Treatment of Parkinson s Disease and of Spasticity. Satpal Singh Pharmacology and Toxicology 3223 JSMBS

Transcription

1 Treatment of Parkinson s Disease and of Spasticity Satpal Singh Pharmacology and Toxicology 3223 JSMBS singhs@buffalo.edu

2 Disclosures NO SIGNIFICANT FINANCIAL, GENERAL, OR OBLIGATION INTERESTS TO REPORT 2

3 Parkinson s Disease 3

4 A Simplistic View of Neurotransmission Balance 4

5 Dopamine Restoration in the Brain Need to restore dopamine in the brain Blood brain barrier for dopamine Levodopa as a precursor to dopamine Decarboxylation to dopamine Use of Levodopa (L-dopa) Aromatic L-Amino Acid decarboxylase 5

6 Central Availability of Levodopa 6

7 Preservation of L-DOPA and Striatal Dopamine COMT: Catechol-O-methyltransferase AADC: Aromatic L-amino acid decarboxylase DOPAC: 3,4- dihydroxyphenylacetic acid 3MT: 3-methoxyltyramine 3-O-MD: 3-O-methyl DOPA DA: Dopamine MAO-B: Monoamine oxidase-b 7

8 Dopaminergic Agonists Dopaminergic agonists - pramipexole (Mirapex), ropinirole (Requip) Bind to dopamine receptors D2 (and D3, D4) and mimic dopamine action 8

9 COMT Inhibitors Inhibition of dopamine degradation via COMT Entacapone: can not cross BBB Tolcapone: can cross into the CNS 9

10 Monoamine Oxidase Inhibitors Inhibition of dopamine breakdown by MAO Non-selective inhibition of MAO Selegiline (Eldepryl) Tyramine related hypertensive crisis Selective inhibition of MAO-B Rasagiline (Azilect): MAO-B present predominantly in the striatum 10

11 Amantadine An antiviral agent Increases dopamine release in the striatum Possible dopamine agonist and/or reuptake inhibitor Anticholinergic properties Initial therapy during mild symptoms Adjunct with Levodopa: dose-related fluctuations; dyskinesias 11

12 Anticholinergic Drugs Restore dopaminergic/cholinergic balance Benztropine (Cogentin) Trihexylphenidyl (Artane) Diphenhydramine (Benadryl) Younger patients to treat tremors 12

13 Treatment Approach Combination therapy with levodopa/carbidopa Dopamine agonists for younger patients and/or to address wearing off effect COMT inhibitors to address the wearing off effect Amantadine during initial stages, and as adjunct with levodopa/carbidopa for dyskinesias Selective MAO-B inhibitors possibly neuroprotective Anticholinergic agents for younger patients to address tremors 13

14 Parkinson s Disease Drugs A 67-year-old man arrives at the physician s office complaining of tremor. On further questioning, he states that his hands shake when he lays them on the table. The shaking subsides when he moves his hands around. He also reports feeling clumsy and unbalanced. Based on his symptoms, the physician prescribes a medication that was once also used as an antiviral agent. Which of the following is the presumed mechanism of action of this medication? Blocks β-adrenergic receptors Serves as precursor to dopamine Prevents serotonin reuptake Promotes dopamine release Inhibits dopamine metabolism Inhibits muscarinic receptors 14

15 Basal Ganglia and Parkinsonism An 80-year-old man presents to the clinic with unsteady gait, trouble smiling, and a rhythmic tremor of his right hand while it is resting on his lap. His disorder is characterized by markedly decreased availability of a certain neurotransmitter. The postsynaptic receptors for this neurotransmitter are located in what basal ganglia structure? Globus pallidus Striatum Substantia nigra Subthalamic nucleus Thalamus 15

16 Amantadine An 55-year-old man comes to the clinic complaining of tremors of his hand at rest. He reports that his mother had similar symptoms and eventually developed a slow gait, dementia, and impaired swallowing. On physical examination, he has a fine resting tremor in his right hand and resistance to arm flexion. His gait, mental status, and cranial nerve examination are normal. He is prescribed a medication to reduce his symptoms. Several weeks later he presents for follow-up, and although his tremor is reduced, he complains of a lace-like purplish discoloration of the skin over his arms, shoulders, and legs. Which of the following medications was he most likely prescribed? Amantadine Bromocriptine Levodopa Carbidopa Benztropine 16

17 Spasticity: Treatment rationale Upper motor neuron lesion leading to muscle activation Reduce neuronal activity Baclofen Tizanidine Cyclobenzaprine Benzodiazepines Reduce muscle response Dantrolene Neuromuscular transmission Botulinum toxin 17

18 Spasticity: Mechanistic Pathways Baclofen, Tizanidine, Benzodiazepines, Dantrolene 18

19 Spasticity: Mechanistic Pathways Reuptake Inhibition by Cyclobenzaprine 19

20 Spasticity: Mechanistic Pathways Dantrolene, Botulinum Toxin 20