Neurodegenerative Disorders/Parkinsons Flashcards
Define neurodegeneration
progressive loss of neuronal function, usually w/neuronal cell death and protein aggregates (inclusion bodies)
What are the 4 major neurodegenerative diseases?
Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS)
Parkinson’s symptoms
resting tremor (“shaking palsy”), bradykinesia, akinesia, muscle rigidity, postural instability, dementia
What are the two most common causes of misdiagnosis for Parkinson’s?
1) Essential tremor (vs resting tremor in PD)
2) Shuffling gait (vs. gait/postural disorders in PD)
How to dx PD tremor? bradykinesia? ridigity? gait/posture?
1) tremor - handwriting differences (micrographia), slower tremor than essential
2) finger tapping test
3) cog wheel or ratchet “catch and release”
4) foot dragging, arm swing reduced on affect side, feet close together, stooped posture, difficulty turning
What are some causes of Parkinsonism
stroke, brain trauma, anesthesia, encephalitis, meningitis, antipsychotic drugs, anti-emetics, intoxication, CO poisoning, etc
Neurological basis for Parkinson’s
Major symptoms caused by depletion of dopamine NT in the substantia nigra pars compacta (80% loss of neurons).
Parkinson’s risk factors
genetics, age (CNS infections), environmental factors/toxins, oxidative stress, glutamate excitotoxicity, protein misfolding, mutations
Dopamine biosynthesis pathway
1) tyrosine–>L-DOPA (tyrosine hydroxylase)
2) L-DOPA–>Dopamine (aromatic AA decarboxylase)
3) Dopamine–>Norepi (dopamine beta-hydroxylase)
Tyrosine, L-DOPA and Dopamine: which cross BBB and which don’t?
Tyrosine and L-DOPA cross BBB; Dopamine does not
Why can’t you treat Parkinson’s patients with dopamine?
it doesn’t cross BBB! Also, oral dopamine will be quickly converted by AAD and COMT so ineffective. Also, low dose can cause orthostatic hypotension, high dose can cause hypertension, tachycardia, nausea and vomiting
What are the cardiovascular effects of dopamine at low dose?
stimulates mesenteric/renal D1 = vasodilation and increased renal blood flow; stimulates presynaptic D2 receptors = decreased alpha1 adrenergic vasomotor tone
What are the cardiovascular effects of dopamine at intermediate dose?
stimulates B-adrenergic in addition to D1; so it will also stimulate myocardial contraction and increase heart rate
What are the cardiovascular effects of dopamine at high dose?
Directly stimulates a1 adrenergic receptors to cause vasoconstriction, inc BP, inc afterload (bad for CHF patient; good only for very low BP circulatory failure ie sepsis/anaphylactic shock)
What dopamine precursor is used to treat Parkinson? What is it’s MOA? What is it used in combo with?
1) Levodopa (L-DOPA)
2) Oral dose absorbed in small bowel and converted to dopamine in periphery by AAD
3) Used in combo with carbidopa
What are some side effects of taking carbidopa and L-DOPA?
Dyskinesias, on-off phenomenon, neuroleptic malignant syndrome, psychosis w/chronic use, (+ hallucinations, GI distress, hypotension, dizziness with L-DOPA)
What are some limitations of dopamine precursor treatment with levodopa/carbidopa?
1) typically effective only for 2-5 yrs (wearing off effect); therefore delay starting tx until older
2) dyskinesias develop after 5-8 yrs
3) “on/off” phenomenon (oscillate between off w/out symptom relief and “on” w/dyskinesia)
What type of drug is Carbidopa? What’s it’s MOA?
Aromatic amino acid decarboxylase inhibitor (AAD inhibitor); it inhibits conversion of L-DOPA to dopamine and doesn’t cross BBB
Compare half lives between carbidopa and levodopa
Levodopa - short half life (1-3hrs); Carbidopa prob more like 4-6 hrs
What is contraindicated with Carbidopa use?
MAO-A inhibitors
What are the two types of Dopamine agonists
Ergot and Non-ergot derivatives
Name 2 Ergot derivatives. Which is no longer used to tx Parkinsons and what’s the reason?
Bromocriptine and Pergolide. Pergolide is no longer used–>causes cardiac valve regurgitation
What is the MOA or Bromocriptine and what does it tx?
MOA: D2 agonist and D1 antagonist
Tx: Mild Parkinson’s; DA agonism in neuroleptic malignant syndrome; hyper prolactinemia
What are some side effects of Bromocriptine?
Pleural effusions, cough, SOB, pulmonary fibrosis; takes weeks to titrate due to hypotension
What are the 3 selective D2 non-ergot receptor agonists that treat mild parkinsons?
Pramipexole, Ropinorole, Rotigotine
What are some common side effects and limitations of the selective D2 agonists?
more acute psychosis, nausea/GI, edema; less effective with motor symptoms of PD
Which D2 agonist also has compulsive behavior as a side effect?
Pramipexole
Which selective D2 agonist causes daytime sleep attacks?
Ropinorole
Which selective D2 agonist is administered as a transdermal patch?
Rotigotine
Which selective D2 agonists treat restless leg syndrome in addition to treating mild parkinsons?
Ropinorole and rotigotine
What is the name of the injectable non-ergot DA receptor agonist? What is it used for?
Apomorphine; used as rescue therapy for “off” periods (immobility)
What are the side effects of Apomorphine use?
psychosis, drowsiness, hypersexuality (increased erections), emesis (pre-administer trimethobenzamide or domiperidone); hypotension/LOC with serotonin receptor antagonists (thus contraindicated)
What are the two COMT inhibitors and how do they act?
Entacapone and Tolcapone; prevent breakdown of DA by prolonging half-life of L-DOPA.
Both reduce “off” time and work in the periphery and are short-acting (2hrs)
Would you administer Entacapone or Tolcapone first and why?
Entacapone because Tolcapone causes fatal hepatotoxicity (and also worse diarrhea). Both cause increase in dyskenesias and urine discoloration.
What are the 2 MAO-B inhibitors used to tx Mild early Parkinsons? How do they act?
Selegiline and Rasagiline. Both prevent breakdown of DA and may delay onset of levodopa therapy
Which MAO-B inhibitor is approved to use as an adjunct w/levodopa?
Rasagiline
What are some side effects of MAO-B inhibitors
hypotension, GI distress, dyskinesia, psychosis, nausea, vomiting
What are some contraindications to using MAO-B inhibitors?
decongestants, dextromethorphan, St. John’s wort, analgesics, methadone, tramadol, propoxyphene, caution w/SSRIs and MAO-A inhibitors
What are the 5 anticholinergics used to treat tremors and really bad drooling in Parkinson’s?
Benztropine, Biperiden, Trihexyphenidyl, Procyclidine, Ethopropazine
What are some side effects of the anticholinergics?
Bad mental symptoms (confusion, impaired memory, hallucinations); also typical anticholinergics (dry mouth, constipation etc)
When are anticholinergics contraindicated? What happens if they are abruptly discontinued?
They are contraindicated in demented Parkinson’s; Abrupt discontinuation exacerbates symptoms
What influenza antiviral drug is used to treat mild early Parkinson’s? What types of receptors does it act on?
Amantadine; acts on dopaminergic, anticholinergic, anti-NMDA receptors
What are some therapeutics of Amantadine?
best as adjunct to levodopa/carbidopa for longterm tx; only adjunct that reduces dyskinesias; tx movement disorders in Huntingtons
What are some contraindications of Amantidine?
Renal dysfunction requires lower dose (excreted unchanged in urine); contraindicated in elderly with dementia
How does deep brain stimulation treat symptoms of Parkinsons?
it hits the subthalamic nucleus to tx motor fluctuations/dyskinesia refractory to other meds; reduces “off” time; may reduce levodopa dosage (note that patients must still be sensitive to levodopa therapy in order to be a candidate)
What are some important side effects of deep brain stimulation?
Fatal intracerebral hemorrhage, cognitive impairment
Order of effectiveness against motor symptoms of PD?
1) Levodopa/carbidopa (age dependent)
2) Doapmine agonists (non-ergot)
3) COMT or MAO-B inhibitors
4) Anticholinergics rarely used (except for tremor/drool tx)
5) DBS (only advanced cases)
Huntington’s Disease effects in brain
Opposite of Parkinson’s: decreased GABAergic inhib drive from SNpr and medial globus pallidus onto VA/VL thalamic nuclei–>end result is increased excitatory input to motor cortex
What does the pharmacologic treatment for Huntington’s target?
None to deter disease progression; tx symptoms of depression, anxiety, irritability, paranoia, psychosis
How to treat movement disorder of Huntingtons?
not treated unless severe; tx w/dopamine-depletion tetrabenzine, reversible VMAT2 inhibitors, reserpine, amantadine; tx chorea with clonazepam and rigidity with antiseizure meds
What is the only approved therapy for ALS? What is its MOA?
Riluzole; it’s a Kainate and NMDA receptor antagonist that may inhibit Na channels and G-protein coupled receptors
What are some side effects of Riluzole? What reverses Riluzole effects?
Rare hepatotoxicity (check serum transaminase levels), nausea, diarrhea
Pertussis toxin reverses Riluzole’s clinical effects
What are two drugs used to treat spasticity associated with ALS?
Baclofen (GABAb agonist) and Tizanidine (a2 agonist)
What should be avoided when taking Baclofen?
Avoid sedative hypnotic muscle relaxants
What are the peripheral adverse effects of carbidopa/levodopa tx?
anorexia, nausea, vomiting, orthostatic hypotension (vascular DA receptor action), cardiac arrhythmia (alpha and beta adrenergic receptor effects) esp in patients w/preexisting condition
