pharmacotherapies for parkinsons disease
Post on 18-Nov-2014
1.549 Views
Preview:
DESCRIPTION
TRANSCRIPT
Pharmacotherapies for Parkinson’s Disease
Brian J. Piper, Ph.D., M.S.
Objectives
• Describe biosynthesis and elimination of dopamine & the importance for PD symptom management.
• Outline the rationale (pros & cons) for different secondary treatments of PD including MAOB-I, & DA agonists.
Disease Frequency in US Genetic Patho-physiology
Neurochem
PharmManagement
Goal Effectiveness
Parkinson’s 500 K low nigra-striatal
DA common sym high
Alzheimer’s 5.4 million moderate diffusecortex
ACh? common sym slight
Huntington’s 30 K high striatum ? uncommon sym small
ALS 25 K low motorneurons
Glut? common sym small
ACh: acetylcholine; DA: dopamine; Glu: glutamine; sym: symptom management
Ideopathic Parkinson’s Disease• Neurodegenerative disease
characterized by:– resting tremor– rigidity– bradykinesia– a + response to PD pharmacotherapy
• Prevalence ≈ 1 million• Risk Factors
– rural > urban– age: > 65 1%; > 80 2.5%– sex: 2 M : 1 F
http://www.youtube.com/watch?v=0-t4RTQ0EsMParkinson’s Symptoms (1st min only):http://www.youtube.com/watch?v=_L_WF6gv5BI
Van Den Eeden et al. (2003). Am J Epidemiology, 157, 1015-1022. Chen et al. (2007). Parkinson’s Disease. In DiPiro Pharmacotherapy.
Pill rolling (20 sec):
Precursors in Dopamine Synthesis
• Phenylalanine: essential amino acid
Food g / 100 gegg (white) 4.74
tofu 2.33
peanuts 1.33
kidney beans 1.28
beef (liver) 1.1
turkey (white) 0.94
salmon 0.91
anchovy 0.79
lobster 0.79
USDA, Summarized athttp://nutrient.javalime.com/nutrient.php/508.2
Biosynthesis• Phenylketonuria: autosomal
genetic disease of dysfunctional phenylalanine hydroxylase
Biosynthesis• Tyrosine: non-essential amino acid
Food g / 100 gegg (white) 3.15
tofu 1.60
peanuts 1.05
kidney beans 0.71
beef (liver) 0.80
turkey 0.82
salmon 0.76
anchovy 0.69
lobster 0.69
USDA, Summarized at: http://nutrient.javalime.com/nutrient.php/509.4
Dopamine Synthesis• Tyrosine hydroxylase: rate
limiting step• L-DOPA
– precursor (pro-drug)
nigrastriatal pathway
History of L-3,4-dihydroxyphenylalanine (1950s)
• L-DOPA (B) used to counteract reserpine (A)• This effect corresponded with dopamine levels in the
brain
Arvid Carlsson, MD
1923 - Carlsson (2001). Science, 294, 1021-1024.
History of L-3,4-dihydroxyphenylalanine (1960s)
• Additional of a peripheral AADC inhibitor improved response and limited nausea
History of L-3,4-dihydroxyphenylalanine (1960s)
• Additional of a peripheral AADC inhibitor improved response and limited nausea
On versus Off L-DOPA: http://www.youtube.com/watch?v=sf1N0Zf5IqA
Limitations of carbidopa/levodopa (1970s)
• competition with other proteins to cross BBB• “unawakening”• dyskinesias occur in majority
Extreme example (1 min): http://www.youtube.com/watch?v=d1jJyk_poqE
Solution #1: Monoamine OxidaseB Inhibition
• MAO is localized presynaptically & extrasynaptically (glia)
• MAO-A: preferentially deaminates– Dopamine & norepinephrine– 5-HT & melatonin
• MAO-B: preferentially deaminates– dopamine & phenethylamine
• Target of older class of antidepressant drugs (1957-1970)
Acronyms:DOPAC: 3,4-dihydoxyphenylacetic acidAD: aldehyde dehydrogenaseHVA: homovanillic acid
Solution #2: COMT Inhibition
• catechol-O-methyl transferase is found centrally & peripherally
COMT: catechol-O-methyl transferase3-O-MD: 3-O-methyl DOPA3MT: 3-methoxyltyramine
Selegiline(L-deprenyl)
Rasagiline(azilect)
Tolcapone(tasmar)
Entacapone(comtan)
mechanism MAOB MAOB
(irreversible)peripheral COMTcentral COMT
peripheral COMT
monotherapy yes yes no no
other meth & amphmetabolites;insomniahallucinations
hepatoxicity 0.5 hour half-life
Chen et al. (2008). Parkinson’s disease. In DiPiro’s Pharmacotherapy.
Slowing of Further Neurodegeneration?
• PD may occur by– DA induced formation of free radicals (H2O2)– apoptosis
• MAOB inhibition may act to prevent these mechanisms but this is difficult to establish clinically
PD Progression
• Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor).
• Webster score, conducted non-blind) includes motor function (hand-bradykinesia, face, speech, flexibility, rising from chair, balance).
Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
PD Progression
• Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor).
• Mortality from a variety of causes were also recorded. 2.8% for Arm 1 & 9.6% for Arm 2.
Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
1920 - 2005
Thanks, home chemists!
• Barry Kidston develops Parkinson’s after synthesizing MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
• Later cases were described as:– “Three of the four patients were hospitalized with 14 days
to 6 weeks of first use of the drug. Examination in each revealed near total immobility, marked generalized increase in tone, a complete inability to speak intelligibly, marked diminution of blinking, fixed stare, constant drooling”
– Stopping L-DOPA resulted in “complete immobility & rigidity, being only able to move his eyes”
Langston et al. (1983). Science, 219, 979-980.
W. Langston, M.D.
MPTP= Parkinson’s model
Parkinson’s Disease Normal
Immunocytochemistry for tyrosine hydroxylase in rhesusmonkeys
Masilamoni et al. (2011). Brain, 134, 2057-2073.
Dopamine Receptors
• Metabotropic• D1 Subfamily:
– Members: D1 & D5
– Gs & ↑cAMP
• D2 Subfamily:– Members: D2, D3, D4
– GI & ↓cAMP
• Striatum: D1 & D2 Postsynaptic
Stahl, S. (2008). Essential Psychopharmacology. p. 95.
Dyskinesia
• Marmosets (N=16) received MPTP. One month later:– Control– ropinirole (D23
agonist)– bromocriptine
(D234 agonist)– L-DOPA
Pierce et al. (1996). British Journal of Pharmacology, 118, 37P.
Dopamine AgonistsRopinirole(requip)
Promipexole(mirapex)
Apomorphine(apokyn)
mechanism D23 agonist D23 agonist D4235 agonist
route oral oral subcutaneous
adverse effects
hallucinationsconfusionsleep attack
hallucinationsconfusionsleep attack
hallucinationsconfusionsleep attacknausea
Compulsive Behaviors with Dopamine23 Agonists
• sexual• gambling• other repetitive behaviors
3 min: http://www.youtube.com/watch?v=3oNkYNVdsioBostwick et al. (2009). Mayo Clinic Proceedings, 84(4), 310-316.
PD Progression with D agonist
benserazide: peripheral DOPA decarboxylase inhibitorbromocriptine: D234 agonist
Rang et al. (2007). Pharmacology. p. 519.
Muscarinic Antagonists• Trihexyphenidyl (Artane) and Benztropine (Cogentin)
• Rationale– Muscarinic Receptors on striatal neurons mediate cholinergic
tremor – May cause presynaptic inhibition of dopamine release
• Adverse effects– “atropine-like”: dry mouth, inability to sweat, impaired vision,
urinary retention, constipation, drowsiness, confusion
SummaryPro Con
L-DOPA awakening unawakeningdyskinesia
MAOB-I delay time until L-DOPA
long-term outcomes*
dopamine agonists reduced dyskinesia compulsionssleep attack
*needs additional study
Caffeine & Decreased PD Risk
• Dietary habits were obtained from middle aged men (N=8,000) in 1965.
• Subjects were monitored for 30 years for incidence of PD.
• Mechanisms– 3rd variable– antioxidant
Ross, G. W. et al. (2000). JAMA, 283, 2674-2679.
Smoking & Decreased PD Risk• A meta-analysis of 44 studies (6,814 cases,
11,791 controls) has revealed a highly consistent reduction.
• Current smokers are 60% less likely to develop PD than non-smokers.
• Ex-smokers are 40% less likely to develop PD than non-smokers
• Potential mechanisms– third variable?– ↑ dopamine– Inhibition of MAOB
Hernan (2002). Annals of Neurology, 52, 276-284.
Relative Risk = Probability Exposed Probability Unexposed
Pesticides & Increased PD Risk
• origin of rural > urban for PD is unclear• Rotenone is an insecticide & piscicide and
causes MPTP like neurodegeneration (animals)• Paraquat is one of the most common
herbicides in the world.
Tanner et al. (2011). Environmental Health Perspectives, 119, 866-872.
Post Semester Entertainment
Terminology Refresherbradykinesia: slowed movementdyskinesia: involuntary movement involving head, neck, or upper extremetiesdystonia: abnormal tone of any tissue, sustained muscle contractions
Pronunciation: http://dictionary.reference.com/browse/dyskinesia?s=thttp://dictionary.reference.com/browse/idiopathic
top related