Pharmacology of Parkinson's Disease Flashcards Preview

Nervous System: Unit III > Pharmacology of Parkinson's Disease > Flashcards

Flashcards in Pharmacology of Parkinson's Disease Deck (14)
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General neurochemistry of Parkinson's disease

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



Fxn of D1 and D2 receptors @ striatum

  • 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


Impacts of decreased dopamine

  • 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


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

  • 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.



Characteristics of L-DOPA and Carbidopa

  • 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.


Characteristics/examples of dopamine agonists

  • 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)


Characteristics of Amantidine

  • 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)


Characteristics of anticholinergic drugs

  • 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


Examples of anticholingeric drugs

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


Characteristics of Dopamine extendors

  • 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.


Examples of Dopamine extendors

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


Direct pathway characteristics

  • 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


Characteristics of indirect pathway

  • 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