Drugs for Parkinson's Disease

Question 1

What are the symptoms of Parkinson’s disease? (4 primary symptoms, 3 secondary symptoms)

Answer 1

• Loss of extrapyramidal movement control -
  (1) Bradykinesia
  (2) Resting tremor
  (3) Rigidity
  (4) Postural instability
  (5) Secondary symptoms include depression (~30%) dementia (~50%) and autonomic dysfunction

Question 2

What is Substantia Nigra (SN) in Parkinson’s disease? (Pathology and Etiology)

Answer 2

• Pathology:
  ~ Loss of 60-80% of dopamine neurons in SN;
  ~ Lewy inclusion body in neurons
• Etiology:
  ~ aging;
  ~ genetic origin (10-15% cases in 30’s and 40’s versus > 80% idiopathic in 60’s);
  ~ environmental toxins (MPTP; rotenone)

Question 3

T/F Dopamine crosses the blood brain barrier.

Answer 3

FALSE; does NOT

Question 4

What are the Pharmacologic Treatments of Parkinson’s disease?

Answer 4

(1) Restore dopaminergic function with Levodopa (L-DOPA)
(2) COMT inhibitors
(3) MAO-B blockers
(4) Dopamine receptor agonists
(5) Muscarinic receptor antagonists
(6) Amantadine

Question 5

Biosynthesis of Dopamine: What is the rate limiting step of dopamine?

Answer 5

Tyrosine hydroxylase (TH)

Question 6

T/F Tyrosine does not increase dopamine levels.

Answer 6

TRUE; because Tyrosine hydroxylase is saturated

Question 7

Biosynthesis of Dopamine: What are the 2 enzymatic pathways in which Dopamine metabolizes?

Answer 7

(1) Monoamine oxidase (MAO)

2) Catechol O-methyltransferase (COMT

Question 8

What is an important therapeutic consideration for L-DOPA?

Answer 8

When administered alone, the vast majority of L-DOPA is converted to dopamine by AAD in peripheral tissues before entering the brain. Therefore, L-DOPA is always administered together with CARBIDOPA, the AAD inhibitor that cannot cross the blood brain barrier.

Question 9

What does Carbidopa do? (2)

Answer 9

• permits more L-DOPA to enter the brain, where it can be decarboxylated to dopamine by brain AAD that is not inhibited by the drug.

(1) Increases the potency of L-DOPA
(2) Decreases the production of dopamine in peripheral tissues, reducing the peripheral side effects (nausea, vomiting, postural hypotension)

Question 10

What are major side effects of L-DOPA?

Answer 10

(1) Extrapyramidal dyskinesias
(2) Nausea and vomiting
(3) Postural hypotension
(4) Sleep disturbances

Question 11

What is the on-off phenomenon? What drug does this pertain to?

Answer 11

L-DOPA effectiveness is on-off

• dietary reason in part
• persistent loss of DA neurons

Question 12

How many patients respond to L-DOPA?

Answer 12

2/3; particularly effective against bradykinesia

Question 13

What happens to L-DOPA with high pyridoxine (vit B6) doses?

Answer 13

It activates peripheral AAD which decreases L-DOPA levels

Question 14

L-DOPA: Wearing off

Answer 14

~5 yr in use, L-DOPA loses its effectiveness; further loss of DA neurons and lack of new DA synthesis from L-DOPA

Question 15

What are the COMT inhibitors?

Answer 15

(1) Entacapone

(2) Tolcapone

Question 16

COMT inhibitors- Mechanism of Action

Answer 16

Inhibits L-DOPA metabolism in peripheral tissues and/or DA metabolism in the brain (striatum)

Question 17

T/F COMT inhibitors are never used with L-DOPA.

Answer 17

FALSE; they are always used with L-DOPA

Question 18

COMT inhibitors- Side effects

Answer 18

(1) Diarrhea

(2) Increased sensitivity to L-DOPA

Question 19

Where are Tolcapone and Entacapone inhibited (central, peripheral)?

Answer 19

• Tolcapone: central and peripheral COMT inhibition: hepatotoxicity
• Entacapone: peripheral COMT only, shorter duration

Question 20

What are the MAO-B blockers?

Answer 20

(1) Selegiline

(2) Rasagiline

Question 21

MAO-B blockers: Mechanism of Action

Answer 21

Blocking dopamine metabolism by inhibiting monoamine oxidase in the striatum

Question 22

MAO-B blockers: Drug interactions

Answer 22

(1) Contraindicated with meperidine or tricyclic antidepressants because of hyperthermic or hypertensive interactions
(2) Use with L-DOPA is complicated because of potential hypertension

Question 23

What enzyme preferentially metabolizes dopamine?

Answer 23

MAO-B

Question 24

What are the dopamine receptor agonists? What are their side effects?

Answer 24

(1) Older agonists: Bromocriptine
- mainly D2 agonist
- side effects: hypotension, nausea dyskinesia
(2) Newer agonists: Pramipexole & Ropinirole
- major side effects: (less severe than ergot derivatives) hypotension, nausea, dyskinesia, sleep disturbances, hallucination/confusion, risky behaviors

Question 25

Which Dopamine receptor agonist has a longer duration of action?

Answer 25

Pramipexole and Ropinirole

Question 26

What are the muscarinic receptor antagonists? What do they do?

Answer 26

(1) Benztropine
- Normally, dopamine released from nigrostriatal neurons activates D2 receptors on cholinergic neurons in the striatum and inhibits the release of acetylcholine

Question 27

T/F In Parkinson disease, reduced dopamine activity leads to cholinergic hyperactivity.

Answer 27

TRUE; this is why it can be counteracted with a muscarinic receptor antagonist.

Question 28

Benztropine: Side effects

Answer 28

Can cause the anti-parasympathetic side effects like other muscarinic blockers:

(1) dry mouth
(2) reduced sweating
(3) increased heart rate
etc. ..

Question 29

What is Benztropine especially effective against?

Answer 29

TREMOR

Question 30

What type of drug is Amantadine? Are the effects are pronounced as L-DOPA?

Answer 30

Antiviral agent (influenza) but also increases dopamine release- found by accident; No, only efficacious in about 50% of cases
- tolerance occurs within a few weeks-

Question 31

Amantadine- Side effects

Answer 31

Usually mild

(1) restlessness
(2) depression
(3) livedo reticularis (purplish, mottled skin discoloration)
(4) edema
(5) hypotension
(6) hallucinations