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					BIOM/PHAR 255                     Pharmacotherapy of Parkinson’s Disease                Spring 2010

                           Thursday, April 22, 2010
Questions for Discussion:

S.J. is a 72-year-old woman who has had Parkinson's disease for one year characterized primarily by

   1. What is Parkinson’s disease (PD)?

   2. How does a physician make the clinical diagnosis of PD?

   3. Use the following highly simplified diagram of the anatomy and function of the basal ganglia
      in a normal individual to demonstrate the neurophysiological/neurochemical origin of the
      motor impairments in PD and to identify major targets for the pharmacotherapy of PD.


                               ACh                     (direct)
                                     D2 (-)   (+) D1      “gas”


                                Substantia nigra
                                  pars compacta

The patient initially showed symptomatic improvement when treated with trihexyphenidyl [Artane®]
2 mg orally three times a day. Over the last six months, however, she has required larger doses to
control her symptoms and has complained of numerous side effects.

   4. What is trihexyphenidyl? Using the above diagram, explain why trihexyphenidyl can help to
      alleviate the motor symptoms of PD.

   5. What are the side effects that limit the use of trihexyphenidyl?

The patient then developed bradykinesia and muscle rigidity. Because of trihexyphenidyl’s side
effects and because the bradykinesia and muscle rigidity were not controlled by this drug, she
discontinued the trihexyphenidyl. Her friend told her that L-dopa was commonly used to treat PD.

BIOM/PHAR 255                     Pharmacotherapy of Parkinson’s Disease                 Spring 2010

S.J. was able to buy 250-mg L-dopa capsules from a health products website and took a 500-mg
dose, as recommended on the website, but within an hour she became extremely nauseous and
started vomiting.

   6. What is the rationale for taking L-dopa?

   7. Why would nausea and vomiting be seen following treatment with L-dopa?

She threw away the L-dopa capsules and consulted her physician, who gave her a prescription for
Sinemet®, a combination of L-dopa + carbidopa.

   8. What is carbidopa? Draw the pathways for dopamine synthesis and metabolism, and use this
      drawing to explain why L-dopa should always be administered in combination of carbidopa.

The patient was put on Sinemet® 25 mg carbidopa/100 mg L-dopa orally four times a day, and after
six weeks of therapy she started to notice much improvement, especially with the bradykinesia. After
six months, however, the Sinemet® no longer controlled her bradykinesia and muscle rigidity, and
the dose had to be increased. Her symptoms were better controlled on the higher dose, but the
patient began to complain that she was having nightmares and hallucinations.

   9. What is a possible explanation for these psychological symptoms?

   10. Would an antipsychotic drug be an appropriate medication for treating hallucinations and
       other psychological symptoms caused by L-dopa?

After two more years on the higher dose of Sinemet®, the patient developed writhing movements of
her arms and limbs.

   11. What is the most likely cause of these abnormal movements?

   12. What can be done to decrease or stop them?

After a total of five years of Sinemet® treatment, benefit from the drug was minimal.

   13. What is the most likely cause of the decreased efficacy of Sinemet®?

   14. What additional therapies are available for the treatment of PD, and what are some of the
       major side effects of each class of agents?

   15. Given what you have learned about PD, what other avenues of therapy might be explored?