Parkinson's Disease

Question 1

Neuropathology of Parkinsons

Answer 1

• loss of dopaminergic (DA) neurons in the susbstantia nigra pars compacta (SNpc) in the basal ganglia
• accumulation of Lewy bodies, primary structural component of which is protein alpha-synuclein
• dopamine is progressively lost

Question 2

MPTP

Answer 2

• caused PD (environmental cause)

- oxidized to free radical

Question 3

PD Treatment

Answer 3

• exogenous dopamine precursor
• inhibitors of dopamine metabolism
• dopamine agonists
• increased dopamine release or re-uptake
• inhibit dopamine degredation
• ** dopamine can’t cross blood brain barrier ***

Question 4

Levodopa (L-Dopa)

Answer 4

• most effective agent for PD treatment
• Levodopa CAN cross blood brain barrier (unlike dopamine)
• ** L-Dopa -> Tyrosine -> Dopamine ***

Question 5

Levodopa Pharmacokinetics

Answer 5

• rate and extent of absorption dependent upon
• – rate of gastric emptying
• – time of exposure to degradative enzymes of gastric and intestinal mucosa
• ORAL*
• absorbed rapidly from small intestine by active transport
• peak plasma 1-2 hrs after oral dose
• t1/2 = 1-3 hours
• transported into brain by active transport system
• – competitive to other stuff

Question 6

Levodopa Metabolism in peripheral tissues

Answer 6

• by L-aromatic amino acid decarboxylase -> Dopamine
• ** BAD: does NOT enter CNS; can be used elsewhere***
• ** Inhibited by Carbidopa ***
• by catechol-O-methyltransferase -> 3-O-methyl-dopa
• – 15-hr t1/2
• – competes with levodopa for transport into brain
• ** if administered alone, only about 1-3% of dose enters CNS
• ** peripheral metabolism produces side effects

Question 7

Carbidopa

Answer 7

• L-aromatic amino acid decarboxylase inhibitor
• does not itself penetrate blood-brain barrier
• increases amount of Levadopa available to enter CNS
• allows REDUCED DOSAGE of levadopa which reduces peripheral side effects

Question 8

Sinemet

Answer 8

Levadopa + Carbidopa
fixed concentrations
1:4 and 1:10 where 1=25 mg

Question 9

Levadopa used alone

Answer 9

• very little enters CNS; many side effects due to peripheral metabolism

Question 10

Sinemet use results

Answer 10

• w/ carbidopa: less dopamine in pheriphery = decreased side effects
• more dopamine reaches CNS

Question 11

Adverse Effects of Levadopa Therapy

GI EFFECTS

Answer 11

• if given without carbidopa, 80% of patients experience
• – anorexia
• – nausea
• – vomiting
• stimulation of emetic center located in brain stem

** combination with carbidopa reduces side effects so 20% of patients **

Question 12

Adverse Effects of Levadopa Therapy

CARDIOVASCULAR EFFECTS

Answer 12

• Arrhythmias
• Postural hypotension
• Hypertension: if very high doses of levodopa is taken or if taken with MAO-A inhibitors
• together with MAO-A inhibitors may cause life threatening hypertensive crisis

Question 13

Low dopamine : __________

High dopamine: __________

Answer 13

Low dopamine = hypotension

High dopamine = hypertension

Question 14

Therapeutic/Adverse Effects of Levodopa Therapy

CNS

Answer 14

Desired: decrease in tremor, rigidity, bradykinesia

Undesired:

• abnormal involuntary movements (dyskinesias)
• psychological disturbances: confusion, hallucination, anxiety
• – conventional anti-psychotic agents are effective but worsen PD
• – “atypical” antipsychotics do NOT worsten symptoms and can be used

Question 15

Levadopa Drug Interactions

Answer 15

• Pyridoxine
• MAO-A ( or nonselective MAO ) inhibitors accentuate peripheral effects of catecholamines (can lead to hypertensive crisis)

Question 16

Levadopa Contraindications

Answer 16

• pyschotic patients
• angle-closure glaucoma
• active peptic ulcer must be managed carefully (GI bleeding)

Question 17

Long Term Effects of Levodopa Therapy

Answer 17

• Response fluctuations
• – 50% of patients after 5 years of therapy
• – 70% of patients after 15 years of therapy
• Honeymoon: symptoms completely disappear for a few years
• Endo-of-Dose: deterioration or wearing-off (predictable)
• On-off phenomenon (unpredictable)
• usually adjunctive therapy is required

Question 18

PD Increase side effects with long term use

Answer 18

• dyskinesias

- psychiatric disturbances

Question 19

Endo-of-Dose Deterioration

Answer 19

(predictable)

• nigrostriatal dopamine system still has ability to retain dopamine, so effects outlast drug lifetime
• eventually buffering capacity (ability to hold dopamine) is lost, and motor state fluctuates dramatically (wearing off phenomenon)
• each dose of Levadopa effectively improves mobility for 1-2 hours, but symptoms return rapidly at the end of the dosing interval

Question 20

On/Off Phenomenon

Answer 20

(unpredictable)

• patients fluctuate between having no apparent effects of medication (off) and having effects of medication (on)
• mechanism unknown
• for severe off-periods if not responding to other measures apomorphine can be used

Question 21

Apopmorphine

Answer 21

for severe off-periods if not responding to other measures apomorphine can be used

Question 22

Tolcapone

Answer 22

catechol-O-methyltransferase inhibitor
- central and peripheral effects
-increase bioavailability of levodopa
- lead to more steady levels of levodopa in peripheral tissues and allow reduction of levodopa use
- used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
* use only if patient is not responding to entacapone*
(can cause hepatotoxicity)

Question 23

Entacapone

Answer 23

catechol-O-methyltransferase inhibitor

• peripheral effects
• increase bioavailability of levodopa
• lead to more steady levels of levodopa in peripheral tissues and allow reduction of levodopa use
• used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 24

Stalevo

Answer 24

levodopa/carbidopa/entacapone

entacapone preferred over tolcapone because no incidence of hepatotoxicity

Question 25

Dopamine Agonists

Answer 25

- directly effect dopamine receptors - less effective in decreasing symptoms - don't compete at brain blood barrier - less incidence of side effects - longer t1/2 compared to levodopa - no potential toxic metabolites

Question 26

Why decreased side effects with dopamine agonists

Answer 26

can target specific receptors; different dopamine receptors are expressed in different areas of the brain

Question 27

Dopamine Agonist types

Answer 27

- Ergot derivatives | - Non-ergot derivatives

Question 28

Bromocriptine

Answer 28

dopamine agonist; ergot derivative - well absorbed orally - plasma t1/2 of 3-7 hours - used as monotherapy in patients with mild-disease - used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 29

Ropinirole

Answer 29

dopamine agonist; non-ergot derivative - metabolized by CYP1A2; drugs metabolized by liver may significantly reduce clearance - used as monotherapy in patients with mild disease - used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 30

Pramipexole

Answer 30

dopamine agonist; non-ergot derivative - excreted largely unchanged in urine - used as monotherapy in patients with mild disease - used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 31

Rotigotine

Answer 31

dopamine agonist; non-ergot agonist - administered as a once-daily transdermal PATCH allowing continuous absorption leading to less serum fluctuation as compared to oral administration several times a day

Question 32

Apomorphine

Answer 32

dopamine agonist - available as a subcutaneous injection to treat OFF episodes in patients with advanced PD - is RAPIDLY TAKEN UP in the brain, leading to quick clinical benefit

Question 33

MAO-B

Answer 33

- metabolizes dopamine selectively; is mostly found in CNS | * ** want to selectively target B to target dopamine in CNS system ONLY! ***

Question 34

MAO-A

Answer 34

- metabolizes norepinephrine, serotonin, and dopamine; in addition to CNS, also found in live and GI tract

Question 35

MAO-B Inhibitors

Answer 35

Selectively target MAO-B

Question 36

Selegiline

Answer 36

MAO-B Inhibitor - selective irreversible MAO-B inhibitor (AT HIGH DOSES INHIBITS A AS WELL) - decreases breakdown of dopamine - used as monotherapy in patients with mild disease - used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 37

Rasagiline

Answer 37

MAO-B Inhibitor - selective irreversible MAO-B inhibitor (MORE SLECTIVE than Selegiline) (at higher doses does still inhibit MAO-A) - decreases breakdown of dopamine - does not produce amphetamine metabolites - used as monotherapy in patients with mild disease - used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations

Question 38

Which MAO-B Inhibitor is more effective | Selegiline or Rasagiline?

Answer 38

Rasagiline: more selective

Question 39

What is unique about Rasagiline/Selegiline

Answer 39

POSSIBLE MECHANISM OF NEUROPROTECTIVE EFFECT - decrease synthesis of toxic metabolites - neuroprotection by reducing oxidation of dopamine

Question 40

Anti-Cholinergics | dNtK specific names

Answer 40

- intentionally causes acetylcholine pathway to deteriorate - reduce acetylcholine signaling, thus somewhat restoring the balance between dopamine and acetylcholine - may improve tremor and rigidity - little effect on bradykinesia - if fail to respond to one drug try another (trial and error to figure out which respond best to)

Question 41

Amantadine

Answer 41

antiviral agent - mechanism is unclear - benefits short-lived - -- may favorably influence bradykinesia, rigidity, and tremor - -- antidyskinetic properties - used as monotherapy in mild cases or adjunct