1. Pharmacology of Drugs Used in Parkinson’s Disease Jose Paciano B.T. Reyes, FPNA ASMPH January 27, 2011

2. Definitions What are Movement Disorders? conditions of abnormal, insufficient, or excessive motor activity clinically, seen as: stiffnessrigidity bradykinesiapaucity of movement tremorsdystonia choreatics myoclonusgait disturbances

3. What causes movement disorders? specific pathologic and biochemical basis for many movement disorders is not known clinical manifestations often implicate the basal ganglia as the primary site of disturbance

4. Definitions What is the basal ganglia? group of interconnected subcortical nuclei (caudate, globus pallidus, putamen, subthalamic nucleus, substantia nigra)‏ exert an inhibitory influence in the premotor area of the cortex by way of output from the ventrolateral thalamus

5. Definitions What is Parkinson’s Disease? a progressive neurodegenerative disorder loss of dopaminergic neurons in the substantia nigra pars compacta more common in the elderly 15% familial

6. Parkinson’s Disease Types: endogenous/idiopathic arteriosclerotic post-encephalitic post-traumatic toxic tumor related drug induced Clinical Features: tremor at rest rigidity bradykinesia postural impairment autonomic symptoms psychic symptoms

7. Parkinson’s Disease Histopathologic Features: degeneration of the nigrostriatal pathway dopaminergic neuron degeneration in the substantia nigra Striatum (caudate+putamen)‏ contains the highest levels of dopamine in the mammalian brain has a high level of cholinergic markers

8. 1. Tremor at rest 2. Cogwheel rigidity 3. Bradykinesia/hypokinesia 4. Flexed posture 5. Loss of postural reflexes 6. Freezing phenomenon At least 2 of these features with at least one being either 1 or 3 Parkinson’s Disease

9. reduced attention span fearful, indecisive, passive lack of motivation depression some cognitive decline slow to respond Parkinson’s Disease

10. oxidative stress hypothesis environmental neurotoxin - MPTP genetic susceptibility - defects in mitochondrial genome Parkinson’s Disease

11. Dopamine Acetylcholine

12. Cell destruction in the substantia nigra Destruction of dopaminergic terminals in the striatum Decreaseddopaminergictransmission Disinhibited cholinergic neurons cholinergic neurons Dominance of cholinergic stimulation rigor, tremor akinesia

13. Sites of Drug Action 1. action potential in nerve presynaptic nerve fiber 2. synthesis of transmitter 3. storage 4. metabolism 5. release 6. reuptake 7. degradation 8. receptor of transmitter 9. receptor-induced increase or decrease in ionic conductance

14. Parkinson’s Disease Treatment Approaches: Enhance dopaminergic function a. Increase synthesis of dopamine b. Increase pre-synaptic release of dopamine c. Decrease dopamine synaptic reuptake d. Stimulate post-synaptic dopamine receptors e. Inhibit metabolic enzymes Reduce cholinergic drive anticholinergic medications

15. Dopamine Synthesis & Metabolism conversion of tyrosine to L- dopa is the rate limiting step action of dopamine is terminated by a reuptake mechanism metabolic degradation of dopamine is facilitated by: 1. monoamine oxidases (MAO-A, MAO-B) 2. catechol-O- methyltransferase (COMT)‏ L-tyrosine L-dopa dopamine dopa decarboxylase tyrosine hydroxylase

16. Dopaminergic neuronal impulse transmission Tyrosine hydroxylase Decarboxylase dopamine agonists

17. Dopamine Receptors 5 types of receptors: D 1 type (D 1, D 5 )‏ D 2 type (D 2, D 3, D 4 )‏ all are G-protein coupled transmembrane receptors thus signal transduction is linked to adenylate cyclase D 1, D 2 receptors are most widespread in the CNS motor effects mediated primarily by D 2 receptors and to a lesser extent by D 1 receptors D 3, D 4, D 5 receptors exert less motor effects

18. Functional pathways: 1. Nigrostriatal (motor control)‏ 2. Mesolimbic & mesocortical (behavioral control)‏ 3. Tuberohypophyseal (endocrine control)‏ Dopamine Receptors

19. Many antipsychotic drugs are D 2 -receptor antagonists thus have Parkinsonian effects due to block of nigrostriatal D 2 -receptors D 2 -receptors occur near the medullary chemoreceptor trigger zone thus most dopamine agonists cause nausea & vomiting

20. Approach to Therapy Begin therapy when work performance or activities of daily living living affected. Minimal dose of antiparkinsonian medication to adequately control motor symptoms. Monotherapy with a dopamine agonist. Add levodopa when agonist cannot control symptoms.

21. Drugs used for Parkinson’s Disease Drugs that enhance dopaminergic function: 1. Levodopa 2. Bromocriptine HCl 3. Amantidine 4. Selegiline 5. Tolcapone 6. Pergolide 7. Apomorphine 8. Entacapone 9. Pramipexole 10. Ropinerole 11. Piribedil Drugs that reduce cholinergic drive: 1. Benztropine 2. Biperiden 3. Trihexyphenidyl 4. Diphenhydramine

22. Levodopa amino acid precursor of dopamine decarboxylated into dopamine clinical use: –most potent agent for symptomatic treatment –unequivocal response to the drug is used as a diagnostic confirmation –combined with peripheral dopa decarboxylase inhibitors (benzeraside, carbidopa) to increase its bioavailability & reduce its side effects

23. 1. GI effects nausea and vomiting, anorexia 2. CVS effects arrhythmia, postural hypotension hypertension (when combined with MAO inhibitors)‏ 3. Dyskinesias chorea, ballismus, athetosis, dystonia, myoclonus, tics, tremor 4. Behavioral effects depression, anxiety, nsomnia, somnolence Levodopa

24. Preparations: Carbidopa / Levodopa: 25/100, 25/250 Benserazide / Levodopa: 50/200, 25/ 100 Usual dose 1tab 25/100 bid, tid 1 tab 25/250 bid

25. Bromocriptine an ergot derivative functions: 1. dopamine agonist at D 2 receptors 2. mild antagonistic activity at D 1 receptors clinically, also used to treat hyperprolactinemia monotherapy/adjunctive therapy

26. Bromocriptine Preparation: 2.5 mg / tab Usual dose: 1.25 - 2.5 mg once a day, before bedtime up to 40 mg/day

27. Synthetic ergot derivative 10x more potent than bromocriptine functions: 1. direct stimulant of post-synaptic dopaminergic receptors in the striatum 2. act mainly as agonist at the D 2 receptors clinically used as an adjunct to levodopa treatment or as monotherapy may cause hypotension Pergolide

28. Pramipexole Non-ergot dopamine agonist D 2 and D 3 agonist efficacy similar to bromocriptine and pergolide 90% excreted in the urine unchanged monotherapy or adjunct with levodopa

29. Pramipexole Preparations: 0.125 mg tabs, 0.25 mg tabs, 1.0 mg tabs, 1.5 mg tabs Usual dose: 0.125 three times daily 4-6 mg three times daily over 4 - 8 weeks

30. AgonistD 1 D 2 D 3 Plasma-half-life (n)Elimination Bromocriptine-+++6Hepatic Cabergoline++++++65Hepatic Dihydroergocryptine +/- +++?15Hepatic Lisuride+/-++++++2-3Hepatic / renal Pergolide+++++++7-16 Hepatic / renal Pramipexole0++++++8-12 Renal Ropinirole0+++++6Renal according to Brecht (1998) and Gerlach et al. (2000)‏ Examples of Dopamine Agonists

31. an antiviral against influenza A function: releases dopamine from nerve terminals weak dopamine agonist with anticholinergic properties clinically, may induce side effects typical of anticholinergic agents Amantidine HCl

32. Preparation: 100 mg / tab Usual dose: 100 mg od to bid upper limit is 100 mg qid

33. functions: 1. selective, irreversible, MAO-B inhibitor 2. prevents the oxidation of dopamine (which produces free radicals and H 2 O 2 ) clinically, the only agent shown to have a possible effect in retarding the progression of Parkinson disease Selegiline

34. Preparation: 5 mg / tab Usual dose: 5 mg once a day up to twice a day

35. function: selective, reversible, peripherally and centrally active COMT inhibitor clinically, increases the T 1/2, bioavailability and plasma levels of levodopa used as an adjunct with levodopa Tolcapone

36. Preparation: 100 mg / tab Usual dose: 50 mg three times a day maximum of 400 mg three times a day

37. Entacapone Selective reversible peripherally acting COMT inhibitor increases bioavailability and half-life of levodopa extends clinical effect of levodopa by 30-45 min. adjunct agent for use with levodopa

38. Entocapone Preparation: 200 mg / tab Usual dose: 200 mg with every dose of levodopa

39. Acetylcholine-Blocking Drugs centrally acting antimuscarinic preparations clinically: 1. improve tremor 2. first line treatment for patients with mild Parkinson’s disease adverse effects constipation, pupillary dilatation (mydriasis)‏ urinary retention, paralysis of accommodation dry mouth, confusion

40. Parkinson’s Disease Dopamine Acetylcholine

41. Thank you!