Parkinson's Tx (plus HD and ALS)

Question 1

Levodopa (L-DOPA)

Answer 1

• DA precursor –> rapidly converted to DA in plasma by peripheral AAD
• administer with Carbidopa
• adverse side effects: wearing off effect, dyskinesias, on-off phenomenon, hallucinations, NMS

Question 2

Dopamine

Answer 2

• doesnt cross BBB
• low doses causes othostatic hypotension, high doses can cause HTN + tachycardia (stimulation of alpha1 adrenergic receptor), N + V

Question 3

carbidopa

Answer 3

• AAD inhibitor (Aromatic AA Decarboxylase)
• given in combo with L-DOPA (prevents conversion in periphery so that L-DOPA can get to brain)
• wearing off effect, dyskinesias, on-off phenomenon, NMS upon withdrawal
• ** too much DA and PT looks hyperkinetic like Huntington’s (too much inhibition of BG –> BG can’t brake enough –> hyperkinetic)

Question 4

Bromocryptine

Answer 4

• ergot derivative
• D2 agonist, D1 antagonist
• must be titrated slowly due to acute hypotension
• peripheral DA-like side effects, can cause pleural effusions, cough, SOB, pulmonary fibrosis

think: old men are cryptic

Question 5

Pramipexole

Answer 5

• Non-ergot D2 receptor agonist (no D1 activity like ergot derivs)
• can cause compulsive/addictive behaviors (ie: gambling, sex)
• *DAR agonist of choice today along with Ropinorole

*think pramSEXipole

Question 6

Ropinorole

Answer 6

• non-ergot D2 receptor agonist (no D1 activity)
• can cause sudden daytime sleep attacks

Question 7

Rotigotine

Answer 7

non-ergot D2 agonist (no D1 activity)

transdermal patch (not in US)

**think goti= old man with a goatee that has Parkinson’s

Question 8

limitations of DAR therapy

Answer 8

• less effective at controlling motor symptoms
• more acute side effects (psychosis, nausea, fatigue, GI disturbances, edema, somnolence)

Question 9

apomorphine

Answer 9

• non-ergot DAR agonist
• rescue tx for sudden “off”times (frozen condition)
• more severe side effects: emesis, hypotension with 5-HT receptor antagonists

**morphine addict is rescued by morphine

Question 10

Entacapone and Tolcapone

Answer 10

• COMT inhibitors (primarly peripheral)
• adjunctive tx- used to tx motor fluctuations
• Entacapone well tolerated, short acting, given in combo with levidopa/carbidopa to prolong levodopa t1/2
• Tolcapone is more potent COMT inhibtors, fatal hepatotoxicity (use when unresponsive to entacapone)
• usual DA side effects also diarrhea and urine discoloration

**think entaCapOne and tolCapOne = COmt inhibs

Question 11

Selegiline and Rasagiline

Answer 11

• MAO-B inhibitors
• MAO-B converts DA to DOPAC in presynaptic terminal
• adjunctive tx to treat motor fluctuations

Question 12

anticholinergics

Answer 12

• benzotropine, trihexyphenadyl, ethopropazine, biperidine, procyclidine
• treat tremor and drool
• little effect on motor symptoms
• typical anticholinergics side effects + mental confusion, impaired memory, hallucinations —> contraindicated in PD with dementia

Question 13

amantadine

Answer 13

• Influenza A antiviral drug
• dopaminergic, anticholinergic and anti-NMDA activities
• most effective as adjunct to levodopa/carbidopa in long term tx bc it reduces dyskinesias associated with long-term levodopa tx
• also treats chorea in Huntington’s

Question 14

deep brain stimulation

Answer 14

• DBS of subthalamic nucleus
• used to tx dyskinesias and motor fluctuations
• PTs must still be responsive to levodopa/carbidopa tx!

Question 15

Huntington’s Disease

Answer 15

• autosomal dominant
• net effect is opposite of Parkison’s: decreased GABAergic inhibitory drive from BG onto VA/VL –> excitatory input to motor cortex –> excessive movement
• no tx to prevent disease progression
• tx psychosis with low dose antipsychotics
• tx movement disorder/chorea with tetrabenazine, amantadine, reserpine
• tx stress/anxiety with clonazepam (chorea increaseswith stress/anxiety)
• tx rigidity with antiseizure meds

Question 16

Amyotrophic Lateral Sclerosis

Answer 16

• 10% autosomal dominant inheritance
• 90% sporadic
• most prevalant mutations occur in SOD gene –> induces selective apoptosis of motor neurons
• only approved tx is riluzole (antag of glutamate receptors)
• spasticity (initial resistance to limb displacement then sudden relaxation) due to loss of higher order suppression of spinal reflexes
• tx spasticity with Baclofen (GABAb agonist) – avoid GABAa agonists that will further weaken respiratory mm

Question 17

Riluzole

Answer 17

• tx ALS
• reduces neuronal excitability
• rare hepatoxicity

Question 18

Baclofen

Answer 18

• treat ALS spasticity
• GABAb agonists–> avoid GABAa agonists (ie: benzos) that will further weaken resp mm

Question 19

mechanism of Parkinson’s

Answer 19

• loss of DA neurons in the SNpc (80%) —> no DA to the neostriatum –> no inhibitory output to the BG –> no inhibition of BG –> excessive inhibition of VA/VL (thalamus)

Question 20

choice of Tx for Parkinson

Answer 20

• early onset (<65 y/o) dopamine agonists (Ropinirole, Pramipexole)
• later onset (> 65 y/o) Carbidopa/Levidopa

Question 21

mechanism of Huntington

Answer 21

• decreased GABAergic inhibitory drive from BG to VA/VL of thalamus
• BG isn’t braking enough –> excessive movement

Question 22

Tx for Huntingtons

Answer 22

• none to deter disease progression
• depression: antidepressants
• paranoia,delusions,psychosis: haloperidol
• movement disorder: DA depleting drug (tetrabenazine or reserpine), amantadine
• antianxiety to prevent chorea from getting worse

Question 23

Peripheral Adverse Effects of L-DOPA/Carbidopa Tx

Answer 23

• anorexia, N+V
• orthostatic hypotension (vascular DA receptor action
• cardiac arrhythmia (alpha and beta-adrenergic receptor action)
• psychosis
• NMS upon withdrawal of DA agonist
• MAO-A inhibitors are contraindicated