Pharmacology: Parkinson’s Disease – Flashcards
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Which receptors are the targets of most antiparkinsonism drugs?
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The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors, but D1-receptor stimulation may also be required for maximal benefit.
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What is the pharmacological goal of therapy in the treatment of Parkinson's disease?
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Therapy is aimed at restoring dopaminergic input in the basal ganglia and/or antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/ACh balance.
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What is levodopa?
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Levodopa is the levorotatory stereoisomer of dopa and a precursor of dopamine; it can restore dopamine levels in the extrapyramidal centers.
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Why is levodopa effective in treating patients in the early stages of Parkinson's?
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In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra is adequate for conversion of levodopa to dopamine.
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Why does levodopa therapy eventually fail?
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With time, the number of neurons decreases and there are fewer cells capable of taking up exogenously administered levodopa and converting it to dopamine for storage and release. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body.
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What is the mechanism of action for levodopa?
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Dopamine can't cross the blood-brain barrier, so its immediate precursor, levodopa, is transported into the CNS via facilitative L-transport system for neutral amino acids, where it is converted to dopamine in the brain. A large fraction of levodopa is decarboxylated to dopamine by L-dopa decarboxylase in the periphery, resulting in peripheral side effects (nausea, vomiting, cardiac arrhythmias, hypotension).
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How can the ingestion of proteins containing neutral amino acids inhibit the effects of levodopa?
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The L-system is also involved in the transport of other L-neutral amino acids including phenylalanine, tyrosine, tryptophane, leucine, isoleucine, methionine, valine, and histadine. The reversal of the effects of levodopa by the ingestion of proteins containing these other amino acids is thought to occur at the blood-brain barrier by competitive inhibition.
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What is sinemet?
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Sinemet is a preparation containing carbidopa and levodopa in fixed proportion (1:10 or 1:4).
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What is carbidopa?
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Levodopa is generally given in combination with carbidopa, a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. This decreases the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing the availability of levodopa to the CNS.
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Which factors affect the bioavailability of levodopa?
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Levodopa is absorbed rapidly from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain.
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What are the metabolites of levodopa?
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About 2/3 of the dose appears in urine as metabolites; the main metabolites are 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC).
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Why must levodopa be given in large amounts? How can this be remedied?
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It must be given in large amounts because *only 1-3% of administered levodopa actually enters the brain unaltered*, the remainder being metabolized extra-cerebrally. *Adding carbidopa can reduce the peripheral metabolism*, leading to higher plasma levels of levodopa, longer half-life, and more availability to the CNS.
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What is the clinical use of levodopa?
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Levodopa with carbidopa is useful in treating Parkinson's disease by substantially reducing the severity of the symptoms in the first few years of treatment. Levodopa does not stop the progression of Parkinson's disease, but early initiation of levodopa therapy seems to lower the mortality rate due to the disease.
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What are the adverse effects of levodopa?
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• Anorexia, nausea and vomiting • Tachycardia, ventricular extrasystoles • Postural hypotension (diminishes with continued use) • Visual/auditory hallucinations and dyskinesia • Mood changes, depression and anxiety, insomnia.
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What is the cause of levodopa fluctuation?
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In some patients, they are related to the timing of levodopa intake, and they are then referred to as wearing-off reactions or end-of-dose akinesia. Other cases are independent of timing (on-off). Off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. The phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown.
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How do you treat off-periods in levodopa treatment?
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For patients with severe off-periods who are unresponsive to other measures, subcutaneous apomorphine may provide temporary benefit.
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What are the contraindications and adverse drug interactions of levodopa?
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• Vitamin B6 (cofactor for L-Dopa decarboxylase) • Phenelzine or tranylcypromine (hypertensive crisis) • Psychotic patients (exacerbates mental disturbance) • Angle-closure glaucoma • Cardiac patients (development of arrhythmias) • Antipsychotic drugs • Active peptic ulcer (GI bleeding) • Malignant melanoma (precursor of skin melanin)
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Can levodopa be given to a patient with open-angle glaucoma?
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Yes, those with chronic open-angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored.
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What is the advantage of using dopamine receptor agonists over levodopa?
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Unlike levodopa, they don't require enzymatic conversion for activity, therefore *they do not depend on the functional capacities of the nigrostriatal neurons*.
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Name the dopamine receptor agonists used to treat Parkinson's.
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• Bromocriptine (ergot derivative) • Pramipexole (nonergot derivative) • Ropinirole (nonergot derivative) • Rotigotine (nonergot derivative) • Apomorphine (nonergot derivative)
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What is bromocriptine?
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Bromocriptine, a D2 agonist, has been widely used to treat Parkinson's disease and has also been used to treat certain endocrinologic disorders, especially hyperprolactinemia.
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What is pramipexole?
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It has preferential *affinity for D3 receptors* an is effective for monotherapy for mild parkinsonism and in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. It may ameliorate affective symptoms. A possible neuroprotective effect may result from scavenging H2O2 and enhancing neutrotrophic activity.
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What is ropinirole?
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Ropinirole is a *relatively pure D2 receptor agonist* used as monotherapy in patients with mild PD, and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. Ropinirole is metabolized by cytochrome P450. Drugs metabolized by the liver may significantly reduce its clearance.
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What is rotigotine used for?
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Rotigotine was approved for the treatment of early stage Parkinson's disease. It's a transdermal formulation that offers the convenience of once-daily use and the advantage of more stable plasma levels.
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What are the adverse effects of dopamine agonists in treating Parkinson's?
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• Anorexia, nausea and vomiting (reduce with food) • Constipation, dyspepsia, and of reflux esophagitis • Bleeding from peptic ulceration. • Postural hypotension may occur. • Cardiac arrhythmias (discontinue treatment) • Peripheral edema is sometimes problematic. • Painless digital vasospasm (long-term ergot use) • Dyskinesias (reduce dose) • Confusion, hallucinations, delusions, etc. are more common and severe than with levodopa.
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What are the additional adverse effects of bromocriptine?
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It may cause headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia.
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What additional adverse effects can pramipexole, ropinirole and rotigotine have?
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They can cause uncontrollable somnolence. This requires discontinuation of the medication.
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In which patients are dopamine agonists contraindicated?
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Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction. Also avoid patients with peripheral vascular disease or peptic ulceration.
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What is apomorphine?
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It's a nonergot dopaminergic agonist approved for rescue therapy for the acute treatment of "off" episodes of akinesia in patients on dopaminergic therapy. Give it SC.
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What are the adverse effects of apomorphine?
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• Highly emetogenic • QT prolongation • Dyskinesias • Drowsiness • Sweating • Hypotension • Bruising at the injection site
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How can emesis caused by apomorphine be treated?
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Pretreatment with the *antiemetic trimethobenzamide* is recommended; oral domperidone is also effective in blocking emesis. *5-HT3 receptor antagonists are contraindicated* because the combination can cause profound hypotension and loss of consciousness.
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How does selegiline affect Parkinson's?
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Since it selectively and irreversibly inhibits MAO-B (which metabolizes dopamine), it retards the breakdown of dopamine in the brain; Selegiline's effect on PD symptoms is modest when given alone. Selegiline is mainly used as adjunctive therapy for patients with a declining or fluctuating response to levodopa.
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What happens if selegiline is taken after mid-afternoon?
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Selegiline is metabolized to methamphetamine and amphetamine; the stimulating properties may produce insomnia if the drug is taken later than midafternoon.
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How is rasagiline used in Parkinson's disease?
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It's a MAO-B inhibitor approved *for early symptomatic treatment and also as adjunctive therapy to prolong effects of levodopa-carbidopa in patients with advanced disease*.
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What is the mechanism of action for entacapone and tolcapone?
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Inhibition of dopa decarboxylase leads to compensatory activation COMT, which increases plasma levels of 3-O-methyldopa. 3-O-MD competes with levodopa for a carrier that governs its transport across the intestinal mucosa and the blood-brain barrier. *Inhibition of COMT by tolcapone and entacapone leads to decreased metabolism of levodopa, decreased plasma levels of 3-O-MD, increased uptake of levodopa and higher concentrations of dopamine in the brain.*
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Which COMT inhibitor may be added to a preparation of levodopa/carbidopa?
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Entacapone is also available as fixed-dose combinations with levodopa/carbidopa. Use of this preparation simplifies the drug regimen and requires consumption of fewer tablets.
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Which COMT inhibitor is preferred in the treatment of Parkinson's?
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Entacapone is generally preferred because it has not been associated with hepatotoxicity.
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How do tolcapone and entacapone compare to one another?
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The pharmacologic effects of tolcapone and entacapone are similar and both are rapidly absorbed, bound to plasma proteins and metabolized prior to excretion. However, *tolcapone has both central and peripheral effects, whereas the effect of entacapone is only peripheral.*
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When are COMT inhibitors used in Parkinson's?
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The COMT inhibitors are useful as levodopa extenders but ineffective when given alone. These agents may be helpful in patients receiving levodopa who have developed response fluctuations (smoother response, more prolonged "on-time", and the option of reducing the total daily levodopa dose).
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What are the adverse effects of COMT inhibitors?
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Adverse effects include dyskinesias, nausea and confusion, diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. *Fulminating hepatic necrosis is associated with the use of tolcapone*.
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What good is amantadine in Parkinson's disease?
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It has antiparkinsonian actions and appears to increase synthesis, release or re-uptake of dopamine from the surviving neurons. It is less efficacious than levodopa and tolerance develops more readily, but it has fewer side effects.
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What are the adverse effects of amantadine?
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• Restlesness, agitation, confusion and hallucinations • Acute toxic psychosis (high doses) • *Livedo reticularis (ends ~1 month of withdrawing)* • Peripheral edema • Headache, heart failure, orthostatic hypotension, urinary retention and GIT disturbances. • Use with caution in patients with seizures/heart failure.
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Which anti-muscarinic drugs may help with parkinsonism?
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Benztropine mesylate and trihexyphenidyl are centrally acting anti-muscarinic agents; they are less efficacious than levodopa and play only an adjuvant role in antiparkinsonian therapy; They may improve the tremor, rigidity and drooling but have little effect on bradykinesia.
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What is the drug of choice for Parkinson's Disease?
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Use levodopa/carbidopa! If that doesn't work, consider adding a non-ergot dopamine agonist; if it still doesn't work, add a COMT inhibitor.
