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