Salvador Dali (Painter) Mao Zedong (Chinese Politician) Michael J Fox (Actor) Pope John Paul II Muhammad Ali (Boxer) Janet Reno (Former AG)

Salvador Dali (Painter)

Mao Zedong (Chinese Politician) Michael J Fox (Actor)

Pope John Paul II

Muhammad Ali (Boxer)

Janet Reno (Former AG)

The Pharmacology of Parkinson’s Disease

May 22, 2014

Symptoms of PD• Resting tremor (“shaking”)- improved with

activity• Rigidity• Impaired balance• Bradykinesia (brady=slow, kinesia=motion)

– Gait disturbances– Loss of automatic movement (blinking, smiling, etc.)

• Additional symptoms:– Muscle aches, pains– Slurred speech– Cognitive (depression, anxiety, confusion)

PD Age of Onset

Substantia Nigra Changes in PD

Major Circuit Important in PD

Substantia NigraCaudate

Just Add Dopamine!

But what’s the problem here?

• Not lipid soluble, can’t cross the BBB

NH3+

What about its precursor- L-DOPA?

• L-DOPA is also charged, but it crosses the BBB anyway… How?

NH3+

LAT1 transporter

L-DOPA is transported across BBB by active transport

DDC in the periphery can also convert L-Dopa to DA-still can’t cross

Current PD Therapy• Carbidopa + L-Dopa

– Peripheral DOPA decarboxylase (DDC) inhibitor

What could be some other drug targets?

Targets for Another Drug?

DA Receptor Agonists

• Apomorphine • Ropinirole

MAO Inhibitor

• Selegiline

– Retards degradation of DA– Somewhat selective inhibitor of an enzyme (MAO)

Can there be a placebo effect in treating PD?

• How might you answer that question?

STN Firing

• PD involves degeneration of the dopaminergic neurons (in the substantia nigra) that results in tremors, rigidity, and gait disturbances

• Occurs mostly in the elderly (prevalence increases with age)

• Drugs available to treat PD increase DA synthesis, prevent metabolism, or activate DA receptors

• The placebo effect is real and produces physiological changes in patients that can be measured and quantified

Major Points of Today’s Lecture

Concept Map

• Parkinson’s Disease• Dopamine• Gait disturbances• Substantia nigra• L-DOPA• BBB• DDC• Tremors• Placebo effect