Parkinson's Medications Flashcards
1
Q
Parkinson’s Disease
Overview
A
A disease of the extra-pyramidal motor system in the brain ⇒ coordinates motor movements, particularly fine motor movements
Caused by a loss of dopaminergic neurons in the substantia nigra
Characteristics:
- Chronic, progressive
- Begins in middle/late life → progressive disability
- Affects all ethnic groups
- Equal gender distribution
- Age group
- 65-74 years of age: 15%
- > 85 years: > 50%
2
Q
Basal Ganglia
Direct Pathway
A
3
Q
Basal Ganglia
Indirect Pathway
A
4
Q
Basal Ganglia
Dopamine Effects
A
5
Q
Dopamine Receptors
A
6
Q
Parkinson’s
Neuroanatomical Correlates
A
- Characterized by a progressive degeneration of the nigrostriatal pathway
- Early in the disease ⇒ remaining neurons fire faster, ↑ receptor density on post-synaptic striatal tissue
- When sx evident ⇒ almost 80% depletion of dopamine in the target area
- Loss of striatal dopamine ⇒ ∆ activity of internal globus pallidus → projections to thalamus → projections to cortex ⇒ controls movement
- Activity influenced by the direct pathway (enables movement) or the indirect pathway (inhibits movement)
- Dopamine stimulates the direct pathway and inhibits the indirect pathway
- Together these pathways result in purposeful movement
7
Q
Parkinson’s Disease
Causes
A
- Most cases are idiopathic
- ? Environmental toxins related to free radicals
-
Carbon monoxide, manganese, or oxidative damage
- MPTP drug destroys dopaminergic neurons ⇒ Parkinson-like sx
- Paraquat (insecticide) ⇒ same effect as MPTP
- MPTP → MPP+ by monoamine oxidase
- MPP+ taken up by nerve terminals through dopamine reuptake system
- ⊗ Complex I of ETC ⇒ ⊗ oxidative phosphorylation ⇒ ↑ oxidative stress/free radicals ⇒ death of neurons in nigrostriatal pathway
- MPTP drug destroys dopaminergic neurons ⇒ Parkinson-like sx
- Antipsychotic drugs ⇒ reversible form of Parkinsonism
- Genetic: mutation of α-synuclein and parkin, among others
8
Q
Parkinson’s Disease
Clinical Manifestations
A
-
Resting tremor
- Fine persistent involuntary tremor, particularly in the hands, fingers and feet
- One typical tremor is the “pill-rolling tremor”
-
Rigidity of the striated musculature due to ↑ muscle tone
- Plastic rigidity: move the afflicted limb into a new position where it will remain
-
Bradykinesia or akinesia
- Bradykinesia: slowed ability to initiate movement
- Akinesia: lack of ability to initiate movement
- Absence of facial expression, shuffling gait, drooling, toneless speech
- Difficulty in initiation of walking, small shuffling steps, no arm swing, stopping difficulty
- Cognitive defect similar to Alzheimer’s
- Depression
9
Q
Treatment Strategies
A
- Restore DA levels by administering precursors
- Replace DA by adding receptor agonists
- Dopamine releasing agents
- Anticholinergics
- Stabilize DA w/ monoamine oxidase inhibitor
- Stabilize DA w/ COMT inhibitor
10
Q
Dopamine Precursors
A
L-DOPA/Carbidopa (Sinemet, Atamet)
- Goal to restore dopamine levels
-
L-DOPA crosses BBB (has both a ⊕ and ⊖ charge)
- Dopamine does not cross BBB
- L-DOPA → dopamine by neurons ⇒ stored in vesicles ⇒ released
- Severity of disease determines pt response
- Need neurons to convert L-DOPA to DA
- Improvement onset may take weeks, optimal benefit 1-2 months
- Order of sx improvement:
- Mood and vigor → bradykinesia and akinesia → tremor
11
Q
L-DOPA/Carbidopa
Indications
A
- Tolerable doses diminish with time
- Efficacy also diminishes with time
- L-DOPA is most effective at diminishing bradykinesia, but also improves other symptoms
12
Q
L-DOPA/Carbidopa
Pharmacokinetics
A
- L-DOPA is rapidly absorbed from the intestine
- Rate influenced by gastric emptying rate, local pH, food
- ~1-3% of L-DOPA reaches the brain; the rest is metabolized by DOPA decarboxylase
-
Co-admin w/ peripheral DOPA decarboxylase inhibitor (Carbidopa)
- ↑ plasma T½ ⇒ ↓ needed dose ⇒ ↓ adverse effects
13
Q
L-DOPA/Carbidopa
Adverse Effects
A
All patients will develop adverse effects
Short-term effects
-
Anorexia, nausea and vomiting (~20%)
- Caused by activation of chemoreceptor trigger zone in the medulla
- ↓ by giving the drug with or after meals or by dividing the dose
- Tolerance develops
-
Orthostatic hypotension
- Centrally mediated
- Tolerance develops
-
Tachycardia
- Due to dopa → NE
- Less prominent w/ Carbidopa
Long-term effects requiring alteration in dose
-
Dyskinesias (80%)
- Facial grimacing, restless feet syndrome, and stereotyped behavior
- Choreoform movements
- Titrate up dose
- May be fleeting or severely debilitating
-
No tolerance
- A previously tolerated dose of L-dopa can induce dyskinesias later
-
Psychiatric and behavioral side effects
- Nightmares or anxiety
- Paranoia, hallucinations and mania
- D/t overstimulation of dopamine receptors
- Reduction in dose can alleviate the problem
-
Aphrodisiac effect
- May be related to improved mood
- DA also involved in hypothalamic/pituitary function
-
Response fluctuations, on-off phenomena
- L-DOPA intake timing (wearing-off, end-of-dose akinesia)
- ↓ Therapeutic window and ↓ half-life of L-DOPA as disease progresses
- ↓ ability to store DA
- Manage w/ dopamine agonists, alteration of diet, or using slow-release L-DOPA
14
Q
L-DOPA/Carbidopa
Interactions and Contraindications
A
-
Drug Interactions:
- Combo w/ monoamine oxidase A inhibitors ⇒ hypertensive crisis
-
Contraindications:
- Psychotic patients
- Open-angle glaucoma
- Cardiac disease
- Peptic ulcer disease
- Hx of melanoma
15
Q
Sinemet CR (controlled release)
A
- Chronic L-DOPA use for many years ⇒ drug begins to wear off before the next dose
- Change to controlled release formulation
- Short-term release of DOPA improves motor symptoms in 30 min
- Controlled release provides DOPA over a prolonged period
- You may want to combine short acting and controlled release
19
Q
Non-Ergot
Dopamine Agonists
A
Pramipexole (D3>D2) and Ropinirole (D2, D3)
- More widely used than the ergots
- Provide greater relief with fewer adverse effects
- More likely to cause sudden sleep episodes
- Compulsive behavior
- Dyskinesia
- Hallucinations
- Cardiovascular side effects are less common, but hypotension does occur
20
Q
Dyskinesias
Effects of T½
A
Prolonged stimulation of dopamine receptors leads to fewer dyskinesias.
21
Q
Selegiline
MOA & Indications
A
-
Monoamine oxidase B inhibitor
- Retards the breakdown of dopamine
- Prolongs the effect of DOPA
- Currently used as an adjunctive therapy
- DOPA dose reduction
- Reduce mild on-off phenomena and wearing off phenomena
- Could enhance the adverse effects of L-DOPA
26
Q
Anticholinergics
MOA & Indications
A
-
Benztropine (Cogentin) or Trihexyphenidyl (Artane)
- Several drugs in this class
- If there is no response to one drug, switch to another
- Restores the dopamine and cholinergic balance within the striatum
-
Indications
- Improves rigidity/tremor
- Only a minor effect on bradykinesia
28
Q
Catechol-O-Methyltransferase (COMT) Inhibitors
MOA & Indications
A
Tolcapone (Tasmar) and Entacapone (Comtan)
-
MOA:
- ⊗ COMT which converts DOPA → 3-O-methyldopa and dopamine → 3-methoxytyramine
- These agents enhance delivery of L-DOPA to the brain and stabilize dopamine
-
Indications:
- ↑ Duration of effect of each L-DOPA dose, without ↑ the peak level of DOPA
- Never used alone
- They may be beneficial in treating ‘wearing-off” phenomena
