What is Parkinson's Disease and who dose it affect?

-What gets degenerated?

-What is a pathologic marker of PD? and what are they?

-What does PD result in? 

-It is a neurodegenerative disorder of the extrapyramidal system and it affects 1% of people over 65 years old. 

--Degeneration of dopaminergic neurons

-Lewy bodies, neurons that develop misfolded alpha synuclein containing protein aggregates and inclusions.

 -muscle rigidity, bradykinesia (slow movement), akinesia(no movement), flat facies, tremor, postural instability.

-What are the 2 inhibitory neurotransmitters in the striatum?

-what is the excitatory one?

-What is the relationship between these? 

-Dopamine and gamma-aminobutyric acid (GABA)

-ACh

-Neurons that release GABA are inhibited by dopamine and are excited by Ach.  When both are working properly, normal movement results. 

-Where are the neurons degenerated in PD?

-Why is there movement disorder in PD?

-What side effects does this resemble? 

-In the striatum duh!

-Because ACh's excitatory influence is unopposed so excessive stimulation of GABAergic neurons.

 -Antipsychotic drugs that block striatal DA receptors

-Where is the dopaminergic pathway in the brain?

-What is a dopamine prodrug, DOC for advanced PD, controlls symptoms for ~2-3 years?

-Does it need careful titration? 

-What phenomenoms does this drug have? 

-How does this drug work? 

-What delays the absorption of this drug? 

-Why it's levodopa

-YEA

-The 'wearing off' phenomenom' and the 'on-off phenomenom'

-By increasing dopamine synthesis in the striatum.  It crosses the BBB and converted by AAD to dopamine.

-High protein foods 

DOPAMINE RECEPTORS

-Which Dopamine receptors are in the D1 receptor family?

-the D2 receptor family? 

-Benefits of D agonists in PD appear to depend mostly on which receptor activation? 

-D1 and D5

-D2,3,and 4

-D2 

-What bad thing is formed when you metabolize L-Dopa?

-Why is it bad?

-What are the adverse side effects of L-Dopa? 

-Hydrogen Peroxide

-because it gets converted to free radicals and can damage the striatal dopaminergic neurons.

-N/V, Abnormal involuntary movements (AIMS), Cardiovascular effects(activates B1 receptors), Postural hypotension, psychiatric effects common, drowsiness, discolaration of urine, sweat saliva, hemolytic anemia 

-Why could your urine, sweat, and salive be discoloured?

-How can you minimalize side effects?

-How do you improve the 'wearing off phenomenom'?

-Should you just stop abruptly? 

-Because excess melanin production

-Start with a low dose then increase gradually. 

-Increasing the dose and frequency of administration. may develop to AIMS tho.

-no, can cause neuroleptic malignant syndrome.(increase temp, muscle rigidity,altered consciousness, sweating) 

-What are the contraindications of L-DOPA?

-Precautions? 

-if you have narrow angle glaucoma, psychiatric disorders, undiagnosed pigmented skin lesions or melanoma.

-May have an increased risk of falling 

-nonselective MAOI's (discontinue 2 weeks b4 taking Ldopa)

-antipsychotic drdugs,

-sympathomimetic drugs,

-antihypertensive drugs,

-pyridoxine (decreases l-dopa's therapeutic effects)

-high protein 

-What does pyridoxine affect that makes it bad to take with levodopa?

-and why is that bad? 

-It stimulates AAD activity

-b/c AAD activity converts l-dopa to dopamine in the periphery so the l-dopa won't get to the brain. 

-What category is Carbidopa in?

-What is Carbidopa's MOA?

-Does it work in the periphery or the brain? 

-What are the advtges of taking this with l-dopa?

-what are the disadvantages? 

-AAD inhibitor

-It inhibits decarboxylases in the periphery and makes l-dopa more available in the CNS.

-obviously just the periphery!

-can decrease the daily requirement of l-dopa, decrease GI and cardiac SE's, rapid onset of effects, avoids pyridoxine interaction, enhanced efficacy, improved control with less variability

-AIMS and psychiatric disturbances may be more intense and occur sooner. 

-What category is Entacapone?

-MOA?

-cross bbb? 

-COMT inhibitor

-inhibits comt, so increases levels of l-dopa and dopamine in brain.

-No 

-No hepatotoxicity but requires more frequent dosing.

--Needs titration. 

-What is amantadine (symmetrel) ? what special category?

-MOA?

-slow or fast response?

-tolerance?

-eliminated? 

-An antiviral

-Not clear but appears to promote release of dopamine. anticholinergic effects, and higher doses may block NMDA receptors.

-Faster then l-dopa but not as efficacious

-Can develop after a few months

-unchanged in kidney 

-Are Amantadine Adverse Effects pretty harsh?

-What are some? 

-High doses can cause what? 

-SE's usually mild and transient

-Anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation), A reversible rash may appear but it can go away, orthostatic hypotension 

-CNS effects; confusion, agitation, hallucinations, sleep disturbance, acute toxic psychosis

-When is the best time to use dopamine receptor agonists?

-What are the 3 dopamine receptor agonists we have to know?

-which one is the prototype? what category is it too. (what is it derived from) 

-What special side effect do dopamine agonists do? 

-In early PD so you can prolong the time before l-dopa has to be used.

-Bromocriptine, ropinirole, pramipexole.

-bromocriptine, ergot derivative

-increases impulsivity- pathologic gambling 

-Is bromocriptine (Parlodel) pretty specific on receptors?

-Does it need titration?

-When is it used for PD?

-actions and effects?

-No it's nonspecific.

-Yes very complex titration

-Rarely used for PD 

-similiar to l-dopa 

-What are the 2 second generation dopamine agonists we have to know?

-What's the postives about 2nd generation dope agonists?

-What are the se's for 2nd generations? 

-Ropinirole(Requip) and Pramipexole(Mirapex)

-no ergot adverse effects and more selective for dope receptors.

-Postural hypotension, nausea, sleep,disturbance, constipation,dyskinesias,confusion,somnolesnce, impulsivity. 

-What is Ropinirole (Requip)'s receptor affinity the highest at?

-What else can you use this for?

-D3 (effects of D3 not really known tho) also selective for D2

-Restless Leg Syndrome 

-Pramipexole (Mirapex), what category is it?

-excreted?

-What can you use htis for as well? 

-which receptors is this selective for? 

-Dopamine agonist 2nd generation

-unchanged in urine! 

 -Restless leg syndrome.

-highest in D3 but also D2 and D4 

-Explain Unintended Sleep Episodes

-What drugs is this associated with?

-How to help with this? 

-sleeping without warning

-All dopaminergic agents including levodopa. 

-use the lowest dose of dopaminergic agent that provides satisfactory clinical response. 

-Why is MAO-B inhibitors great for PD?

-What is a selective irreversible MAO-B inhibitor?

-Why should you not take too much of this inhibitor?

-Cheese Rxn? why?

-How does this work? 

-Well it's because by blocking MAO-B, you can decrease dopamine metabolism but not that of NE or 5-HT.

-Selegiline. (eldepryl) 

-b/c at too high doses, it affects MAO-A too.  but to low to moderate doses, it affects MAO-B in the striatum.

-Nope, it doesn't inhibit peripheral metabolism of catecholamines. 

-By prolonging the duration that dopamine is in your system. 

-When's the best time to use Selegiline (eldepryl)?

-What's special about this?

-What is MPTP 

-Does it need titration?

-Cross BBB? 

-Early PD, i can delay need for l-dopa.

-It may delay progression of PD. It also inhibits conversion of MPTP to toxic metabolite MPP+ 

-It degenerates dopaminergic neurons.

-No titration

-does cross BBB 

-What are the D/I's of Selegiline (eldepryl)?

-How are anticholinergics used to help PD?

--When is taking this group of meds preferred?

-What is the drug that you need to know that is in this group? 

-Acts by preventing activation of chilinergic receptors in the CNS b/c PD symptoms are caused by excessive stimulation of muscarinic receptors in striatum.

-with younger patients with mild parkinsonism... don't use in elderly.

-Benztropine(Congentin)