Chapter 21

1. Chapter 21 Drugs for Parkinson’s Disease

2. Parkinson’s Disease • Parkinson’s disease (PD) is a neurodegenerative disorder of the extrapyramidal system associated with disruption of neurotransmission in the striatum • Characterized by dyskinesias and akinesia • Proper function of the striatum requires a balance between the neurotransmitters dopamine and acetylcholine (ACh) • Imbalance between dopamine and ACh results from degeneration of the neurons that supply dopamine to the striatum.

3. Parkinson’s Disease • Affects more than 1 million Americans • Second only to Alzheimer’s disease as the most common degenerative disease of neurons • Symptoms generally appear in middle age and progress • No cure for motor symptoms • Drug therapy can maintain functional mobility for years (prolongs/improves quality of life).

4. Cardinal Symptoms of PD • Dyskinesias • Tremor at rest • Rigidity • Postural instability • Bradykinesia (slowed movement) • Tremor • In addition to motor symptoms • Autonomic disturbances • Depression • Psychosis and dementia

5. Dopamine/ACh Imbalance in Striatum • Imbalance results from degeneration of the neurons that supply dopamine to the striatum. • Without adequate dopamine, ACh causes excessive stimulation of GABA-releasing neurons. • Overactivity of GABA neurons contributes to the motor symptoms of PD. • Uncertain of cause of degeneration—may be alpha-synuclein.

6. Fig. 21-1. A model of neurotransmission in the healthy striatum and parkinsonian striatum.

7. Parkinson’s Disease • Therapeutic goals • Ideal treatment (reverse neuronal degeneration or prevent further degeneration) does not exist. • Goal is to improve patient’s ability to carry out activities of daily life. • Drug selection and dosages are determined by extent to which PD interferes with work, dressing, eating, bathing, and other activities of daily living.

8. Drug Therapy for Parkinson’s Disease • Two major categories • Dopaminergic agents • By far the most commonly used drugs for PD • Promote activation of dopamine receptors • Levodopa (Dopar) • Anticholinergic agents • Prevent activation of cholinergic receptors • Benztropine (Cogentin)

9. Drug Therapy for Parkinson’s Disease • Levodopa (drug holidays recommended) • Levodopa/carbidopa • Dopamine agonists • Pramipexole (Mirapex) • Entacapone (Comtan) • Amantadine (Symmetrel) • Selegiline (Eldepryl, Carbex)

10. Dopaminergic Agents • Mechanisms of action • Levodopa: promotes dopamine synthesis • Dopamine agonists: stimulate dopamine receptors directly • Selegiline: inhibits dopamine breakdown • Amantadine: promotes dopamine release • COMT inhibitors: enhance effects of levodopa by blocking its degradation

11. Drug Selection: Initial Treatment • Mild symptoms: MAO-B inhibitor • Selegiline or rasagiline • More severe symptoms: levodopa or a dopamine agonist • Levodopa more effective than dopamine agonists, but long-term use carries a higher risk for disabling dyskinesias • Management of motor fluctuations • “Off” times (can be reduced with dopamine agonists, COMT inhibitors, and MAO-B inhibitors) • Drug-induced dyskinesias

12. Fig. 21-2. Steps leading to alteration of CNS function by levodopa.

13. Fig. 21-3. Conversion of levodopa to dopamine.

14. Levodopa • Only given in combination with carbidopa or carbidopa/entacapone • Highly effective, but benefits diminish over time • Orally administered, rapid absorption from small intestine • Food delays absorption. • Neutral amino acids compete with levodopa for intestinal absorption and for transport across blood-brain barrier. • High-protein foods will reduce therapeutic effects.

15. Levodopa • Adverse effects • Nausea and vomiting • Dyskinesias • Cardiovascular effects • Psychosis • May darken sweat and urine • Can activate malignant melanoma • Drug holidays • Drug interactions: first-generation antipsychotics, MAOIs, anticholinergics, pyridoxine • Food interactions: protein and vitamins with pyridoxine

16. Carbidopa • Advantages • No adverse effects of its own • Increases available levodopa in the CNS and allows for 75% decrease in levodopa dosage; therefore, reduces cardiovascular and GI adverse effects • Effects come mainly from levodopa when given in combination. • Levodopa/carbidopa (Sinemet, Paracopa) • Carbidopa alone (Lodosyn)

17. Fig. 21-4. Fate of levodopa in the presence and absence of carbidopa.

18. Dopamine Agonists • First-line drugs for PD • Direct activation of dopamine receptors in striatum • Comparison with levodopa • Less effective than levodopa • Not dependent on enzymatic conversion to be active • Do not compete with dietary proteins • Lower incidence of response failure and less likely to cause dyskinesias • Two types of dopamine agonists • Derivatives of ergot • Nonergot derivatives

19. Nonergot Dopamine Agonists • Pramipexole (Mirapex) • Used alone in early PD and with levodopa in advancing PD • Maximal benefits take several weeks to develop. • Adverse effects • Monotherapy – nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations • Combined – orthostatic hypotension and dyskinesias and increase in hallucinations • Rare instances of pathologic gambling and other compulsive self-rewarding behaviors

20. COMT Inhibitors • Inhibit metabolism of levodopa in the periphery • No direct therapeutic effects of their own • Two COMT inhibitors available • Entacapone (safer and more effective) • Tolcapone

21. Entacapone • Selective, reversible inhibitor of COMT • Only for use with levodopa • Inhibits metabolism of levodopa in the intestines and peripheral tissues • Prolongs time that levodopa is available to the brain • Increases levodopa availability by inhibiting COMT, which decreases production of levodopa metabolites that compete with levodopa for transport • Adverse effects: from increasing levodopa levels

22. Levodopa/Carbidopa/Entacapone • Fixed-dose combinations sold as Stalevo • More convenient than taking separate doses • Costs a little less • Disadvantage • Available only in immediate-release tablets • Available in only three strengths

23. MAO-B Inhibitors • Considered second- and third-line drugs for treatment of PD • Combination with levodopa – can reduce the wearing-off effect • Selegiline

24. Selegiline (Eldepryl, Zelapar) • Monotherapy or used with levodopa • Modest improvement in motor function • Causes selective, irreversible inhibition of type B monoamine oxidase (MAO-B) • Can suppress destruction of dopamine derived from levodopa and prolong the effects of levodopa • Adverse effects • Monotherapy: insomnia • Drug interactions: levodopa

25. Nonmotor Symptoms and Their Management • 90% of patients develop nonmotor symptoms (autonomic disturbances, depression, dementia, and psychosis). • Depression • Amitriptyline: only effective drug • TCA • Anticholinergic effects that can exacerbate dementia • Antiadrenergic effects that can exacerbate hypotension