Term
| what is a tremor? what are the 2 kinds? |
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Definition
| a rhythmic oscillatory movement around a joint of which there are 2 kinds: 1) postural, which occurs during sustained posture (cardinal feature of benign essential/familial tremor). 2) intention, which results from a lesion of the brain stem/cerebellum or alcohol toxicity and occurs during movement. |
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Term
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Definition
| irregular, unpredictable, involuntary muscle jerks which occur in different parts of the body and impair voluntary activity. if the abnormal movements are particularly violent, the term ballismus has been used to describe them. |
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Term
| what is athetosis? dystonia? |
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Definition
| athetosis = abnormal movements which may be slow and writhing in character. if these movements are more properly regarded as abnormal postures = dystonia. either may occur w/perinatal brain damage or focal/generalized cerebral lesions. |
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Term
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Definition
| sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head, especially in children, and can be suppressed voluntarily for short periods of time |
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Term
| what is the pathophysiology of parkinson's? |
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Definition
| the substantia nigra under-produces dopamine (due to degeneration of the pars compacta) which normally inhibits the striatum's inhibition of the external globus pallidus (external) which inhibits the subthalamic nucleus which excites the internal globus pallidus, which inhibits the thalamus which excites the cortex (indirect pathway). since there is less inhibition of the subthalamic nucleus, the internal globus pallidus overinhibits the thalamus, causing less signaling to get to the cortex = rigidity, bradykinesia, tremor, and postural instability. various other neurotransmitters, such as norepinephrine, are also depleted in the brain in parkinsonism, but these deficiencies are of uncertain clinical relevance. |
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Term
| what genetic etiologies are associated w/parkinson's? |
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Definition
| mutations of the alpha-synuclein gene at 4q21, the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen, and the UCHL1 gene may cause autosomal dominant parkinsonism. mutations in the parkin gene (6q25.2–q27) may cause early-onset, autosomal-recessive, familial parkinsonism, or sporadic juvenile-onset parkinsonism. genetic factors are more important when considering pts under 50. |
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Term
| what drugs can induce parkinson's? |
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Definition
| dopamine receptor antagonists or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] (leads to the destruction of the dopaminergic nigrostriatal neurons) |
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Term
| why is levodopa used to tx parkinson's? |
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Definition
| dopamine does not cross the blood brain barrier, but (–)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine. (levodopa is the levorotatory stereoisomer of dopa - which is the amino acid precursor of dopamine and norepinephrine) |
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Term
| which types of dopamine receptors are most responsive to rx stimulation? |
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Definition
| the D2 receptors (located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia) seem to provide most of the benefit, but the D1 type (located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra) may be required for maximum benefit. |
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Term
| what characterizes absorption of levodopa? |
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Definition
| levodopa is absorbed in the small intestine, but ingestion of food delays this. plasma concentrations usually peak between 1-2 hrs and the half-life is between 1-3 hrs. 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the BBB (however, when given in combination with a dopa decarboxylase inhibitor that does not penetrate the BBB such as carbidopa, the peripheral metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain = reduction in levodopa requirement by 75%). |
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Term
| what characterizes the clinical use of levodopa? |
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Definition
| the benefits of levodopa tx often begin to diminish after about 3 or 4 years of therapy, regardless of the initial therapeutic response (to avoid ADRs resulting from a progressively lower tolerance). although levodopa therapy does not stop the progression of parkinsonism, its early initiation lowers the mortality rate. levodopa is generally given w/carbidopa and started at small doses which are gradually increased to carbidopa 25 mg/levodopa 250 mg 3-4x daily. monotherapy by intraduodenal infusion of levodopa-carbidopa appears to be safe and is superior to a number of oral combination therapies in patients with response fluctuations. levodopa can ameliorate all the clinical features of parkinsonism, but it is particularly effective in relieving bradykinesia and any disabilities resulting from it in 1/3 of pts. |
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Term
| what are the GI ADRs associated w/levodopa? |
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Definition
| if given w/o carbidopa (peripheral decarboxylase inhibitor), anorexia and n/v occurs in 80% of pts - but this drops to 20% w/carbidopa. |
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Term
| what are the CV ADRs associated w/levodopa? |
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Definition
| commonly: postural hypotension and HTN (esp if nonselective monoamine oxidase inhibitors/sympathomimetics/massive doses are taken). uncommonly: tachycardia, ventricular extrasystoles and, more rarely, atrial fibrillation |
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Term
| what characterizes the incidence of dyskinesias w/levodopa tx? |
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Definition
| dyskinesias occur in up to 80% of pts on long term levodopa tx w/choreoathetosis of the face and distal extremities being the most common. |
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Term
| what characterizes the incidence of behavioral effects w/levodopa tx? |
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Definition
| depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality have been reported and are more common in pts also on a decarboxylase inhibitor rather than levodopa alone. |
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Term
| what characterizes the incidence of fluctuations in response w/levodopa tx? |
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Definition
| as tx continues, wearing-off reactions/end-of-dose akinesia may occur which relates to timing of levodopa intake OR the on-off phenomenon may occur where off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia (more common in pts who initially responded well to tx). |
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Term
| what misc ADRs are associated w/levodopa tx? |
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Definition
| mydriasis (excessive pupillary dilation, can lead to acute glaucoma), various blood dyscrasias, positive coomb's test (w/evidence of hemolysis), hot flushes, aggravation/precipitation of gout, abnormalities of smell/taste, brownish discolorations of saliva, urine, or vaginal secretions; priapism, and mild elevations of BUN, serum transaminases, alk phos, and bilirubin. |
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Term
| are drug holidays recommended for levodopa? |
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Definition
| no - this carries risks for aspiration pneumonia, venous thrombosis, pulmonary embolism, and depression resulting from the immobility accompanying severe parkinsonism |
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Term
| are there any drug interactions for levodopa? |
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Definition
| vit B6 (pyridoxine) enhances extracerebral metabolism of levodopa therefore a peripheral decarboxylase inhibitor is necessary and if levodopa is combined w/monoamine oxidase A inhibitors w/in 2 weeks = hypertensive crisis. |
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Term
| what contraindications exist for levodopa? |
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Definition
| levodopa can exacerbate psychotic pts' condition. levodopa is contraindicated in pts w/angle-closure glaucoma (but can be administered to open angle glaucoma). pts w/peptic ulcers can take levodopa, but require close management. pts w/a melanoma hx will require dermatologic monitoring as levodopa is precursor to skin melanin. |
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Term
| what characterizes the use of dopamine receptor agonists in parkinson's tx? |
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Definition
| dopamine receptor agonists do not require enzymatic conversion to an active metabolite like levodopa and do not compete w/other substances for active transport sites into the blood and across the BBB. dopamine receptor agonists may also have more limited ADRs than levodopa - particularly the newer agents (pramipexole and ropinirole) vs the older agents (bromocriptine and pergolide - which are ergot derivatives). dopamine agonists have an important role as 1st-line therapy for parkinson's as they have lower incidence of response fluctuations and dyskinesias. dopamine receptor agonists may also be combined w/a low dose of carbidopa plus levodopa or administered to pts w/end-of-dose akinesia or on-off phenomenon or are becoming resistant to treatment with levodopa. however, the response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa. |
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Term
| what specifically characterizes the dopamine receptor agonist bromocriptine? |
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Definition
| bromocriptine (ergot derivative) is a D2 older agonist, used less commonly now. it is absorbed in the GI and excreted in the bile/feces. peak plasma levels are reached in 1-2 hours, and to minimize ADRs, the dose is built up slowly over 2-3 months. |
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Term
| what specifically characterizes the dopamine receptor agonist pergolide? |
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Definition
| peroglide, an ergot derivative, stimulates both D1 and D2 receptors and has been shown to be more effective than bromocriptine - however it is no longer used due to its association w/valvular heart disease development. |
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Term
| what specifically characterizes the dopamine receptor agonist pramipexole? |
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Definition
| pramipexole is not an ergot derivative and has an affinity for D3 receptors. it may be used as monotherapy for mild parkinsonism or along w/levodopa in advanced cases to help reduce and smooth out response fluctuations. a possible neuroprotective effect has been suggested for pramipexole due to its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures. it is absorbed to peak plasma concentrations in approx 2 hours and is excreted unchanged in urine (renal insufficiency may necessitate dosage adjustment). |
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Term
| what specifically characterizes the dopamine receptor agonist ropinirole? |
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Definition
| ropinirole is not an ergot derivative but is a relatively pure D2 receptor agonist and is metabolized by CYP1A2. it is effective as monotherapy in pts w/mild diseases and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. |
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Term
| what specifically characterizes the dopamine receptor agonist rotigotine? |
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Definition
| rotigotine is delivered through a skin patch (intended to supply a more continuous dopaminergic stimulation than oral rx in *early disease). it was recalled due to crystal formation on the patches which affected the availability and efficacy. |
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Term
| what GI ADRs are associated w/the dopamine agonists? |
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Definition
| anorexia and nausea may occur w/initiation of tx and can be minimized if taken w/a meal. constipation, dyspepsia, and GERD are also possible. |
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Term
| what CV ADRs are associated w/the dopamine agonists? |
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Definition
| postural hypotension esp at initiation of therapy, painless digital vasospasm w/long term tx, cardiac arrhythmias (indication for discontinuation of tx), peripheral edema, and cardiac valvulopathy are also possible. |
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Term
| can dopamine receptor agonists lead to dyskinesias? |
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Definition
| yes, abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken. |
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Term
| can dopamine receptor agonists lead to mental disturbances? |
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Definition
| confusion, hallucinations, delusions, and other psychiatric reactions are potential complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. impulse control disorders are also possible and may lead to: compulsive gambling, shopping, betting, sexual activity, and other behaviors. these will clear w/discontinuation of tx. |
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Term
| what misc ADRs are associated w/dopamine receptor agonists? |
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Definition
| headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural/retroperitoneal fibrosis, erythromelalgia - all from ergot-derived dopamine receptor agonists (bromocriptine and pergolide). in rare instances, an uncontrollable tendency to fall asleep at inappropriate times has occurred, particularly in patients receiving pramipexole or ropinirole (this requires discontinuation of the medication). |
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Term
| what contraindications exist for dopamine receptor agonists? |
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Definition
| pts w/a hx of psychotic illness, recent MI, or w/active peptic ulceration. the ergot derived agonists (bromocriptine and pergolide) should be avoided in pts w/peripheral vascular disease. |
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Term
| what characterizes the use of monoamine oxidase (MAO) inhibitors in parkinson's? |
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Definition
| there are 2 kinds of MAO - monoamine oxidase A, which metabolizes norepinephrine/serotonin/dopamine and monoamine oxidase B, which metabolizes dopamine selectively. the 2 MAO inhibitors used in parkinson's are selegiline and rasagiline. |
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Term
| what characterizes the use of selegiline in parkinson's tx? |
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Definition
| selegiline is a selective irreversible inhibitor of MAO-B at normal doses (at higher doses it inhibits MAO-A as well), which slows breakdown of dopamine - enhancing/prolonging the effect of levodopa (allowing a dose reduction). it may cause insomnia if taken later than lunchtime. if administered as a monotherapy, selegiline only has a minor therapeutic effect |
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Term
| what characterizes the use of rasagiline in parkinson's tx? |
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Definition
| rasagiline is a MAO-B inhibitor and more potent than selegiline in preventing MPTP-induced parkinsonism and is being used for early symptomatic treatment. rasagiline is also used to prolong the effects of levodopa-carbidopa in patients with advanced disease. it may also provide a neuroprotective benefit. |
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Term
| what are the contraindications for the MAO inhibitors used in parkinsons tx? |
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Definition
| neither selegiline nor rasagiline should be taken by patients receiving meperidine. MAO inhibitors should be used w/care in pts on tricyclic antidepressants or serotonin reuptake inhibitors (due to a theoretical risk of acute toxic interactions of the serotonin syndrome type). nonselective MAO inhibitors should not be combined w/levodopa as this can lead to a hypertensive crisis (due to peripheral accumulation of norepinephrine). |
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Term
| what characterizes use of catechol-o-methyltransferase (COMT) inhibitors in parkinson's tx? |
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Definition
| inhibition of dopa decarboxylase is associated w/compensatory activation of other pathways of levodopa metabolism - esp COMT (which produces 3-O-methyldopa: 3-OMD). 3-OMD competes w/levodopa for active transport in the intestinal mucosa/BBB. therefore, selective COMT inhibitors tolcapone and entacapone prolong the action of levadopa by diminishing its peripheral metabolism (levodopa bioavailability is is increased, but neither time to peak concentration or max concentration are affected). |
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Term
| what characterizes the pharmacologic effects of tolcapone and entacapone? |
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Definition
| tolcapone and entacapone have similar pharmacologic effects (both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion). however, tolcapone has central and peripheral effects and entacapone only has peripheral effects. both drugs have a ~2 hr half-life, but tolcapone has a slightly longer duration of action and is slightly more potent. entacapone is generally preferred because it has not been associated with hepatotoxicity. a commercial preparation stalevo consists of a combination of levodopa with both carbidopa and entacapone (simplifies drug regimen). |
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Term
| what characterizes the ADRs associated w/tolcapone and entacapone? |
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Definition
| dyskinesias, nausea, confusion (reversible w/levodopa dosage drop), as well as diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. |
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Term
| what is apomorphine? ADRs? |
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Definition
| a potent dopamine agonist, which is used for temporary relief (rescue) of off-periods of akinesia in pts on optimized dopaminergic tx. it is administered via subcu injection, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. nausea is often a problem, therefore pretreatment with the antiemetic trimethobenzamide is recommended then continued for 1 month - infinity. other ADRs associated w/apomorphine include: dyskinesias, drowsiness, chest pain, sweating, hypotension, and bruising at the injection site. |
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Term
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Definition
| an antiviral agent found to have antiparkinsonian properties - it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. it has been reported to antagonize the effects of adenosine at adenosine A2A receptors (which are receptors that may inhibit D2 receptor function). release of catecholamines from peripheral stores has also been documented. peak plasma conc is reached 1-4 hrs after oral dose and the half life is between 2-4 hrs. most of the drug is excreted in the urine. |
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Term
| what characterized the clinical use of amantadine? |
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Definition
| amantadine is less efficacious than levodopa and short lived, but it can favorably influence the bradykinesia, rigidity, and tremor of parkinsonism. |
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Term
| what ADRs are associated w/amantadine? |
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Definition
| restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion. ODs may produce an acute toxic psychosis and convulsions. livedo reticularis, peripheral edema, headache, heart failure, postural hypotension, urinary retention, and GI disturbances have also been reported. all these ADRs can be reversed by stopping the drug. amantadine should be used w/caution in pts w/a hx of seizures or heart failure. |
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Term
| what acetylcholine-blocking (antimuscarinic) drugs can be used in tx of parkinson's? |
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Definition
| benztropine mesylate, biperiden, orphenadrine, procyclidine, and trihexyphenidyl all may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. tx is started with a low dose of one of the drugs in this category, the dosage gradually being increased until benefit occurs or until adverse effects limit further increments. if patients do not respond to one drug, a trial with another member of the drug class is warranted and may be successful. |
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Term
| what ADRs are associated w/the ACh-blocking drugs used against parkinson's? |
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Definition
| antimuscarinic drugs have a number of undesirable CNS and peripheral effects and are poorly tolerated by the elderly. dyskinesias occur in rare cases. acute suppurative parotitis sometimes occurs as a complication of dryness of the mouth. if the rx is withdrawn, this should be accomplished gradually rather than abruptly to prevent acute exacerbation of parkinsonism. |
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Term
| what surgical procedures are used in tx of parkinson's? |
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Definition
| thalamotomy (for conspicuous tremor) or posterovertebral pallidotomy are older treatments which have been mostly replaced. current sx tx generally consists of electrical stimulation of the subthalamic nucleus or globus pallidus and has yielded good results for management of clinical fluctuations occurring in advanced parkinsonism (contraindicated in pts w/secondary or atypical parkinsonism, dementia, or failure to respond to dopaminergic medication). transplantation of dopaminergic tissue (fetal substantia nigra tissue) has been reported to confer benefit in some parkinsonism patients. |
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Term
| what neuroprotective therapy is used in tx of parkinsonism? |
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Definition
| antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, coenzyme Q10, creatine, and anti-inflammatory drugs may slow disease progression. |
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Term
| what gene therapy is in used for parkinson's? |
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Definition
| infusion into the striatum of adeno-associated virus type 2 as the gene vector for: glutamic acid decarboxylase (the precursor of GABA, an inhibitory neurotransmitter) in the subthalamic nucleus for inhibition, aromatic acid decarboxylase in the putamen for increased metabolism of levodopa to dopamine, and neurturin (a growth factor that may enhance the survival of dopaminergic neurons) in the putamen. |
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Term
| what therapy exists for nonmotor parkinsonism manifestations? |
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Definition
| cognitive decline: rivastigmine, memantine, or donepezil. affective disorders: antidepressants or anxiolytic agents. excessive daytime sleepiness: modafinil. bladder and bowel disorders: appropriate symptomatic therapy. |
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Term
| what are the general guidelines for parkinson's tx? |
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Definition
| when symptomatic tx becomes necessary, a trial of rasagiline, amantadine, or an antimuscarinic drug may be worthwhile. w/disease progression, dopaminergic therapy becomes necessary. this can be initiated with a dopamine agonist, either alone or in combination with low-dose sinemet therapy. physical therapy is helpful in improving mobility. in pts with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of tx with a COMT inhibitor or rasagiline may be helpful. regulation of dietary protein intake may also improve response fluctuations. deep brain stimulation is often helpful in pts who fail to respond adequately to these measures. treating pts who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration. |
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Term
| what drugs can induce parkinsonism? |
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Definition
| tetrabenazine deplete biogenic monoamines from their storage sites, whereas haloperidol, metoclopramide, and the phenothiazines block dopamine receptors. the disorder caused by these tends to be symmetric w/an inconspicuous tremor and is generally related to high dosage and clears over several weeks or months after withdrawal. antimuscarinic agents may also be used to reverse this effect. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a protoxin is converted by monoamine oxidase B to N-methyl-4-phenylpyridinium (MPP+) which is taken up by cells in the substantia nigra where it inhibits oxidative phosphorylation = cell death and thus striatal dopamine depletion and parkinsonism. this chemical was used by pts in the 80's trying to support their opioid habit with a meperidine analog synthesized by an amateur chemist. (recognition of the effects of MPTP suggested that spontaneously occurring parkinson's disease may result from exposure to an environmental toxin that is similarly selective in its target. however, no such toxin has yet been identified.) |
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Term
| does the combination of levodopa and a decarboxylase inhibitor have its most positive impact on motor ability in parkinson's pts in the early or late stage of the disease? |
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Definition
the clinical outcome as evaluated by the selected UPDRS motor scores was better for L-dopa treated patients who received selegiline within 5 years from the onset compared with those who
received selegiline (levodopa and a decarboxylase inhibitor) approximately 10 years from the onset. |
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Term
| is there a benefit between administering IPX054, a bilayer tablet of immediate- and extended-release carbidopa/levodopa (CD/LD) given twice daily to the standard CD/LD given 4 times daily to parkinson's pts? |
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Definition
| in stable PD patients, no difference was detected between twice-daily treatment with IPX054 and CD/LD given 4 times daily. in this group, substitution with IPX054 reduced dosing frequency while maintaining CD/LD efficacy. in clinical practice, this ease of administration may offer improved treatment compliance. |
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Term
| what is the effect of expectation on placebo-induced dopamine release in parkinson's disease? |
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Definition
the strength of belief of improvement can
directly modulate dopamine release in patients with PD. uncertainty
and/or salience carry influence over and above a patient’s prior treatment
response in regulating the placebo effect and have important implications for the interpretation and design
of clinical trials. significant dopamine release occurred when the
declared probability of receiving active medication was 75%, but not at other probabilities. placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. whereas response to prior medication was the major determinant of placebo induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required
to drive dopamine release in the ventral striatum. |
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Term
| is there a benefit in switching parkinson’s pts with a fluctuating response to levodopa (L-dopa) from the adjunctive dopamine agonist treatment to tolcapone (a COMPT-inhibitor)? |
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Definition
tolcapone, in principle, seems to be an alternative adjunct for patients, who fail to receive sufficient benefit from a dopamine agonist, for example, in case they do not tolerate an increase in
dose or have unacceptable side effects. the switch from a dopamine agonist to tolcapone can be done safely within a few days. |
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