1. Parkinson’s Disease

2. Degenerative disease of the nervous system First described by James Parkinson (1817)  Tremor  Weakness  Propensity to bend the trunk forward  Propensity to pass from a walking to a ruunning pace  Senses and intelect uninjured 1841 – paralysis agitans (Marshall Hall)

3. Parkinson’s Disease Idiopathic Parkinson disease is observed in all ethnic groups and all socioeconomic classes  Incidence in afroamericans is ¼ that in whites  In asians incidence is 1/3-1/2 that in whites Incidence is about 1% in population over age 65 years (1 million patients in North America)

4. Parkinson’s Disease Begins between 40 and 70 years, peak age of onset in the sixth decade Incidence somewhat greater in men Risk for the first degree relatives about 5% Genetic aspects  Evidence of striatal dysfunction in 75% of asymptomatic monozygotic twins of Parkinson patients (pet scanning for dopamine metabolism)  Familial cases – there was identified forms with clear established genetic defects (less than 25% from all cases)

5. Progresion of Parkinsons Disease

6. Parkinson’s Disease Familial cases - earlier onset (the fourth decade) and a relatively rapid course (10 years from onset to death) Mutation in the gene enconding the protein α-synuclein (main component of the Levy body ) (crs 4q) Mutations of exons in Park2 gene (chr 6q) – the commonest types are point mutations or deletions in exon 7 but abnormalities of the other 12 exons evince similar syndromes  50% of families with early onset of parkinson disease harbor mutations in this gene  Up to 2% of late onset cases and 18% of sporadic cases with early onset are due to parkin mutations (Kahn et all) Mutations in genes park 5, 6, 7, 8, NR4A2

7. Parkinson’s Disease Lewy bodies (LB) are considered as the histological hallmark of Parkinson's disease;  They were first described in cholinergic neurons of substantia innominata ("unnamed substance")  Then described in dopaminergic neurons of substantia nigra (pars compacta) in association with cells depletion and replacement gliosis  There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies.  A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein and alpha B crystallin Lewy bodies and Lewy neurites in PD

8. Parkinson’s Disease : Pathophysiology The major neuropathologic findings in Parkinson disease are a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies Primary neurochemical deficiency in Parkinson's disease is the loss of dopaminergic projections of the striatum.  There are also others pigmented an nonpigmeted neuronal population in midbrain and lower brainstam wich are affected  Other neurotransmitter deficiencies such as norepinephrine, serotonin, acetilcholine and gamma amino butyric (GABA) due to neuronal loss in locus ceruleous, lateral tegmental areas of the brain, nucleus basalis of Meynert, raphe nuclei may contribute to secondary symptoms Recent data suggests that many neurodegenerative diseases (AD, PD) are overlaping

9. Loss of pigmented neurons in substantia nigra Normal Parkinson Disease

10. Symmetrycal activity of striat (healthy volunteer) Asymmetrycal decrease of striatal activity in a PD patient Patients may follow or not dopaminergic therapy Reprinted from Parkinson Study Group. Neurology. 2000;55:1540-1547. Loss of pigmented neurons in substantia nigra

12. Clinical Features Frequently unilateral onset, early symptoms may be overlooked by patient or family members Initial symptoms in patients with PD (Hoehn and Yahr) Tremor70% Gait disturbance 11% Rigidity10% Slowness of voluntar movement 10% Muscular aches 8% Loss of dexterity 7% Handwriting disturbance (micrographia) 5% Depression, nervousness, other psychiatric disturbance 4% Speech disturbance 3%

13. Clinical Features Hipokynesia / bradykinesia Resting tremor Postural instability Rigidity

14. Clinical Features Tremor  Frequently unilateral onset  4~6Hz frequency,  Most conspicuous at rest, it increases at times of emotional stress and often improves during voluntary activity.  Fluctuations of intensity - is aggravated by emotions or walk Frequency remains constant  “Pill-rolling” or “money-counting” character  EMG – alternating burst of activity in agonist and antagonist muscles  Negro’s sign (cogwheel phenomenon)

15. Clinical Features Rigidity  It tends to appear in the more advanced stages of the disease  It can be felt by the palpating finger and seen as a salience of muscle groups in active and pasive movements or even when the patient relaxes. It affects both the extensor and flexor groups.  Rigidity and cogwheel feature can be elicited or enhanced by having the patient engage the the opposite limb in a motor task requiring some degree of concentration  In the muscle of the trunk, postural hypertonuspredominates in yhe flexor groups and confers on the patient the characteristic flexed posture  Muscle aches (back, neck, shoulders, hips)

16. Clinical Features Bradykinesia – slowness in initiation and execution of a movement Hypokinesia – reduced frequency and amplitude of movement  Infrequency of blinking (associated with widening of the palpebral fissures – stelwag sign), infrequency of swallowing, slowness of chewing,  Limited capacity to make postural adjustments  Absence of arm swing in walking, lack of small “movements of cooperation”  Difficulty in executing two motor acts simultaneously, alternating movements become progressively impeded and finally are blocked completely or adopt the the rhythm of the patient alternating tremor  Micrographia: small, tremulous, cramped handwriting (Charcot)  “hypokinetic dysarthria” (Caekebeke): voice softens, speech seems hurried, monotonous and mumbling Kinesis paradoxica – in the excitement of some unusual circumstance, the patient is capabil of brief but remarkably effective movement

17. Clinical Features Gait disturbance  Walking is shuffled, the patient frequently loses balance, walking forward and backward may seem to be “chasing” the body’s center of gravity with a series of short steps in order to avoid falling (festination)  Defence and righting reactions are faulty  Falls occur surprisingly infrequently given the degree of postural instability  Gait is typically improved by sensory guidance, as by holding yhe patient at the elbow  Obstacles such as door tresholds causes the patient to”freeze” in place

18. Clinical Features Dementia – 10-15% of oatients (Mayeux)  Incidence increases with advancing age aproaching 65 percent in patients above 80 years of age  Sometimes associated with lesions in white matter Hypersalivation (failure to swallow with normal frequency), seborheea, excessive sweating Other involuntary movements (dystonias)

19. Compensatory changes in dopaminergic synapse in PD Presynaptic:  Hiperactivity of restant dopaminergic neurons (increasing of dopamine turnover) Postsynaptic  Increasing of receptor’s sensitivity for dopamine 100% 80% 60% 40% 20% 0% Compensate (no simptoms) Adaptative capacity Uncom - penste Mild simptomatology Important simptomatology Most symptoms do not appear until striatal DA levels decline by at least 70-80%.

20. Stimulating the release of dopamine (amantadine) Increasing the synthesis of dopamine (levodopa) Stimulating the dopamine receptor sites directly (agonists) Inhibiting the catabolism of dopamine (MAO B and COMT inhibitors) Treatment of Parkinson’s Disease

21. Drug Therapy Against Parkinson Disease D1 D2 PRESYNAPTIC POSTSYNAPTIC

22. Levodopa metabolism Intestinal wall Levodopa COMT Inhibited by Entacapone, Tolcapone Dopamine Inhibited by Carbidopa, Benserazide decarboxylase 3-Ο methyl dopa MAO-B MAO-B inhibitors (Selegiline) Deaminated metabolites BBB LevodopaDopamine decarboxylase COMT Inhibata de Tolcapone 3-Ο methyl dopa MAO-B Inhibitori de MAO B Deaminated metabolites MAO-B Deaminate d metabolites methoxytyramine MAO-B Homovanillic acid COMT

23. L-Dopa therapy Action:  L Dopa fairly effective in eliminating most of the symptoms of Parkinson disease bradykinesia > rigidity > tremor  L Dopa less effective in eliminating postural instability, shuffling gait, dysarthria, vegetative disturbance meaning other neurotransmitters are involved in Parkinson disease  Decrease of action: frequently after 3-5 years motor fluctuations and dyskinesias may occur  Delivers to restant neurons in substantia nigra the substrate for dopamine sinthesis Drugs:  L-Dopa andBenserazide : Madopar 125/250 tb., 62,5/125 cps., Madopar LT tb. (125mg), Madopar 125 Depot-Kapseln;  L-Dopa and Carbidopa: NacomR 100/250 tb., Nacom retard 100/200 tb.; Isicom 100/250 tb., StriatonR 200 tb.

24. Effects of chronic levodopa administration  End-of-dose wearing-off effect  On/off oscillations  Freezing during movement  Dose failure (drug resistance)  Dyskinesia at peak dose

25. Complications of long-term therapy with L-dopa Motor Fluctuations:  beneficial effects of levodopa last a few hours and then diminish: "wearing-off"  Rapid and unpredictablechange from a state of relative freedomof symptoms to one of complete immobility: "on-off"  Off-period dystonia and early morning dystonia : painful contractions of ankle muscles  “Delayed on” : long interval between administration of pill and onset of on effect  “No on” : no response to l-dopa administration  "freezing“ phenomenon

26. Motor complications of long-term therapy with L-dopa Dyskinesias (choreic, athetosic, dystonic, balistic movements)  “peak-dose” dyskinesia (choreic movement)  “end-of-dose" dyskinesia (dystonic aspect)  diphasic dyskinesia (choreic and balistic movements) Almost always dyskinesias are combined with on-off fluctuations

27. Catechol-O-methyltransferase inhibitors (COMT) Action: inhibits metabolisation of L-Dopa to 3-Ο methyl dopa in peripheral tissues (Tolcapone acts in periphery and also centraly, Entacapone only in periphery ) Increases the duration of effect of levodopa dose Drugs :  Entacapone (Comtan) tb. 200mg;  Tolcapone (Tasmar) tb. 100/200mg;  Hepatic toxicity STALEVO – combination 1:4:8 of carbidopa, levodopa and entacapone (tablets 50, 100 and 150 mg)

28. Inhibitors of Monoamine Oxidase B (MAO-B) Action: inhibits the metabolic breakdown of dopamine. Selegiline: Deprenyl tb. 5mg;  Stimulatory amphetaminic effect  selectively inhibits monoamine oxidase B which metabolizes dopamine, but does not inhibit monoamine oxidase a which metabolizes norepinephrine and serotonin Rasagiline (Azilect) 1 mg/day  rapidly absorbed, reaching peak plasma concentration in approximately 1 hour.  Monotherapy in early stages and combined with Levodopa in advanced stages of disease (beneficial effects on dopaminergic motor dysfunction.)  There are some data wich suggests un possible neuroprotective efect  Early use of rasagiline may delay the progression of symptoms  Patients treated early with rasagiline have a lower functional decline comparative with those patients who takes rasagiline with a delay of 6 months

29. Dopamine agonists Action: the direct influence of the D1 and D2 receptor, dopamine independently different half-lives Generics and preparations:  Bromocriptine, Cabergolin; Lisurid; Pergolid; α-dihidroergocriptine:  Ropinirol: Requip cp 0,25/0,5/1/2/5mg;  Ropinirol retard cp 2/4/8 mg  Pramipexol: cp0,125/0,25/1mg.

30. Dopamine agonists Effective even in monotherapy - postponing the need to introduce levodopa with 12-36 months Symptomatic benefit less than levodopa Delay / Reduce motor complications May delay disease progression Have a sparing effect of levodopa Start with a low dose and slowly increase Titrate to therapeutic efficacy o pramipexole 1.5-4.5 mg/day o ropinirole 3-24 mg/day o bromocriptina 7.5-30 mg/day o pergolide 1.5-4.5 mg/day Acute side effects: nausea, dizziness, drowsiness, confusion Not affected by dietary protein intake

31. NMDA antagonists Low affinity blocker of the NMDA receptor channel, increases the release of dopamine, blocks up the dopamine reuptake and cholinergic effects Amantadine: 100mg cp Modest effects on tremor, hypokinesia and postural symptoms May cause edema, worsen heart failure, exaggerate cognitive impairment disorders,worsen the glaucoma

32. Anticolinergics Action: central and peripheral muscarinic receptor blockade Clinical action especially on tremor and rigidity Cognitive side effects, hallucinations, prostatic obstruction The effect is cumulative and occurs after several days of dosing. Dose titrated up to the best into balance between effectiveness and side effects Generics and preparations:  Benzatropin: Cogentinol cp. 2mg;  Biperiden: Akineton cp. 2mg,  Trihexiphenidil: Artane cp. 2/5mg, Artane retard

33. Deep Brain Stimulation in Parkinsons Disease In Parkinson's disease, the rest tremor seems to be caused by a neuronal group located in the thalamus and basal ganglia downloading signals synchronous Under physiological conditions, these neurons download signals in a chaotic mode It acts as a pacemaker and enables the premotor cortex, the motor cortex area, and the additional motor Stimulation of thalamic / subthalamic with high frequency (high frequency periodic pulse - 4100 Hz) suppresses the activity of peace maker, and consequently the peripheral tremor It was approved by FDA in 2002 Cost: £ 25-30000

34. Deep Brain Stimulation in Parkinsons Disease Thalamic stimulation has a favorable effect on tremor especially =>seems to be particularly useful in patients with essential tremor Pallidal stimulation is effective on dyskinesias, improves rigidity, increases periods "on", has minimal effect or worsens bradykinesia Subthalamic stimulation is effective on tremor, rigidity, bradykinesia. Could improve stability, walking, states "freezing" Requires lower stimulation intensities (longer use)

35. Continuous Dopaminergic stimulation - DUODOPA The concept of continuous dopaminergic stimulation reprezents a new trend in the PD pharmacology The fundamental theory behind this concept consists in the fact that physiological striatal dopaminergic stimulation is constant and that the oral therapy with levodopa cand replace this constant stimulation in a intermitent and non pysiological way This pulsatile stimulation of the dopaminergic receptors is belived to contribute to the development of the motor fluctuations, which are common after a few years of levodopa treated PD patients and can affect the quality of life

36. Levodopa – Duodenal Infusion “Bypass“- stomach area L-dopa infused directly in duoden/jejuni