Flashcards in parkinsons pharm Deck (27)
1. Know neurochemistry of Parkinson’s Disease.
Destruction of the dopamine cells in the pars compacta of the substantia nigra and loss of the neurotransmitter dopamine in the caudate and putamen
risks for developing parkinsons
Drinking well water, working with pesticides, working in plants with metals like copper and iron
metabolism of dopamine
Synthesis: Tyrosine >(tyrosine hydroxylase) > L-dopa > (dopa decarboxylase) > dopamine. Breakdown: Dopamine > (MAO) > Dopac > (COMT) > HVA
L dopa pharmacokinetcs
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
L-dopa side effects
nausea, hypotension, depression, psychosis, drug induced dyskinesias (long term)
A. L-DOPA and Carbidopa - MOA, half life, side effects.
(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
Function of dopamine receptor agonists
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.
List dopamine receptor agonists
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.
dopamine receptor agonists side effects
nausea, hallucinations, sudden onset of sleep, Pergolide (cardiac valve thickening)
G. Amantadine (Symmetryl)- MOA
Facilitates release of endogenous dopamine and acts as glutamate antagonist
Anticholinergic drugs- MOA, effectiveness
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.
anticholinergics side effects
Reflect block of peripheral parasympathetic activity including dry mouth, constipation, and urinary retention.
H. Trihexyphenidyl (Artane)
I. Benztropine (Cogentin)
J. Diphenhydramine (Benadryl)
Monoamine oxidase inhibitors -MOA
Prevent breakdown of dopamine, prolonging action of dopamine produced from L-dopa.
Monoamine oxidase inhibitors- types and side effects
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.
K. Selegiline (Eldepryl)
How should the dose of sinemet be changed if taking a MAOI
reduce dose of sinemet by 20-30%
MPTP and MAOIs
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
L. Tolcapone (Tasmar)
Catechol-o-methyl transferase inhibitor. Inhbits liver enzymes and can cause liver toxicity
M. Entacapone (Comtan)
Catechol-o-methyl transferase inhibitor
COMT inhibitors- MAO
prevents breakdown of L-dopa and dopamine by COMT
genes linked to familial parkinsons
alpha-synuclein (AD), Parkin (AR), UCH-L1(AD)
How has L-dopa affected excess mortality
Excess mortality has dropped from 2.9 to 1.5 in 10 years since L-dopa use
drugs that may prevent progression of parkinsons
Co-enzyme Q-10 (1200mg/day) is in study, creatine, caffeine and adenosine A2 antagonists are being tested, minocyline and Vitamin E failed testing