FOCUSSING ON TRIPPLE COMBINATION THERAPY FOR PARKINSONISM

2. • 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.
PARKINSON’S DISEASE

3. • 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).
PARKINSON’S DISEASE

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

5. • 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.
DOPAMINE/ACH
IMBALANCE IN STRIATUM

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

7. • 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.
PARKINSON’S DISEASE

8. • 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)
DRUG THERAPY FOR
PARKINSON’S DISEASE

9. • Levodopa (drug holidays recommended)
• Levodopa/carbidopa
• Dopamine agonists
• Pramipexole (Mirapex)
• Entacapone (Comtan)
• Amantadine (Symmetrel)
• Selegiline (Eldepryl, Carbex)
DRUG THERAPY FOR
PARKINSON’S DISEASE

10. • 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
DOPAMINERGIC AGENTS

11. • 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
DRUG SELECTION: INITIAL
TREATMENT

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

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

14. • 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.
LEVODOPA

15. 15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Mechanism of action
Levodopa is converted to dopamine via the action of a naturally occurring
enzyme called DOPA decarboxylase. This occurs both in the peripheral
circulation and in the central nervous system after levodopa has crossed the
blood brain barrier.
LEVODOPA

16. • 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
LEVODOPA

17. • 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)
CARBIDOPA

18. 18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
It works by being converted to dopamine in the brain. Carbidopa is in a class
of medications called decarboxylase inhibitors. It works by preventing
levodopa from being broken down before it reaches the brain. This allows for
a lower dose of levodopa, which causes less nausea and vomiting
CARBIDOPA

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

20. • 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
DOPAMINE AGONISTS

21. • 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
NONERGOT DOPAMINE
AGONISTS

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

23. • 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
ENTACAPONE

24. • 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
LEVODOPA/CARBIDOPA/ENTACA
PONE

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

26. • 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
SELEGILINE

27. • 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
NONMOTOR SYMPTOMS AND
THEIR MANAGEMENT

28. 28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
THANK YOU
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