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49 Cards in this Set
- Front
- Back
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1. Describe the major anatomical pathways and neurotransmitter systems involved in control of motor function
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a. Dopaminergic neurons project from the substantia nigra to the corpus striatum, and convey inhibitory signals to GABAergic neurons located there. Stimulatory striatal cholinergic neurons also act on GABAergic neurons in the striatum.
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parkinsons is a disease with low levels of what?
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striatal dopamine
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what is a theory about what causes the damage in parkinsons?
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free radicals
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why are free radicals an issue in parkinsons?
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Enzymatic dopamine oxidation in the glia (by monoamine oxidase) may contribute to the generation of radicals. The reaction generates hydrogen peroxide, which is normally detoxified by glutathione but which in the presence of iron can undergo the Fenton reaction, resulting in hydroxyl free radicals (see figure on p. 515). Since there is a lot of iron in dopaminergic neurons (it is a cofactor for tyrosine hydroxylase), there is a lot of potential for free radicals to be generated.
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what is the role of the the striam in voluntary movement?
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a. Voluntary movement is controlled by a balance between inhibitory nigrostriatal dopaminergic and stimulatory striatal cholinergic neurons acting on striatal GABAergic neurons. In normal tissue dopaminergic and cholinergic signaling are in balance.
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what is the goal in pahrkinsons treatment?
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b. In Parkinson’s Disease, this balance is disturbed by degeneration of dopaminergic neurons. Therapies for PD are therefore aimed at restoring the balance between dopaminergic and cholinergic signaling. Most of these therapies are directed towards enhancing dopamine levels.
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what is the predicited result of drugs that suppress dopamine levels?
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can induce Parkinsonism.
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what is the issue with voluntary movement in huntingtons?
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c. In contrast to PD, Huntington’s disease is the result of loss of GABAergic neurons (and some cholinergic neurons). Therefore the problem is not dopamine signaling (there are regular dopamine levels), but rather GABA signaling (see figure on p. 516). Therapies that work for PD will not be effective for HD.
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what is levodopa?
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a. Levodopa is a precursor of dopamine that is able to cross the blood brain barrier. In the striatum it is converted to dopamine and increases dopamine levels.
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what is the problem with solitary treatment with levodopa?
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. However, when given alone only 1-3% of the levodopa will enter the brain unaltered because most of it is metabolized to dopamine in the periphery.
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what is the use of carbidopa?
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b. Carbidopa can be given to increase the amount of levodopa that is delivered to the brain.
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what is the MOA of carbidopa?
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Carbidopa inhibits peripheral dopa-decarboxylase, the enzyme that metabolizes dopa to dopamine. The result is that you need a lower total dose to get the same total levodopa delivery to the brain
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what are side effects of Levodopa?
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c. Side effects of levodopa include peripheral and CNS toxicities. Peripheral toxicities include GI symptoms (nausea, vomiting, anorexia), and cardiovascular symptoms (postural hypotension). CNS effects include neurological symptoms (dyskinesias) and behavioral symptoms (insomnia, anxiety, 15% suffer confusion, psychosis).
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how can some of levodopa's side effects be reduced? what is the problem with it?
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Combination therapy with carbidopa decreases the peripheral side effects of levodopa, but increases the CNS side effects.
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the three major classes of direct DA receptor agonists are?
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the ergot alkaloids
the non ergot dopamine agonists apomorphine |
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what are the ergot alkaloids?
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Bromocriptine and Pergolide
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what are the adverse effects of the ergot alkaloids?
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Their adverse effects include hypotension, nausea, and hallucinations.
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what are the nonergot dopamine agonists
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Pramipexole and Ropinirole
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what is the main use of apomorphine in movement disorders?
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c. Apomorphine is an additional dopamine agonist that is used for temporary relief or “rescue” from off-periods of akinesia. It is injected subcutaneously, with rapid uptake and clinical benefit within 10 minutes
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what are the adverse effects of apomorphine?
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A side effect is nausea and vomiting, which can be prevented by pretreatment with an antiemetic.
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what is sinemet?
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carbidopa + levodopa, 1:4 or 1:10 ratio
i. Combination increases the effectiveness of levodopa therapy. |
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what is amantadine?
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d. Amantadine: increases the synaptic concentration of dopamine (is not an agonist, rather it stabilizes dopamine in the synapse).
i. Need to know tradename – Symmetrel |
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what is efficacy of amantadine vs levodopa?
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ii. Amantadine demonstrates less efficacy and less toxicity than levodopa. It is frequently administered with levodopa.
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why is apomorphine needed even during treatment with levodopa for parkinsins?
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i. During levodopa therapy, an “on-off” phenomenon is observed during which the patient experiences changes is the effectiveness of the therapy. During the “off” periods, they may experience symptoms that need treatment with Apomorphine.
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what are the important anticholinergic drugs?
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i. Trihexyphenidyl, Benztropine, Biperiden, Orphenadrine, Procyclidine
ii. Need to know tradename of Benztropine – Cogentin iii. Need to know tradename of Trihxyphenidyl – Artane |
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what is the main use of anticholinergics?
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v. These drugs are not really used to treat Parkinson’s Disease anymore. They are more efficacious in treating and therefore used to counteract drug induced Parkinsonism.
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what are the trade names of the ergot alkaloids?
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2. Need to know tradename of Bromocriptine – Parlodel
3. Need to know tradename of Pergolide – Permax |
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what is selegiliine?MOA
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inhibition of Monoamine Oxidase B (present in glial cells, not periphery) prevents metabolism/breakdown of dopamine and production of hydrogen peroxide.
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what is the use of selegiline?
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i. Decreases the incidence of dyskinesias and “on-off” fluctuations. Also prolongs the usefulness of levodopa (increases the number of years that it will be effective).
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what is the trade name of selegiline?
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ii. Need to know tradename – Eldepryl, Carbex
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what is Catechol-O-Methyltransferase (COMT) Inhibitors MOA?
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ii. Inhibit peripheral metabolism of levodopa to 3-O-methyldopa and enhance the uptake of levodopa.
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what are the Catechol-O-Methyltransferase (COMT) Inhibitors examples and which is prefered?
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i. Entacapone, Tolcapone
iii. Entacapone is preferred due to the potential hepatotoxicity of tolcapone. |
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what are the drugs that cause parkinsonism?
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a. Drugs that suppress dopamine, such as the antipsychotic haloperidol, can cause Parkinsonism. Drugs that increase cholinergic signaling can also produce Parkinson-like symptoms.
b. Exposure to the dopamine neurotoxin MPTP causes a syndrome indistinguishable from Parkinson’s disease. MPTP is a contaminant that can result from sloppy synthesis of MPPP, a street analog of the opioid meperidine (Demerol). |
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what is used to treat drug induced parkinsonism?
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c. Drug-induced Parkinsonism is often treated by the ergot alkaloids.
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presenation of huntingtons?
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a. Huntington’s disease is an autosomal dominant inherited disorder characterized by the gradual onset of motor incoordination and cognitive decline in midlife. Symptoms include either a movement disorder manifested by brief, jerklike movements of the extremities, trunk, face, and neck (chorea) or personality changes, or both.
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treatement for huntingtons?
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b. Therapy for Huntington disease involves symptomatic treatment only.
c. Pharmacological therapy for the movement disorder of HD is usually only indicated in those with large-amplitude chorea causing frequent falls and injury. Therapy includes dopamine-depleting agents such as tetrabenazine and reserpine. |
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what is a good treatment for depression and irritability in huntingtons?
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ii. Fluoxetine is effective treatment for both the depression and the irritability manifest in symptomatic HD.
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what can carbamazepine be used for in huntingtons?
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iii. Carbamazepine also has been found to be effective for depression.
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when are peak plasma conc. of levodopa?
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1-2 hours
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what will delay absorption of levodopa
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food in stomach
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what is levodopa metabolized to?
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HVA and DOPAC
2/3 of oral dose in urine as these metabolites in 8 H |
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what is the wearing off or end of dose fluctuation in the therapeutic response to levodopa?
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akinesia begins as the you get close to your next dose time.
can be related to timeing of the dose or bc of nigrostriatal tract degen |
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what are some drug interactions of levodopa?
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beta agonists-increased cardic stim
pyridoxine(vit. B6)- decreases devodopa by increased extracerebral metabolism antipsychotic - decrease efficacy of levodopa MAOI- hypertensive crisis |
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what is the target of carbidopa?
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blocks peripheral
dopa-decarboxylase |
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what is used to treat restless leg?
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pramiplexole and ropinrole
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what drugs are linked to complusive gambling
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pramipexole and ropinirole
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which drug targets D3? D2? both?
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D3-pramipexole
D2-ropinirole both-apomorphine |
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what is genetic cause of huntingtons?
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triplet repeat expansion in IT15 gene on chrom 4
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what is the codon repeat in huntingtons?
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CAG 40-100 repeats
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