Drugs for Parkinson’s

Question 1

what are the adverse effects of levodopa?

Answer 1

N/V, arrhythmias, hypotension, dyskinesias, behavior disturbances

after several years: wearing off reactions or on-off phenomenon

Question 2

levodopa is contraindicated with ______ inhibitors, as well as Vitamin _____

Answer 2

levodopa is contraindicated with nonspecific MAO inhibitors - cause hypertensive crisis

as well as Vitamin B6 (pyridoxine) - enhances extracerebral metabolism of levodopa

Question 3

describe the pharmacokinetics of levodopa

Answer 3

oral, plasma t1/2 is 1-3 hours; can also be used as duodenum infusion

metabolized mostly by L-AAD (L-aromatic amino acid decarboxylase) and COMT

absorbed from small intestine/transported by active transport, competitive with aromatic amino acids (high protein meal may reduce peak plasma concentration)

Question 4

name an inhibitor of peripheral L-AAD, an inhibitor of central COMT, and an inhibitor of peripheral [only] COMT used in combination with levodopa to reduce its metabolism

(so 3 drugs total)

Answer 4

carbidopa: inhibits peripheral L-AAD (L-aromatic amino acid decarboxylase)

tolcapone: inhibits peripheral + central COMT (catechol-O-methyltransferase)

entacapone: inhibits peripheral only COMT

Question 5

describe the pharmacokinetics of tolcapone vs entacapone

which is preferred?

Answer 5

tolcapone = peripheral + central COMT; oral, plasma t1/2 2-3 hours, metabolized by glucuronidation… note some hepatotoxicity

entacapone = peripheral COMT; oral, plasma t1/2 1-2 hours, metabolized by glucuronidation

however, entacapone is preferred due to no incidence of hepatotoxicity

Question 6

to which dopamine receptors do the following agonists bind?
a. bromocriptine
b. pramipexole
c. ropinirole
d. rotigotine

how are they used?

Answer 6

bromocriptine: D2
ropinirole: D2

pramipexole: D3
rotigotine: D3 (not very selective)

all used as monotherapy in patients with mild Parkinson’s, or as adjunct to levodopa in patients with advanced disease

Question 7

which of the following dopamine agonists is an ergot derivative? what is the clinical significance of this?
a. ropinirole
b. bromocriptine
c. rotigotine
d. pramipexole

Answer 7

b. bromocriptine: binds D2, ergot derivative (contains lysergic acid moiety)

because of this, behavioral disturbances (hallucinations, confusion) are more severe

also, unique side effects (ergot causes vasoconstriction): fibrosis, erythromelalgia, digital vasospasm

therefore, rarely used

Question 8

which of the following dopamine agonists is metabolized by CYP1A2 in the liver?
a. ropinirole
b. bromocriptine
c. rotigotine
d. pramipexole

Answer 8

a. ropinirole: binds D2

therefore, other drugs that are also metabolized by CYP1A2 in the liver may reduce clearance

Question 9

which of the following dopamine agonists undergoes renal clearance?
a. ropinirole
b. bromocriptine
c. rotigotine
d. pramipexole

Answer 9

d. pramipexole: binds D3, excreted largely unchanged by renal clearance

all others are primarily metabolized by liver

Question 10

sort the following dopamine agonists by increasing half life:
a. ropinirole
b. bromocriptine
c. rotigotine
d. pramipexole

Answer 10

1. bromocriptine: 3-7 hours
2. ropinirole: 6 hours
3. pramipexole: 8 hours, renal clearance
4. rotigotine: once-daily transdermal patch

Question 11

what is the MAO and clinical use of apomorphine?

Answer 11

dopamine agonist at D2/3/4/5, nonergot

used as rescue treatment in levodopa-induced “off” akinesia episodes in patients with advanced Parkinson’s

subcutaneous injection, effects within 10 mins

Question 12

dopamine agonist used as rescue treatment in levodopa-induced “off” akinesia episodes in patients with advanced Parkinson’s

Answer 12

apomorphine: dopamine agonist at D2/3/4/5, nonergot

subcutaneous injection, effects within 10 mins

Question 13

with what class of drugs is apomorphine contraindicated? why?

Answer 13

dopamine agonist used as rescue treatment in levodopa-induced “off” akinesia episodes

contraindicated with antiemetics of 5HT3 serotonin receptor class —> causes severe hypotension and loss of consciousness

Question 14

what is the MAO and clinical use of rasagiline and selegiline?

Answer 14

irreversible MAO-B (monoamine oxidase B) inhibitors used to treat Parkinson’s - monotherapy if mild, adjunct if advanced

both taken orally (t1/2 2-3 hours) and metabolized in liver

Question 15

what additional side effects can be caused by selegiline as compared to rasagiline and why?

Answer 15

both MAO-B inhibitors used to treat Parkinson’s

selegiline can cause insomnia and anxiety because it’s metabolites include amphetamine and methamphetamine

Question 16

what kind of drugs are trihexyphenidyl, benzotropine, biperiden, orphenadrine, and procyclidine?

Answer 16

anti-cholinergic (antagonists at M receptors)

can be used to improve tremor and rigidity of Parkinson’s

side effects are what you would expect - sedation, mydriasis, urinary retention, constipation, confusion, dry mouth

Question 17

what symptoms of Parkinson’s are anti-cholinergics such as trihexyphenidyl, benzotropine, biperiden, orphenadrine, and procyclidine best at treating?

Answer 17

may improve tremor and rigidity; little effect on bradykinesia

can be used as monotherapy in mild disease or adjunct in advanced if tremor/rigidity are predominant symptoms

Question 18

name an anti-viral agent that is used to treat Parkinson’s

Answer 18

amantadine: helps ameliorate symptoms of PD, also has anti-dyskinetic properties

taken orally (t1/2 ~10 hours), renal clearance

may cause restlessness, hallucinations, confusion, sleep disturbances, N/V, seizures, heart failure

Question 19

what adverse effects occur if levodopa is given without carbidopa? why?

Answer 19

anorexia, N/V - due to stimulation of emetic center in brain stem outside of BBB