Pharmacologic Treatment of Parkinson s Disease. Nicholas J. Silvestri, M.D. Assistant Professor of Neurology

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1 + Pharmacologic Treatment of Parkinson s Disease Nicholas J. Silvestri, M.D. Assistant Professor of Neurology

2 + Overview n Brief review of Parkinson s disease (PD) n Clinical manifestations n Pathophysiology n Pharmacologic treatment of PD n Levadopa/carbidopa n COMT inhibitors n Dopamine agonists n MAO-B inhibitors n Amantadine n Anticholinergics

3 + Clinical Features n Second most common neurodegenerative disorder n Incidence and prevalence increase with age n Incidence of PD in recent Olmstead County study: n 1/100,000 between ages of n 17/100,000 between ages of n 93/100,000 between ages of n Risk factors n Higher risk in males, Hispanics n Lower risk associated with smoking and caffeine use n Several genetic mutations

4 + Clinical Features n Motor symptoms n Rest tremor n Bradykinesia n Rigidity (with cogwheeling) n Postural instability

5 + Clinical Features n Non-motor symptoms n Olfactory disturbances n Sensory symptoms n Gastrointestinal disturbances (e.g. constipation) n Urinary symptoms (nocturia, frequency, urgency) n Orthostasic intolerance and other signs of dysautonomia n Sleep disorders n Dementia n Depression

6 + Pathophysiology n Loss of dopaminergic neurons in the substantia nigra pars compacta

7 + Pathophysiology

8 + Dopamine

9 + Levadopa/Carbidopa n Trade name: Sinemet n Levadopa is dopamine precursor n Carbidopa is a peripheral dopa decarboxylase inhibitor n Dosage n Initial: 25/100mg tab p.o. t.i.d. n Adjust based on response up to total of 200/2000mg/day

10 + Levadopa/Carbidopa n Wearing off phenomenon n Motor Fluctuations n Freezing n Apomorphine: injectable dopamine agonist n Dyskinesias

11 + Levadopa/Carbidopa n Adverse effects n Dyskinesias n Impulse control disorders (e.g. pathologic gambling) n Orthostatic hypotension n Nausea n Somnolence n Psychosis n Exacerbation of glaucoma n NMS with abrupt withdrawal

12 + COMT inhibitors n Entacapone (Comtan) n Tolcapone (Tasmar) n Mechanism of action: inhibit catechol-o-methyl transferase, prolonging action of levadopa n Dosage: n 200mg with each dose of levadopa/carbidopa up to total daily dose of 1600mg/day

13 + COMT Inhibitors n Adverse reactions n Dyskinesias n Diarrhea n Orthostatic intolerance n Psychosis n Nausea n Orange-brown discoloration of urine n Hepatic failure with tolcapone

14 + Dopamine Agonists n Ergot derivatives n e.g. Bromocriptine n No longer widely used due to risk of cardiac valvular fibrosis n Non-ergots n Pramipexole (Mirapex) n Ropinirole (Requip)

15 + Dopamine Agonists n Mechanism of action: Bind to D2 (and also D3, D4) receptors, activating dopaminergic circuits n Dosage: n Pramipexole: 0.125mg p.o. t.i.d., titrating up to 4.5mg/total daily dose as needed n Ropinirole: 0.25mg p.o. t.i.d., titrating to 1mg p.o. t.i.d. over 4 weeks and then up to 24mg/total daily dose as needed n Both are also available in extended release formulations

16 + Dopamine Agonists n Adverse effects n Somnolence n Orthostatic hypotension n Nausea n Peripheral edema n Hyperhydrosis n Impulse control disorders n Dyskinesias n Psychosis

17 + MAO Inhibitors n Non-selective: selegiline (Eldepryl) n Available both p.o. and transdermally n Risk of hypertensive crisis with tyramine n Selective (MAO-B): rasagiline (Azilect) n Dosage: 0.5mg p.o. q.a.m., can increase to 1mg if needed n Possibly neuro-protective

18 + MAO-B Inhibitors n Adverse effects: n Somnolence n Nausea n Orthostasis n Psychosis n Rarely, serotonin syndrome if taken in conjunction with tricyclic antidepressants

19 + Amantadine n Trade name: Symmetrel n Mechanism of action: possible dopamine agonist and/or reuptake inhibitor,? NMDA receptor antagonist n Useful in treatment of dyskinesias and tremor n Dosage: n 100mg p.o. b.i.d. up to 400mg/day as needed n Adverse effects: n Peripheral edema, livedo reticularis

20 + Anticholinergics n Benztropine (Cogentin) n Trihexylphenidyl (Artane) n Diphenhydramine (Benadryl) n Mechanism of action: restore natural balance of dopamine and acetylcholine in the basal ganglia n Useful in treating tremor in younger patients

21 + Anticholinergics n Adverse effects: n Encephalopathy n Tachycardia n Xerostomia and xerophthalmia n Constipation n Urinary retention

22 + Basic Principles n Levadopa/carbidopa still the drug of choice n COMT inhibitors for wearing off n Dopamine agonists probably almost as effective as levadopa/carbidopa and useful for younger patients n Rasagiline possibly neuroprotective n Amantadine for dyskinesias n Anticholinergic agents for tremor-predominant disease in younger patients

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