Anti-migraine Drugs Courtney Geiger Medicinal Chemistry Dr. Buynak November 18, 2004.
Treatment of Parkinson’s Disease Christopher Buchanan CHEM 5398/Buynak April 3, 2007.
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Transcript of Treatment of Parkinson’s Disease Christopher Buchanan CHEM 5398/Buynak April 3, 2007.
Parkinson’s Disease Overview
• Prevalence: 0.3% of U.S. Population– Increases to 4-5% for those 85 years
old and older
• Dopaminergic degeneration in the substantia nigra– in the deep gray matter of the brain– Basal ganglia produce less dopamine
Parkinson’s Overview (cont’d)
• Symptoms:– Bradykinesia (slowed movements)– Resting tremor– Rigidity
• Other Neurotransmitters are affected– Non-Adrenergic, Serotinergic, and Cholinergic
neurons are lost– Results in: cognitive decline, sleep
abnormalities, depression, gastrointestinal and genitourinary problems
– Usually Seen in Later Stages of Parkinson’s
Therapy
• Therapy should begin when normal functions are impaired to due to symptoms (i.e. limits daily activities)– Therapy must be individualized based
on progression and time of onset
• Therapies vary depending on age of onset, progression of symptoms, and side-effects of drugs
Medicinal Therapy
• Levadopa (L-DOPA)– Still the preferred medication to control
Motor symptoms– Used in combination with Carbidopa to
prevent premature decarboxylation• Drug: Sinemet
HO
HO
HN
CO2H
NH2
H3C
HO
HO
NH3+
O O
H
L-DOPA Carbidopa
L-DOPA
-Adapted from Presentation Slide from Dr. John Buynak
• Levodopa is decarboxylated to form dopamine, thus replenishing the dimished supply
• Dopa Decarboxylase is saturated at 70 to 100 mg/day
HO
NH2
CO2H
L-Tyrosine
Tyrosine
hydroxylase HO
NH2
CO2H
Levodopa(L-DOPA)
HO
HO
NH2
Dopamine
HODopa
Decarboxylase
Dopamine
β-hydroxylase
HO
HO
NH2
OH
Norepinephrine(Noradrenaline)
HO
HO
NHMe
OH
Epinephrine(Adrenaline)
N-methyl transferase
(in Adrenal medulla)
L-DOPA
• Downsides– Continual use can lead to motor
complications (dyskinesia), which must be treated
– This can be somewhat offset by lowering the dosage
• This is an important factor for patients with Early Onset Parkinson’s Disease
Dopamine Agonists
• Directly stimulate dopamine receptors
• Bromocriptine (Perlodel)
• Pergolide (Permax)
wikipedia http://en..org/wiki/Parlodel
http://en.wikipedia.org/wiki/Pergolide
Dopamine Agonists
• Often used in combination with Levadopa
• Studies have shown that its use alone delays or lowers the incidence of motor complications associated with the use of Levadopa
• Often prescribed to patients with mild disease at a younger onset age
Late Stage Parkinson’s
• Seen in 40% of Patients having received Levadopa treatment for 5+ years– Motor complications usually arise
• Patients experience a “wearing off” effect– Each dose of levadopa has a shorter duration
of effect
• Motor Complications treated with:– Dopamine Agonists, MAO-B Inhibitors, COMT
Inhibitors
MAO-B Inhibitors
• MAO = monoamine oxidase
-Oxidative deamination
• Reduce disability and delay need for Levadopa– Believed to be somewhat neuroprotective
H R-C-NH2 + O2 + H2O → R-C=O + NH3 + H2O2 H H
MAO-B Inhibitors
• Selegiline (Eldepryl)
• Rasagiline (Azilect)
http://en.wikipedia.org/wiki/Selegiline
http://en.wikipedia.org/wiki/Rasagiline
COMT Inhibitors
• COMT: catechol O-methyltransferase• Inhibition increases the half life of Levadopa -->
decreases “Off” times• Tolcapone (Tasmar):
• Monitored closely due to rare side effect of fatal hepatotoxicity
http://en.wikipedia.org/wiki/Tolcapone
New Therapeutic Approaches
• Glial Cell-line-Derived Neurotrophic Factor (GDNF)– Shown to aid degenerating neurons– However, there is very little evidence to
support it’s widespread use• Adenosine Antagonists
– Colocalized with striatal dopamine (D2) receptors
– Studies show that they often reverse motor defects from Parkinson’s
Novel Approaches
• N-methyl-D-Aspartate (NMDA) Receptor Antagonists– Shown to reduce motor complications
from L-DOPA therapy– Amantadine (Symmetrel):
http://en.wikipedia.org/wiki/Amantadine
Surgical Therapies
• Deep Brain Stimulation– With precise brain mapping, stimulation
of the subthalamic nucleus can be performed
– Improves motor function– Reduces dyskinesia and need for
medications– Downfall: often causes destructive
lesions
Interesting Observations
• An inverse relationship between smoking and Parkinson’s has been demonstrated– Mechanism of protection (if any) is
unknown
• Consuming Caffeine (an adenosine antagonist) has been linked with a lesser risk of developing Parkinson’s
Sources
Figures: Wikipedia.org
Schapira, Anthony H., Bezard, Erwan, et. al “Novel Pharmacological targets for the treatment of Parkinson’s Disease.” Nature Reviews: Drug Discovery. 5 (2006): 845-854.
Rao, Shobha A., Hoffman, Laura A., and Shakil, Amer. “Parkinson’s Disease: Diagnosis and Treatment.” American Family Physician. 74 (2006): 2046-2054
Jankovic, Joseph. “An Update on the Treatment of Parkinson’s Disease.” Mount Sinai Journal of Medicine. 73 (2006): 682-689