PD

Question 1

PD symptoms

Answer 1

resting tremor, rigidity, bradykinesia, impaired balance, mask-like appearance, speech difficulties, cognitive deficits*

Question 2

PD is characterized by…

Answer 2

• PD is characterized by a loss of dopaminergic neurons in the substantia nigra**: Gradual loss of darkly pigmented, dopamine-releasing neurons in the SN pars compacta in the midbrain
• presence of Lewy bodies in the various regions of the brain: Enriched with fibrillar forms of the protein α-synucelin, Aggregation of α-synuclein: Stage 1: Lower brainstem**, Stage 2: Raphe, Stage 3: SN (-> classic PD symptoms), Stage 4: mesocortex/thalamus, Stage 5: neocortex, Stage 6: entire neocortex

Question 3

Neurotoxic/ Neuroprotective mechanisms in PD

Answer 3

• Mitochrondria: electron chain dysfunction increase build up of ROS
• α-synuclein is oxidized and aggregates

Question 4

Midbrain

Answer 4

• SN pars compacta provides input to the basal ganglia and supplies dopamine
• Undergoes neurodegeneration in PD

Question 5

Basal Ganglia

Answer 5

• Striatum (caudate nucleus, putamen*)
• Globus pallidus (external and internal segments)
• Dopamine Signaling: Direct Pathway: involving D1 receptors in the striatum; Indirect Pathway: involving D2 receptors in the striatum; Effect of thalamocortical signaling is disrupted in PD**

Question 6

antimuscarinics

Answer 6

• adjunct therapy
• Loss of dopamine = increase in cholinergic activity** (sort of compensation)
• Cholinergic antagonists (antimuscarinic) can partially compensate for over activity

Question 7

LDOPA

Answer 7

• gold standard for PD therapy
• Precursor of dopamine, but needs to be converted in SN, not periphery
• L-DOPA crosses BBB, dopamine does not cross BBB
• Carbidopa is a peripherally acting DOPA decarboxylase inhibitor** to prevent conversion of L-DOPA -> dopamine in the periphery
• Carbidopa does not penetrate BBB, so does not inhibit conversion in SN
• Challenges: In PD there are less nigral dopaminergic neurons to convert L-DOPA to dopamine over time, Dyskinesias : aberrant and exaggerated motor effects, Address these challenges by using dopamine receptor analogs as a possible alternative

Question 8

DA receptor agonists

Answer 8

apomorphine, ergolines, nonergolines

Question 9

apomorphine

Answer 9

(mixed D1/D2 agonist): used in late-stage PD; use is limited due to N/V

Question 10

ergolines

Answer 10

bromocriptine, pergolide

• Bromocriptine: used as adjunct to L-DOPA to be able to lower dose
• Pergolide: very potent D2 agonist used to treat PD (no longer in US)

Question 11

nonergolines

Answer 11

ropinirole, pramipexole, rotigotine

• D2/D3 agonists with fewer side effects than ergolines
• Generally used as monotherapy for early-stage PD
• Rotigotine offered in a transdermal patch

Question 12

MAOB inhibitors

Answer 12

selegiline and rasagiline**

• These drugs inhibit the oxidation of dopamine to DOPAL by MAO-B
• Both drugs can initially be used to delay first use of L-DOPA or as adjuncts to L-DOPA

Question 13

dopamine metabolism inhibition

Answer 13

COMT inhibitors (entacapone, tolcapone)

• Inhibition of COMT by entacapone decreases metabolism of L-DOPA in the periphery, allowing more to reach the brain
• Tolcapone works in CNS to increase CNS levels of dopamine from L-DOPA
• Entacapone can increase duration of effect

Question 14

propargylamines

Answer 14

R2N-CH2-C—CH

Question 15

PD motor symptoms

Answer 15

tremor, bradykinesia, rigidity, Parkinsonian gait

Question 16

PD nonmotor symptoms

Answer 16

Anxiety, depression, constipation, dementia, insomnia, orthostatic hypotension, psychosis/delirium, sexual dysfunction

Question 17

non-pharmacological treatment

Answer 17

exercise/physical therapy, nutritional counseling, occupational therapy, psychotherapy, speech therapy, support groups

Question 18

pharmacological treatment

Answer 18

• 1st Line: Dopamine agonist, Dopamine precursor (L-DOPA)

- 2nd Line: MAO-B Inhibitor

Question 19

LDOPA

Answer 19

• Effective monotherapy for motor symptoms (gold standard); adjunctive treatment with DA agonists
• Side Effects: N/V, orthostatic hypotension, dyskinesias/motor fluctuations, hallucinations
• Clinical Pearls: on empty stomach if does not cause nausea; titrate up to balance efficacy and side effects

Question 20

dopamine agonists

Answer 20

• Non-Ergots (Pramipexole, Ropinirole, Rotigotine(patch)) are first line for initial therapy
• Effective monotherapy for motor symptoms**; adjunct with L-DOPA
• Side Effects: N/V, orthostatic hypotension, sudden onset sleep, hallucination, impulse control disorder (must switch to a different class)**
• Clinical Pearls: uptitrate dose to minimize side effects; potentially better for younger patients

Question 21

MAOB inhibitors

Answer 21

• Second line for initial PD therapy
• Managed L-DOPA motor fluctuations*
• Side Effects: H/V, HA, insomnia, hypotension/hypertension
• Clinical Pearls: delay need for CD/LD; Risk of serotonin syndrome with serotonin drugs (contraindicated with dextromethorphan, meperidine, methadone, tramadol)

Question 22

COMT inhibitors

Answer 22

entacapone

• Management of CD/LD induced motor fluctuations (i.e. will only be using if on L-DOPA)
• Side Effects: N/V, brown/orange urine discoloration, hepatotoxicity* (tolcapone limiting side effect*)
• **Early PD: no benefit of COMT inhibitors with CD/LD versus CD/LD monotherapy
• **Reserved for management of freezing seen with CD/LD

Question 23

amantadine

Answer 23

• Management of CD/LD induced motor fluctuations; effective for controlling motor symptoms (tremors)
• Side Effects: insomnia, confusion/hallucinations
• Clinical Pearls: utility limited due to cognitive side effects; usually reserved for tremors (monotherapy/CD-LD induced)

Question 24

anticholinergics

Answer 24

• Management of tremor***-predominant PD inpatients under 65 years old
• Side Effects: confusion, urinary retention, constipation, blurry vision, dry mouth
• Clinical Pearls: used in younger PD patients with tremor as primary symptom; avoid if >65 years old (would use Amantadine if >65 years old)

Question 25

management of motor fluctuations

Answer 25

- Wearing Off: Increase CD/LD dose; add DA agonist or MAO-B inhibitor; CR L-DOPA - Peak-dose dyskinesias: Decrease CD/LD dose; adjunct amantadine - Delayed onset: Take CD/LD on empty stomach; avoid CR CD/LD; ODT dosage form - Freezing: increase CD/LD dose frequency; add MAO-B inhibitor or COMT inhibitor

Question 26

treatment of nonmotor symptoms

Answer 26

- Constipation: increase fluids; stool softeners - Insomnia: non-pharmacological counseling; melatonin, non-benzo (e.g. zolpidem), AVOID benzos (Lorazepam, diazepam, oxazepam) - Orthostatic Hypotension: non-pharmacological counseling; medical equipment to stabilize patients - Anxiety/Depression: MAO-B inhibitor, SSRI, SNRI - Dementia: AVOID anti-cholinergics, benzos, antihistamines, sedatives; could try cholinesterase inhibitors (donepezil, rivastigmine) - Psychosis/Delirium: Reduce PD doses, Preferred anti-psychotics: quetiapine, clozapine,AVOID: haloperidol, olanzapine, paliperidone, risperidone