Fourteen Flashcards
What are 3 possible etiologies of PD? What are some examples? How common are they?
Idipoathic (no known cause) – vast majority of cases (>80%). Symptoms appear >60 years of age.
Familial (linked to a specific genetic mutation) – approximately 10-15% cases – symptoms appear at a much younger age.
Environmental – similar symptoms seen in individuals exposed long-term to heavy metals (Mn2+ miners e.g.), pesticides (rotenone, paraquat), viral infections of CNS (postencephalitic Parkinsonism observed after Spanish Flu pandemic of 1918), and drugs of abuse (MPTP).
What is the pathophysiology of PD?
Although the etiology may differ in patients diagnosed with Parkinson’s disease, the end-point symptoms are the same and result from degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) in the basal ganglia that disrupt normal motor control.
What are 5 evidences that DA is deficient in PD?
Evidence for Deficient Dopamine Activity
a) Drugs that deplete dopamine (reserpine) or block dopamine receptors in brain (chlorpromazine, haloperidol) mimic both the symptoms and biochemistry of Parkinson’s disease.
b) Biochemical distribution of dopamine in the nigra-striatal system is consistent.
c) Lesions of the nigra-striatal dopamine fibers will induce Parkinson’s disease.
d) Postmortem chemical examination of brain material of Parkinsonian patients indicates a marked depletion of dopamine and homovanillic acid in the basal ganglion.
e) The use of levodopa improves the symptoms of Parkinson’s Disease. Biochemical evidence reveals a build up of dopamine, itself.
What does ACh do at the striatum? What about DA?
ACh has actions that are the opposite of DA at the striatum. DA makes the inhibition of the indirect pathway less effective and makes the enabling of the direct pathway more effective. Without it, in PD, the inhibition of the indirect pathway is more effective and the enabling of the direct pathway is less effective. ACh makes the inhibition of the indirect pathway more effective and the enabling of the direct pathway less effective.
What are 5 evidences that a disproportionate amt. of ACh (compared to DA) is an important part of PD?
a) Empirical observations of an ACh-atropine antagonism (i.e., symptoms are improved following anticholinergic drugs).
b) Tremors mimicking Parkinson’s disease can be produced by cholinomimetic drugs such as tremorine. This effect can be altered by anticholinergic drugs
c) Anticholinesterase agents that pass the blood-brain barrier (i.e., physostigmine) will aggravate the symptoms of Parkinson’s disease while anticholinesterase agents which do not pass the blood-brain barrier do not.
d) A direct demonstration of an ACh-anticholinergic antagonism in patients can be seen.
e) The biochemical distribution of ACh, choline acetyl transferase, and acetylcholinesterase reveal high concentrations in the human caudate nucleus.
What are five therapeutic strategies to treat PD?
Replace endogenous dopamine
Prolong availability of dopamine
Replace endogenous dopamine’s effects
Restore balance in basal ganglia
Bypass dopamine circuitry – Deep Brain Stimulation
What is used to replace endogenous DA? What is it converted to (which enzymes)? What is administered with it to reduce peripheral side effects? What are some problems with this therapy? Of the side effects, which is most common, are they in the central or periphery, is tolerance to them gained, and how can you help with them?
- L-Dopa (levodopa, laradopa) – Gold Standard therapy since the1960’s.
- Neurons convert L-Dopa to DA via L-aromatic amino acid decarboxylase (dopa decarboxylase)
- L-Dopa can also be metabolized via COMT to 3-O-methyldopa
A dopa decarboxylase that doesn’t pass the BBB is administered with it to reduce peripheral side effects
Problems include desensitization/tolerance and Side effects
• Nausea, vomiting. Central/Periph, tolerance, take with food
• Dyskinesias (involuntary movements) - overstimulation of neurons involved in controlling movement—most common, Central, no tolerance, reduce dose
• Psychiatric/behavioral – depression, paranoia, insomnia, mania, anxiety, increased sexual behavior. Central, No tolerance, reduce dose or stop
• Cardiovascular (Hypotension)-Central/Periph, tolerance, reduce dose
What does MAO do? What do MAO inhibitors do? How do MAO-A and MAO-B differ? Why are selective inhibitors of MAO-B used? What are 2 selective inhibitors of MAO-B that are used?
- Monoamine Oxidase breaks down monoamines including dopamine
- MAO Inhibitors block monoamine oxidase and increase the amount of dopamine and its effectiveness
- MAO-A – dopaminergic neurons, MAO-B extraneuronal astrocytes (responsible for most of DA metabolism)
MAO-B is targeted because one of the main targets of MAO-A is NE and you want to stay away from that.
Selegiline, Rasagiline
What are 3 things Selegiline does? When is its peak response? What are the side effects? Why else is it problematic?
Inhibits MAO-B, Neuroprotective (prevents radicals from being formed), Inhibits MPTP to MPP+ conversion preventing MPTP induced Parkinsonian symptoms
Peak response in 7 days.
Side effects include: insomnia, hallucinations and Nausea, exacerbate L-dopa dyskinesias
Problematic b/c it has amphetamine metabolites
What are 3 things rasagiline does? How does it differ from selegiline? What are its side effects? Why else is it problematic?
Inhibits MAO-B, neuroprotective, augments Levodopa effectiveness.
It is newer, has no amphetamine metabolites
Side effects include insomnia, hallucinations, nausea, ortho hypotension,
It has been associated with serotonin syndrome
What are 2 ways to prolong the availability of DA?
Selective MAO-B inhibitors, COMT inhibitors?
What does COMT do? What are two COMT inhibitors that are used and where do they work (central or peripheral)? What is their goal? What are the side effects of each?
- Catechol-O-methyltransferase breaks down dopamine and also L-Dopa
- COMT inhibitors Entacapone (peripheral) or Tolcapone (peripheral and central) given with L-DOPA to prolong the life of L-Dopa and also the dopamine that is produced
- Reduces the dose and frequency of L-DOPA treatment needed
Each have side effects of basically worsening the symptoms of L-DOPA treatment (dyskinesias, psychiatric), but tolcapone also can alter liver function.
What is used to replace endogenous DA effects? What are 4 examples?
Dopamine Receptor Agonists
- Ideal compounds act directly on the dopamine receptors and can also reach the brain
- Take over the role of dopamine at the receptors
Pramipexole, ropinirole, Bromocriptine, and Pergolide
What DA receptor does Pramipexole have preferential affinity for? Is it used as a monotherapy or add on? What are some side effects? What are some off label uses? Same questions for ropinirole?
Pramipexole has preferential affinity for the D3 receptors (D3>D2). It is effective when used as monotherapy for mild parkinsonism. Also useful for patients with advanced disease, this allows for a reduction in the dose of levodopa. May also alleviate affective symptoms.
Side effects of pramipexole include dizziness, orthostatic hypotension, drowsiness, hallucinations, twitching, twisting or unusual body movements, sudden falling asleep
during activities of daily living. Several unusual adverse effects include compulsive gambling, hypersexuality and overeating. This may be linked to activation of D3
receptors located in regions involved in mood, behaviors and reward. Has been referred to as “The Las Vegas Pill”
Pramipexole has been used off label for cluster headaches, restless leg syndrome and bipolar depression.
Ropinirole. This is another newer agent with greater affinity for the D3 receptor over the D2 receptor. It is also effective as monotherapy or as a means of smoothing the response to levodopa in patients with more advanced disease. Side effects include excessive sedation, vivid dreams and hallucinations. Both ropinirole and pramipexole delay the onset of “off” periods and dyskinesia in Parkinson’s patients.
Ropinirole has also been approved for “Restless Leg Syndrome”. This is a syndrome which occurs at night, is precipitated by dopamine antagonists or SSRIs and relieved by dopamine agonists. It is felt that it is due to low dopamine levels but does not involve the basal ganglia.
Why are Bromocriptine (Parlodel™) and Pergolide (Permex™) used less? Which receptors do they work at?
These are ergot derivatives and were the first directly acting dopamine agonists used. They produce more unwanted side effects than roprinirole and pramipexole. They can cause significant nausea, peripheral edema and hypotension; therefore are not used as readily as the newer agents. They are only effective for a certain amount of time. Bromocriptine (D2) doesn’t work for 30% of patients. Pergolide (D2=D3, partial D1) is used if L-Dopa doesn’t work.
