1. Drugs used in Parkinson disease 2011

2. Historical Perspective Dr. James Parkinson (1755-1828) 1817 “ involuntary tremulous motion ” “ pass from a walking to a running pace ” “ shaking palsy ” London home

3. Epidemiology Average incidence is 20 per 100,000 in North America 1 Million affected in the United States 50,000 new cases per year Cost estimated to exceed $5.6 Billion annually

4. Epidemiology Average age of onset 62.5 Men and women affected equally Genetic Link African-Americans and Asians less likely than Caucasians to develop Parkinson ’ s Caffeine and smoking shows some protective effects

5. Pathogenesis Four Theories Oxidative damage Impaired protection Environmental toxins MPTP-Methyl-phenyl tetrahydropyridine Genetic predisposition Mutations in the gene for the protein alpha-synuclein located on chromosome 4 Accelerated aging

6. Pathophysiology Imbalance of dopamine and acetylcholine Loss of 80 to 90% of dopaminergic production in the substantia nigra Lewy Bodies

7. Degenerative disease of the basal ganglia causing tremor at rest, muscle rigidity hypokinesia, often with dementia. Associated with aggregation of α-synuclein (a protein normally involved in vesicle recycling) in the form of characteristic Lewy bodies. Often idiopathic but may follow stroke or virus infection; can be drug-induced (neuroleptic drugs). Rare familial forms also occur, associated with various gene mutations, including α- synuclein. Associated with early degeneration of dopaminergic nigrostriatal neurons, followed by more general neurodegeneration. Can be induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), a neurotoxin affecting dopamine neurons. Similar environmental neurotoxins, as well as genetic factors, may be involved in human Parkinson's disease.

9. PARKINSON'S is a progressive disorder of movement that occurs mainly in the elderly. The chief symptoms are: tremor at rest, usually starting in the hands which tends to diminish during voluntary activity muscle rigidity, detectable as an increased resistance in passive limb movement suppression of voluntary movements (hypokinesis), due partly to muscle rigidity and partly to an inherent inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate.

10. Parkinsonian patients walk with a characteristic shuffling gait. They find it hard to start, and once in progress they cannot quickly stop or change direction. PD is commonly associated with dementia, probably because the degenerative process is not confined to the basal ganglia but also affects other parts of the brain.

11. Parkinson's disease often occurs with no obvious underlying cause, but it may be the result of cerebral ischaemia, viral encephalitis or other types of pathological damage.

12. The symptoms can also be drug-induced, the main drugs involved being those that reduce the amount of dopamine in the brain (e.g. reserpine) or block dopamine receptors (e.g. antipsychotic drugs such as chlorpromazine;).

13. There are rare instances of early-onset PD that runs in families, and several gene mutations have been identified, the most important being synuclein and parkin. Study of these gene mutations has given some clues about the mechanism underlying the neurodegenerative process

15. Neurotoxins In 1982, a group of young drug addicts in California suddenly developed an exceptionally severe form of PD (known as the 'frozen addict' syndrome), and the cause was traced to the compound 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), which was a contaminant in a preparation used as a heroin substitute. MPTP causes irreversible destruction of nigrostriatal dopaminergic neurons in various species, and produces a PD-like state in primates. MPTP acts by being converted to a toxic metabolite, MPP+, by the enzyme monoamine oxidase (MAO, specifically by the MAO-B subtype). MPP+ is taken up by the dopamine transport system, and thus acts selectively on dopaminergic neurons; it inhibits mitochondrial oxidation reactions, producing oxidative stress

16. MPTP appears to be selective in destroying nigrostriatal neurons and does not affect dopaminergic neurons elsewhere-the reason for this is unknown. Selegiline, a selective MAO-B inhibitor,prevents MPTP- induced neurotoxicity by blocking its conversion to MPP+. Selegiline is also used in treating PD as well as inhibiting dopamine breakdown, it might also work by blocking the metabolic activation of a putative endogenous, or environmental, MPTP-like substance, which is involved in the causation of PD. It is possible that dopamine itself could be the culprit, because oxidation of dopamine gives rise to potentially toxic metabolites.

17. Whether or not the action of MPTP reflects the natural pathogenesis of PD, the MPTP model is a very useful experimental tool for testing possible therapies. Various herbicides, such as rotenone, that selectively inhibit mitochondrial function cause a PD-like syndrome in animals, suggesting that environmental toxins could be a factor in human PD, because impaired mitochondrial function is a feature of the disease in humans.

18. Molecular aspects

19. Dopamine in the CNS

20. Molecular aspects

21. There are five dopamine receptor subtypes. D1- and D5-receptors are linked to stimulation of adenylate cyclase. D2-, D3- and D4-receptors are linked to inhibition of adenylate cyclase. Most known functions of dopamine appear to be mediated mainly by receptors of the D2 family. There are five dopamine receptor subtypes. D1- and D5-receptors are linked to stimulation of adenylate cyclase. D2-, D3- and D4-receptors are linked to inhibition of adenylate cyclase. Most known functions of dopamine appear to be mediated mainly by receptors of the D2 family. Receptors of the D2 family may be implicated in schizophrenia. The D4-receptor shows marked polymorphism in humans. Receptors of the D2 family may be implicated in schizophrenia. The D4-receptor shows marked polymorphism in humans. Parkinson's disease is associated with a deficiency of nigrostriatal dopaminergic neurons. Parkinson's disease is associated with a deficiency of nigrostriatal dopaminergic neurons.

22. Pharmacotherapy Levodopa Dopamine agonists COMT inhibitors Amantadine Anticholinergics MAO-B inhibitor ex.Selegiline

24. Drugs used in Parkinson'sdisease Drugs act by counteracting deficiency of dopamine in basal ganglia or by blocking muscarinic receptors. None of the available drugs affect the underlying neurodegeneration.

25. Drugs include: levodopa (dopamine precursor;), given with an inhibitor of peripheral dopa decarboxylase (e.g. carbidopa ) to minimise side effects; sometimes a catechol-O-methyltransferase inhibitor (e.g. entacapone ) is also given, especially to patients with 'end of dose' motor fluctuations

26. bromocriptine (dopamine agonist;) selegiline (monoamine oxidase B inhibitor) amantadine (which may enhance dopamine release) benztropine (muscarinic receptor antagonist used for parkinsonism caused by antipsychotic drugs). Neurotransplantation, still in an experimental phase, may be effective but results are variable.

27. levodopa

28. Dopamine is a neurotransmitter as well as being the precursor for noradrenaline. It is degraded in a similar fashion to noradrenaline, giving rise mainly to dihydroxyphenylacetic acid and homovanillic acid, which are excreted in the urine. There are three main dopaminergic pathways: nigrostriatal pathway, important in motor control mesolimbic/mesocortical pathways, running from groups of cells in the midbrain to parts of the limbic system, especially the nucleus accumbens, and to the cortex; they are involved in emotion and drug-induced reward systems

29. tuberohypophyseal neurons running from the hypothalamus to the pituitary gland, whose secretions they regulate

30. levodopa levodopa (dopamine precursor;), given with an inhibitor of peripheral dopa decarboxylase (e.g. carbidopa ) to minimise side effects; sometimes a catechol-O- methyltransferase inhibitor (e.g. entacapone ) is also given, especially to patients with 'end of dose' motor fluctuations

31. Levodopa L-Dopa (Larodopa by Roche) Introduced in the late 1960s Crosses the blood-brain barrier Adverse effects such as nausea, vomiting, postural hypotension, involuntary movements, restlessness, and cardiac arrhythmias

34. Dopamine Agonists “ Synthetic Dopamine ” Bromocriptine Mesylate (Parlodel) Pergolide Mesylate (Permax) Pramipexol (Mirapex) Ropinirole HCL (Requip)

35. Dopamine Agonists Monotherapy or combination Are particulary usefull for: Prolonging the effective treatment period in patients with deteriorating response. Delaying the onset of L-dopa therapy. Particularly in younger patients. Treating patients who cannot tolerate high doses of L-dopa. Associated with more side effects than L-dopa Potential adverse effects include somnolence, dyskinesias, nausea, vomiting, orthostatic hypotension, nightmares, hallucinations, confusion, dizziness

36. COMT Inhibitors Entacapone (Comtan) Tolcapone (Tasmar)

37. COMT Inhibitor Entacapone (Comtan) Adjunct therapy Initial dose of 200mg with each dose of levodopa up to 8 times daily Decrease of L-dopa may be necessary Exacerbation of L-dopa side effects, diarrhea, urine discoloration, abdominal pain

38. COMT Inhibitor Tolcapone (Tasmar) Adjunct therapy Initial 100mg TID up to 200mg TID More potent and longer acting than entacapone Decrease L-dopa by 25 to 50% Exacerbation of L-dopa side effects, diarrhea, urine discoloration, liver toxicity.

39. Amantadine Amantadine HCL (Symmetrel) Inhibits dopamine recapture Blocks acetylcholine and glutamate receptors Dose 100mg BID to TID Caution in renal failure patients Currently used to reduce choreic movements Narrow therapeutic range Unpleasant side effects such as nausea, dizziness, confusion, hallucinations, nightmares, dry mouth peripheral edema.

40. Anticholinergics Trihexyphenidyl HCL (Artane) Benztropine Mesylate (Cogentin) Monotherapy or adjunct most effective for reducing tremor Use Limited by side effects especially in the elderly.

41. Anticholinergics Trihexyphenidyl HCL (Artane) Initial dose of 1mg and increase by 2 mg every 3 to 5 days until 6 to 10 mg/day. Usually given TID with meals or QID with meals and at bedtime. Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation. Benztropine Mesylate (Cogentin) Initial dose of 0.5 to 1 mg at bedtime. Increase by 0.5mg every 5 to 6 days up to a total daily dosage of 6mg. Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation.

42. Selegiline Selegiline HCL(Eldepryl)

43. Selegiline Monotherapy or adjunct MOA-inhibits monoamine oxidase-B (MAO-B) Inhibition of MAO-A does not occur Dosage of 5 mg BID with breakfast and lunch When used as monotherapy delays the need of L-dopa by an average of nine months. Possible adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of L-dopa side effects Controversial theory of decreased rate of neuronal death due to a reduction of free radicals.

44. Surgical Options Pallidotomy and Pallidal Stimulation Thalamotomy and Thalamic Stimulation Introduced in 1950 Pallidotomy improves tremor, rigidity, and bradykinesia Thalamotomy relieves tremor, rigidity, but not bradykinesia Neurosurgical treatment came to a end with the introduction of L-dopa in late 1960s Resurgence of neurosurgical intervention with the failure of pharmacological treatments after 10 to 15 years of disease progression Two methods: Ablation and deep brain stimulation

45. Grafting Suprarenal to brain transplantation Fetal tissue transplantation Cell culture transplantation

46. Under Investigation Implantable pumps Implantable capsules containing dopamine- producing cells New medications to target one of the five individual brain receptors for dopamine Continued genetic research