilitation of presynaptic dopamine release, blocking dopamine reuptake, an anticholinergic effect, and also as a N-methyl-d-aspartate (NMDA) receptor antagonist. Initially employed in the early stages of treatment, where its effects are mild and relatively short-lived, interest has focused more recently upon the use of amantadine as an antidyskinetic
agent in advanced disease Daily doses of 100–300 mg amantadine may be used

29. Amantadine

30. Treatment
Tricyclic antidepressant have anticholinergic properties, alow dose of TCAs e.g amitriptyline mg at night improving sleep and improving performance early in the morning .
Apomorphine the most potent dopamine agonist used SC injection alternatives route is transdermal and transnasal route.

31. Treatment

32. Surgical treatment
Deep brain stimulation has the advantage of being reversible but is costly.
Surgery may also play role in neurorestorative treatment such approaches include stem cell and fetal cell transplantation.and also xenotransplantation

33. Patient care
See table 32.5 lists some common therapeutic problem page 470 .
Diary cards when they begin to experience problems with either bradykinesia or dyskinesia .
Careful changes in timing of drug therapy or meals may intially be sufficient to reduce variation in performance

34. The treatment of the patient with severe disease remains one of the greatest challenges in the management of Parkinson's disease. On–off fluctuations
may be refractory to oral dopaminergic therapies. Sudden freezing episodes compound failing postural stability

35. Autonomic problems
Disorder of gut motility – constipation or difficulty with swallowing , disturbances of micturition , nocturia and postural hypotension . See page 471
Solving these problems recommended .

36. Psychosis and dementia
When cognitive impairment is problematic, the use of conventional antipsychotic medication is inappropriate because such drugs can precipitate a catastrophic worsening of Parkinsonism. Behavioural disturbances require discussion with carers and, if possible, with the patient him- or herself an atypical antipsychotic drug may be considered. In practice, the choice narrows down to quetiapine or clozapine, since risperidone and olanzepine are associated with worsening Parkinsonism, even in low doses.