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71 Cards in this Set
- Front
- Back
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What are the symptoms of Parkinson's disease caused by?
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Loss of dopaminergic cells in substantia nigra leading to dysregulation of the basal ganglia
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What is the best drug for treating Parkinson's?
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Levodopa - L-dopa
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What is the rationale for giving Levodopa?
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Restoration of Dopamine levels in the basal ganglia
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How does Levodopa enter the brain?
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Via amino acid transporters
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Why is the AA transporter mechanism for Levodopa entering the brain important to remember?
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Because after a meal, AA's will compete for the transporter binding sites, so the patient has to be consistent in either taking it with or w/o a meal.
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What happens to the Levodopa upon entering dopaminergic and other neurons?
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It is acted on by Aromatic Amino acid decarboxylase to make dopamine.
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How much of a dose of Levodopa will get into the brain?
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2% at most
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What happens to the other 98% of a levodopa dose?
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It gets converted to dopamine by L-AAAD in peripheral tissues (esp the liver), and a bit by COMT.
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What 2 problems result from how Levodopa is handled in the body?
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-Too much Dopamine in periphery
-Not enough in the brain |
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What are 2 inhibitors of L-AAAD that prevent too much Dopamine from being activated?
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-Carbidopa
-Tolcapone |
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What is the difference between Carbidopa and Tolcapone?
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Carbidopa doesn't cross the BBB so it only inhibits L-AAAD in the periphery;
Tolcapone inhibits COMT in both periphery and CNS |
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So can you give L-Dopa, Carbidopa, and Tolcapone all at the same time?
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Yes
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What are the 2 main side effects of too much Dopamine in the periphery?
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-Nausea (activates CTZ)
-Cardiovascular |
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What are 3 CV side effects of dopamine? Which is common/rare?
Why are these effects seen? |
-Postural hypotension - common
-Arrythmias - rare -Hypertension Seen bc DA can increase NE and act as a sympathomimetic agent. |
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What are 4 CNS side effects of Dopamine?
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-Wearing off
-On-off phenomena -Dyskinesias -Hallucinations/confusion esp in the elderly |
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What causes the wearing off side effect of Levodopa, and how can it be improved?
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-Caused by L-DOPA clearance from the body
-Improve by decreasing the dosing interval (but they'll be popping pills often then) |
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What is the On-Off phenomena seen with Levodopa therapy?
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A sudden loss of mobility that was achieved by the drug, due to loss of too many DA neurons or a sudden burst of Dopamine
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How long is Levodopa effective as a treatment for Parkinsons, and what is the implication of this?
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-Only effective for 3-5 yrs
-Reserved for patients that definitely show debilitation, not just to reduce resting tremor for cosmetic reasons. |
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How effective is Levodopa?
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Highly effective - it treats all the symptoms of Parkinson's!
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If Levodopa doesn't improve symptoms in a patient, what is the likely reason?
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The patient doesn't have Parkinson's
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What are 4 drug interactions with Levodopa?
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-Pyridoxine
-MAOIs (not selegiline though) -Halothane -Typical antipsychotics |
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How does Pyridoxine interact with Levodopa?
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Vit B6 activates LAAAD in the periphery
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What results from Halothane interaction with Levodopa? Why?
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Arrythmias due to increased sensitivity of the heart to catecholamines
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How do the typical antipsychotics interact with Levodopa?
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They block D2 receptors
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What 4 conditions are contraindications to Levodopa?
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-Glaucoma
-Psychosis -Cardiac arrythmias -Malignant melanoma |
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So what drug blocks L-AAAD in the periphery and does not cross the BBB?
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Carbidopa
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What drug blocks COMT in the periphery and CNS?
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Tolcapone
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What are the 3 D2 agonists? How can you remember them?
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-Bromocriptine
-Pramipexole -Ropinirole Bro Pra Rope |
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Which Dopamine agonists are selective for D2 receptors only?
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-Pramipexole
-Ropinirole |
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What is Bromocriptine selective for?
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-Full D2 agonist
-Partial D1 agonist |
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What is the rationale for giving Dopamine receptor agonists?
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Mimics the effects of Dopamine without needing intact nerve terminals.
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Where do the Dopamine agonists act?
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On DA receptors in the striatum
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What are 4 advantages of Dopamine agonists over Levodopa?
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1. No conversion needed - can use in late disease
2. Selective for DA receptor subtypes 3. Longer Half life 4. No oxidative stress on neurons |
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Why is longer half life of the dopamine agonists advantageous?
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It causes fewer on-off effects and dyskinesias
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When are the Dopamine agonists used in Parkinson's therapy?
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Earlier in the disease
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So what is currently used for initial therapy in young patients? Older patients?
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Young = Dopamine agonists
Old = Levodopa |
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What are 4 side effects of dopamine agonists?
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1. Nausea
2. Fatigue 3. Sudden daytime sleep attacks 4. CNS toxicity |
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What Dopamine agonist especially causes nausea?
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Bromocriptine
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What type of CNS toxicity do the dopamine agonists cause?
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Confusion - worse than L-DOPA
Dyskinesia - not as bad as Ldopa |
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What drug can potentiate the endogenously produced Dopamine by inhibiting its catabolism?
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Selegiline
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What is Selegiline?
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An irreversible MAO-B inhibitor
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Why is it important that Selegiline is an MAO-B inhibitor specifically?
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It avoids hypertensive crisis that can occur if a patient on a nonspecific MAOI eats tyramine
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What is Tyramine found in?
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Cheese, beer, wine, etc.
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What isoform of MAO is found in the brain? What is it responsible for?
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MAO-B; responsible for DA catabolism in the striatum.
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What is an added benefit of Selegiline in addition to prolonging Dopamine levels by inhibiting its catabolism?
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Reduced oxidative stress on neurons (less H2O2 produced)
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How effective is Selegiline when given alone?
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Modest
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How is Selegiline mostly prescribed for Parkinson's?
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Alone, at first presentation of symptoms (mild resting tremor)
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Does Selegiline slow the progression of Parkinson's?
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no
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How is Selegiline prescribed in more advanced cases of Parkinson's?
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In combo with Levodopa to prolong its therapeutic half life
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What is the halflife of Levodopa?
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1-3 hrs
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What are side effects of Selegiline like in general?
-For early cases -For advanced cases |
Not too bad - well tolerated in patients with early PD, maybe worse CNS side effects of L-DOPA in advanced patients.
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What is the main reason for side effects of Selegiline?
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It is metabolized to amphetamine which can cause anxiety/insomnia
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What is a 'side effect' of less NE catabolism due to Selegiline?
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It acts as an antidepressant
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What are 3 drug interactions with Selegiline?
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-Meperidine
-TCA -SSRIs |
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What is the rationale for giving Antimuscarinic agents for Parkinson's?
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Cholinergic interneurons normally inhibited by DA in the striatum are overactive in PD
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Why were antimuscarinics originally given to PD patients?
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To reduce the drooling often seen in these patients.
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So what is the mechanism of anticholinergics?
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Antagonism of Striatal Muscarinic receptors
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What are the 2 antimuscarinic drugs prescribed for Parkinsons?
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-Trihexyphenidyl
-Benztropine |
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What are the tope 3 drugs used for treating PD, and in what order?
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1. Dopamine agonists
2. Levodopa 3. Antimuscarinics |
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Why do the antimuscarinics fall in 3rd place for treating PD?
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They have many side effects
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What are 3 side effects of Trihexyphenidyl and Benztropine?
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-Sedation
-Mental confusion -Anticholinergic effects (red as a beet, dry as a bone, hot as hare) |
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What are 3 contraindications to prescribing anticholinergics for PD?
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-Benign prostatic hypertrophy
-Obstructions in the GI tract -Closed angle glaucoma |
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What is the efficacy of Antimuscarinics given for PD?
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Modest
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What is the way that Antimuscarinics are most often prescribed for PD?
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In early disease, in the ELDERLY or as an adjunct with Levodopa.
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What drug was discovered by serendipity for treating PD?
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Amantadine
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What is Amantadine?
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An anti-viral agent
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What are the 3 mechanisms of Amantadine?
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-Increases DA release
-Mildly anticholinergic -Blocks NMDA receptors |
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How effective/clinically useful is Amantadine?
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-Modest effectiveness
-Short-lived benefits |
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How is Amantadine mostly prescribed for PD?
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-With L-DOPA in patients that show end-of-dose problems
-With cholinergics |
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What are 4 side effects of Amantadine?
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-Dizziness
-Lethargy -Anticholinergic effects -Peripheral edema |
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In what patients is Amantadine contraindicated?
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PAtients with congestive heart failure
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