parkinsons pharm

Question 1

1. Know neurochemistry of Parkinson’s Disease.

Answer 1

Destruction of the dopamine cells in the pars compacta of the substantia nigra and loss of the neurotransmitter dopamine in the caudate and putamen

Question 2

risks for developing parkinsons

Answer 2

Drinking well water, working with pesticides, working in plants with metals like copper and iron

Question 3

metabolism of dopamine

Answer 3

Synthesis: Tyrosine >(tyrosine hydroxylase) > L-dopa > (dopa decarboxylase) > dopamine. Breakdown: Dopamine > (MAO) > Dopac > (COMT) > HVA

Question 4

L dopa pharmacokinetcs

Answer 4

absorbed orally, crosses BBB and is converted in brain to dopamine by L-amino acid decarboxylase found in surviving dopaminergic nerve terminals. 95% is decarboxylated in intestine, liver and peripheral organs, so large doses required

Question 5

L-dopa side effects

Answer 5

nausea, hypotension, depression, psychosis, drug induced dyskinesias (long term)

Question 6

A. L-DOPA and Carbidopa - MOA, half life, side effects.

Answer 6

(Sinemet)- Carbidopa blocks decarboxylase in intestines and peripheral organs, but does not cross BBB. Reduces L-dopa requrements by 90%. Half life of one hour. Short-term toxicity is mostly gastrointestinal; after several years, dyskinesia at peak blood levels and psychosis are common side effects which limit therapeutic effectiveness

Question 7

Function of dopamine receptor agonists

Answer 7

Directly stimulate the dopamine receptors in the
caudate/putamen. The drugs are usually not a substitute for Sinemet. Most of the available drugs work at the dopamine D2 receptor. Are usually given to smooth the short half-life of LDOPA. Some neurologists start treatment with a dopamine agonist rather than L-DOPA because there is less risk of dyskinesia. Ultimately, nearly all patients require L-DOPA.Directly stimulate the dopamine receptors in the
caudate/putamen. The drugs are usually not a substitute for Sinemet. Most of the available drugs work at the dopamine D2 receptor. Are usually given to smooth the short half-life of LDOPA. Some neurologists start treatment with a dopamine agonist rather than L-DOPA because there is less risk of dyskinesia. Ultimately, nearly all patients require L-DOPA.

Question 8

List dopamine receptor agonists

Answer 8

a. Bromocriptine (Parlodel) b. Pergolide (Permax) c. Pramipexole (Mirapex), D2 + D3 agonist d. Ropinirole (Requip), D2 agonist e. Cabergoline (Dostinex), D2 agonist, very long half-life, approximately 65 hours.

Question 9

dopamine receptor agonists side effects

Answer 9

nausea, hallucinations, sudden onset of sleep, Pergolide (cardiac valve thickening)

Question 10

G. Amantadine (Symmetryl)- MOA

Answer 10

Facilitates release of endogenous dopamine and acts as glutamate antagonist

Question 11

Anticholinergic drugs- MOA, effectiveness

Answer 11

Less effective than L-DOPA. Sometimes used for initial therapy of tremor. Parkinson’s results in less dopaminergic neurotransmission in caudate and putamen. Since dopamine is inhibitory to cholinergic interneurons, cholinergic neurons discharge faster and release too much acetylcholine onto medium spiny neurons which project to the globus pallidus. The anticholinergics used for Parkinson’s block muscarinic receptors.

Question 12

anticholinergics side effects

Answer 12

Reflect block of peripheral parasympathetic activity including dry mouth, constipation, and urinary retention.

Question 13

H. Trihexyphenidyl (Artane)

Answer 13

anticholinergic

Question 14

I. Benztropine (Cogentin)

Answer 14

anticholinergic

Question 15

J. Diphenhydramine (Benadryl)

Answer 15

anticholinergic

Question 16

Monoamine oxidase inhibitors -MOA

Answer 16

Prevent breakdown of dopamine, prolonging action of dopamine produced from L-dopa.

Question 17

Monoamine oxidase inhibitors- types and side effects

Answer 17

MAO-A inhibitors can cause dangerous episodes of hypertension after release of norepinephrine from
sympathetic nerve terminals. MAO-B inhibitors like have been found to be safer for treatment of Parkinson’s disease. Side effects include worsening of postural hypotension.

Question 18

K. Selegiline (Eldepryl)

Answer 18

MAOI

Question 19

How should the dose of sinemet be changed if taking a MAOI

Answer 19

reduce dose of sinemet by 20-30%

Question 20

MPTP and MAOIs

Answer 20

MPTP is metabolized to highly toxic compound by MAO-B and is selectively taken up in dopaminergic neurons causing cell death. Selegiline blocks this oxidation and prevents toxicity

Question 21

L. Tolcapone (Tasmar)

Answer 21

Catechol-o-methyl transferase inhibitor. Inhbits liver enzymes and can cause liver toxicity

Question 22

M. Entacapone (Comtan)

Answer 22

Catechol-o-methyl transferase inhibitor

Question 23

COMT inhibitors- MAO

Answer 23

prevents breakdown of L-dopa and dopamine by COMT

Question 24

genes linked to familial parkinsons

Answer 24

alpha-synuclein (AD), Parkin (AR), UCH-L1(AD)

Question 25

How has L-dopa affected excess mortality

Answer 25

Excess mortality has dropped from 2.9 to 1.5 in 10 years since L-dopa use

Question 26

drugs that may prevent progression of parkinsons

Answer 26

Co-enzyme Q-10 (1200mg/day) is in study, creatine, caffeine and adenosine A2 antagonists are being tested, minocyline and Vitamin E failed testing

Question 27

How many years does it take for any surgical therapy to be cost effective

Answer 27

1-3 yrs