Antiparkinson Drugs

Question 1

What causes Parkinson’s disease?

Answer 1

Actual cause is unknown but there is a loss of neurons in the substantia nigra leading to decreased dopamine

Question 2

What aa is dopamine formed from? How is this precursor transported across the BBB to be used in dopamine synthesis in the brain?

Answer 2

Dopamine is formed from tyrosine which is transported by system L across the BBB in a sodium INdependent manner

Question 3

What is the rate limiting step in dopamine synthesis?

Answer 3

tyrosine hydroxylase

Question 4

Describe the actions of the two dopamine receptors in the brain: D1 and D2. Which one is most important in treatment of Parkinsons?

Answer 4

D1: increases adenylyl cyclase
D2: decreases adenylyl cyclase, inc K+ conductance, and decreases calcium conductance

(+) of D2 provides the majority of the benefits for antiparkinsonism, but D1 (+) is needed for maximal benefit

Question 5

Describe how loss of dopamine can lead to loss of control of motor movement in the nigrostriatal pathway

Answer 5

Dopaminergic neurons synapse on GABAergic neurons and usually inhibit GABAergic ouput (cholinergic neurons also synapse on the same GABA neurons and stimulate them). Loss of dopamine means loss of inhibition of the GABA neurons, and thus loss of control.

Question 6

What % of neurons must be destroyed in the substantia nigra for patients to present with symptoms of parkinsons? How many are destroyed as seen in autopsy?

Answer 6

70% for symptoms, 95% for death

Question 7

Based on the pathophys of Parkinsons, what are the basic ideas behind formulating a treatment?

Answer 7

can either increase dopamine and restore its inhibitory effects on the GABA neurons

OR

decrease the unopposed cholinergic stimulation to the GABA neurons (ie ACh antagonists)

Question 8

Name the two major mechanisms of action of the drugs used to treat Parkinson’s

Answer 8

Drugs that increase dopamine and antimuscarinics

Question 9

What drug can be used to treat Parkinson’s in the early stages of the disease and only provides relief while the drug is present in the body? why?

Answer 9

Levodopa

Precursor to dopamine and can only work while enough neurons are left to convert it to dopamine. Because it is a dopamine substitute, this is also why it only works while the drug is present.

Question 10

why does levodopa cause many peripheral side effects like nausea, vomiting, arrhythmias, and hypotension? What can be given to help lessen this and how does it work?

Answer 10

much of the drug is decarboxylated to dopamine in the periphery

Give Carbidopa - its a dopa decarboxylase inhibitor that doesnt cross the BBB (decreases peripheral decarboxylation of levodopa so more makes it to the CNS)

Question 11

where is the majority of levodopa decarboxylated?

Answer 11

70% in the GIT (40% when given with carbidopa)

Question 12

describe the on-off phenomenon in Parkinson’s treatment with levodopa - what drug can be given to help?

Answer 12

There are fluctuations in response unrelated to the timing of the doses (mechanism unknown) - can give Apomorphine SC

Question 13

What two groups of drugs should be avoided when treating with levodopa? why?

Answer 13

MAO inhibitors - hypertensive crisis

Antipsychotics - parkinsonian syndrome

Question 14

What condition is contraindicated for levodopa admin and what is another that needs to be carefully monitored?

Answer 14

Contraindicated in angle-closure glaucoma

Monitored in cardiac patients for arrhythmias

Question 15

What ergot dopamine agonist is used to treat Parkinsons and can cause pulmonary infiltrates and GI/cardio adverse effects? when should it be given?

Answer 15

Bromocriptine

only given to patients who respond to levodopa therapy (won’t work in patients not responding)

Question 16

Name two nonergot dopamine agonists use to treat Parkinson’s patients first line (even before levodopa) esp in younger patients

Answer 16

Pramipexole and Ropinirole

Question 17

what drug is only available to treat Parkinson’s in a transdermal patch?

Answer 17

Rotigotine

Question 18

What drug is used to treat “off” episodes in Parkinson’s treatment? What is the major side effect of this drug and how do you help it?

Answer 18

Apomorphine

Emetogenic - give antiemetic like trimethobenzamide

Question 19

Which MAO selectively metabolizes dopamine? which two drugs are used to irreversibly inhibit this enzyme in Parkinson’s treatment?

Answer 19

MAO-B

Selegiline and Rasagiline

Question 20

What does the ending -giline mean?

Answer 20

MAO inihibitor

Question 21

Which two enzymes catabolize both levodopa and dopamine?

Answer 21

MAO and COMT

Question 22

Which antiparkinson’s drug is associated with fulminating hepatic necrosis? MOA? what drug is preferred instead?

Answer 22

Tolcapone - hepatotoxic

Entacapone is less toxic, preferred

both COMT inhibitors

Question 23

what does the ending -capone mean?

Answer 23

COMT inhibitor

Question 24

which antiviral drug can be used to treat Parkinson’s and has fewer side effects than levodopa?

Answer 24

Amantadine

Question 25

Which antiparkinson’s drug is associated with livedo reticularis? (lace-like purplish discoloration of the skin) MOA?

Answer 25

Amantadine - antiviral

Question 26

what class of drug can be given improve tremor and reduce drooling in Parkinsons? Name two

Answer 26

antimuscarinics

Benztropine and Trihexyphenidyl

Question 27

What is the best combination treatment for Parkinson’s treatment?

Answer 27

levodopa + carbidopa

Question 28

What two types of drugs can be added to levodopa to reduce motor fluctuations in late stages of Parkinson’s?

Answer 28

COMT and MAO inhibitors