Pharmacology of Parkinson's Disease

Question 1

General neurochemistry of Parkinson’s disease

Answer 1

• Deficiency of dopamine neurons and dopamine release.
• Substantia nigra has neurons that connect to striatum sending dopamine to both D1 and D2 receptors.

Question 2

Fxn of D1 and D2 receptors @ striatum

Answer 2

• D1 receptors stimulate cAMP, which stimulates the GABA-ergic neurons from the striatum (putamen) to the globus pallidus.
  
  • Favors direct pathway
• D2 receptors are inhibitory in the striatum. Favors indirect pathway. From the striatum inhibitor neurons hit GPE which has inhibitory neurons onto Subthalamic nucleus which has excitatory neurons hitting the GPi-SNr

Question 3

Impacts of decreased dopamine

Answer 3

• decreased dopamine ==> decreased D2 inhibition (of GABA-nergics @ GPE) ==> decreased activity @ GPE ==> decreased inhibition of subthalamus = greater activity @ subthalamus ==> increased activity @ GPI ==> increased inhibition @ thalamus.
• decreased dopamine @ D1 ==> decreased inhibition of GPI = greater activity @ GPI ==> increased inhibition of thalamus

Question 4

Rationale for drugs used to improve clnical symptoms of Parkinson’s

Answer 4

• L-DOPA = most important drug for treating Parkinson’s disease.
• Combined with the peripheral decarboxylase inhibitor carbidopa as Sinemet, L-DOPA provides useful clinical benefit for 5 to 20 years after diagnosis.
• There is an exotic array of dopamine agonists (bromocriptine, pergolide, and others), anticholinergics, and MAO and COMT inhibitors (selegiline, tolcapone, and others).
• Despite this selection of drugs with different sites of action, when the quality of the L-DOPA response fails, other drugs provide only partial improvement in clinical symptoms.

Question 5

Characteristics of L-DOPA and Carbidopa

Answer 5

• L-dopa and Carbidopa : precursor to dopamine, oxidized in brain to dopamine.
• Sinemet (the combo of L-Dopa and Carbidopa) blocks decarboxylase in intestine
  
  • Most important
  • Peak 30-60 minutes, lasts 2 hours.
  • Take every 2 hours, or make drink and sip all day long.

Question 6

Characteristics/examples of dopamine agonists

Answer 6

• most work at D2, help with short half life of L-Dopa
• Bromocriptine(Parlodel)
• Pergolide (Permax)
• Pramipexole (Mirapex)
• Ropinirole(Requip)
  
  • Dopamine receptor agonist (D2) direct
  • ½ life is 6 hours, thus sustained dopamine activity
• Cabergoline (Dostinex)

Question 7

Characteristics of Amantidine

Answer 7

• Causes increased release of endogenous dopamine
• Not really sure why it works well for parkinson’s, experimental evidence says it’s useful
• Maybe a glutamate antagonist, usually taken for the flu, increases availability of dopamine (maybe)

Question 8

Characteristics of anticholinergic drugs

Answer 8

• Less effective than L-DOPA.
• Sometimes used for initial therapy of tremor.
• Balance the overactivity of the cholinergic interneurons in the caudate/putamen caused by the lack of dopamine.
  
  • Dopamine is normally inhibitory to cholinergic interneurons
  • Parkinsons: cholinergic neurons release too much ACh onto medium spinu neurons ==> GP

Question 9

Examples of anticholingeric drugs

Answer 9

• Trihexyphenidyl (Artane)
• Benztropine (Cogentin)
• Diphenhydramine (Benadryl)

Question 10

Characteristics of Dopamine extendors

Answer 10

• Example: MAO inhibitors and COMT inhibitors
• Mechanism:
  
  • MAOI: monoamine oxidase inhibitors (MAOI) prevent the breakdown of dopamine, these agents can prolong the action of dopamine produced from L-DOPA.
  • COMT inhibitor (catechol o-methyl transferase): Prevent breakdown of L-DOPA and dopamine by COMT.

Question 11

Examples of Dopamine extendors

Answer 11

• Selegiline (Eldepryl): MAO-B.
  
  • MAO-A are dangerous.
• COMT inhibitor (catechol o-methyl transferase)
  
  • Tolcapone(Tasmar)
  • Entacapone (Comtan)

Question 12

Direct pathway characteristics

Answer 12

• Dopamine ==> D1 @ striatum (caudate/putamen) ==> increased activity of GABA-nergic neurons = increased inhibition ==> Globas pallidus (internal)
• ==> decreased inhibition = increased activity @ VA/VL complex of thalamus ==> increased activity @ premotor cortex

Question 13

Characteristics of indirect pathway

Answer 13

• Dopamine ==> D2 @ striatum (caudate/putamen) ==> inhibition of GABA-nergic = activation of Globus pallidus (external) ==> increased inhibition of subthalamic nucleus ==>
• decreased activity @ Globus pallidus (internal) ==> decreased inhibition of VA/VL complex @ thalamus