Pharmacologic Management of Parkinsonism & Other Movement Disorders, Chapter 28

1. Pharmacologic Management of Parkinsonism & Other Movement Disorders, Chapter 28 OBJECTIVES Describe the neurochemical imbalance underlying the symptoms of Parkinson's disease. 2. Identify the mechanisms by which levodopa, dopamine receptor agonists, selegiline, and muscarinic blocking drugs alleviate parkinsonism. 3. Describe the therapeutic and toxic effects of the major antiparkinsonism agents. 4. Identify the compounds that inhibit dopa decarboxylase and catechol-O-methyltransferase and describe their use in parkinsonism. 5. Identify the chemical agents and drugs that cause parkinsonism symptoms. 6. Identify the drugs used in management of tremor, Huntington's disease, and drug-induced dyskinesias.

2. Parkinson’s disease (bradykinesia, akinesia, rigidity, tremor, postural disturbances) Huntington’s disease (hyperkinesia)

3. Parkinson’s disease • Parkinson’s disease results from the degeneration of dopaminergic neurons in the substantia nigra • These neurons project to other structures in the basal ganglia • The basal ganglia includes the striatum, substantia nigra, globus pallidus and subthalmus

4. Parkinson’s disease • Parkinson’s disease is characterized by resting tremor, rigidity, akinesia (difficulty in initiation of movement) and bradykinesia (slowness in the execution of movement). • These symptoms are due to loss of function of the basal ganglia which is involved in the coordination of body movement.

5. Hoehn and Yahr Staging of Parkinson's Disease • Stage 1: Mild signs and symptoms on one side only, not disabling but friends notice. • Stage 2: Symptoms are bilateral, minimal disability, posture and gait affected • Stage 3: Significant slowing, dysfunction that is moderately severe • Stage 4: Severe symptoms, walking limited, rigidity, bradykinesia, unable to live alone • Stage 5: Cachectic, complete invalidism, unable to stand, walk, require nursing care

6. Parkinson’s disease • Loss of dopaminergic neurons in the substantia nigra lead to decreased activity in the direct pathway and increased activity in the indirect pathway. • As a result, thalamic input to the motor area of the cortex is reduced and the patient exhibits rigidity and bradykinesia.

8. Treatments of PD • Drugs that increase dopamine levels • Dopamine receptor agonists • Acetylcholine receptor antagonists

11. Drugs that increase dopamine levels • Levodopa is the biosynthetic precursor of dopamine. L-dopa can cross the blood-brain barrier • Dietary amino acids compete with L-dopa for transport • Large first pass effect before L-dopa reaches target in CNS due to metabolism in peripheral tissues by LAAD and COMT

12. L-dopa • L-dopa taken up by dopaminergic neurons in the substantia nigra and converted to dopamine by L-Amino Acid Decarboxylase (LAAD) • As the disease progresses, more dopaminergic neurons are lost and the effectiveness of L-dopa as a replacement therapy declines.

13. Substantia Nigra Neuron • Pump that transport large neutral amino acids • L-aromatic amino acid decarboxylase (LAAD) • Catechol-O-methyltransferase (COMT) • Monoamine oxidase type-B (MAO-B)

14. Carbidopa • Analog of L-dopa • Inhibits the conversion of L-dopa to dopamine by LAAD in peripheral tissues • Carbidopa is highly ionized at physiological pH and does not cross the blood-brain barrier • Combination therapies of L-dopa and carbidopa allow for a reduction in the amount of L-dopa needed

16. Adverse Effects of L-dopa • Nausea, orthostatic hypotension and cardiac arrhythmias can occur • These effects due to the formation of dopamine in peripheral tissues • Carbidopa blocks formation of dopamine in the periphery and can reduce adverse effects

17. Adverse Effects of L-dopa • Long-term use of L-dopa can lead to the development of involuntary movement of dyskinesia • L-dopa can cause psychotic effects due to excess of dopamine in the mesolimbic and mesocortical pathways

18. L-dopa drug interactions • Anticholinergic drugs may block absorption of L-dopa • Drugs that increase gastric emptying may increase L-dopa bioavailability • MAO inhibitors may slow metabolism of dopamine and cause a hypertensive crisis in PD patients taking L-dopa • Antipsychotics may block dopamine receptors and exacerbate motor dysfunction

19. Parkinson’s disease • Cholinergic neurons also participate in the interconnections between the nuclei of the basal ganglia • Loss of dopaminergic neurons in the substantia nigra leads to excessive cholinergic activity in these pathways.

20. Dopamine Receptor Agonists • Directly activate dopamine receptors in the striatum • Do not require a functional dopaminergic neuron and may be most useful in advanced PD when the majority of dopaminergic neurons are lost • Activation of D2 receptors leads to inhibition of the indirect pathway and increases thalamic stimulation of the motor areas of the cortex

21. Amantadine • Antiviral agent • Increases the release of dopamine from the nigrostriatal neurons (probably) or inhibits the reuptake of dopamine by these neurons • Better tolerated but less effective than L-dopa

22. Tolcapone • Inhibits COMT • Increases oral bioavailability and half-life of L-dopa • 3OMD competes with L-dopa for transport across the blood-brain barrier and may contribute to the “wearing off” and“on-off” effects seen in patients taking L-dopa

23. Drug-induced parkinsonism Antipsychotics (haloperidol, phenothiazines) block D2 dopamine receptors MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

24. Surgical procedures Pallidotomy (lesion) Deep brain stimulation (subthalamic nucleus, globus pallidus internus) Neural transplantation

25.   X

26. Huntington’s disease • Characterized by loss of GABAergic medium spiny projection neurons in the striatum • Caused by glutamate-induced neurotoxicity (?) • Loss of GABAergic neurons that project of GP leads to disinhibition of thalamic nuclei and increase output to motor area of the cortex • Symptoms consistent with excess dopaminergic activity

27. Huntington’s disease • D2 receptor antagonist such as haloperidol and chlorpromazine have some effect at controlling the excess movement and some aspects of the psychiatric dysfunction • Diazepam potentiates GABA and may reduce excess movement but only in the early stages of the disease • Depression and impulsive behaviours may respond to antidepressant or propranolol (-adrenergic antagonist)