Parkinson drugs Flashcards
Parkinson Disease
• Parkinson disease (PD) is a neurodegenerative disorder of the extrapyramidal system associated with the disruption of neurotransmission in the striatum
• Characterized by dyskinesias and akinesia
• Properfunctionofthestriatumrequiresabalancebetween
the neurotransmitters dopamine and acetylcholine (ACh)
• ImbalancebetweendopamineandAChresultsfromthe degeneration of the neurons that supply dopamine to the striatum
Therapeutic goals
- Idealtreatmentthatreversesneuronaldegenerationor prevents further degeneration does not exist
- The goal is to improve the patient’s ability to carry out the activities of daily life
- Drug selection and dosages are determined by the extent to which PD interferes with work, dressing, eating, bathing, and other activities of daily living
• Dopaminergic agents
- By far the most commonly used drugs for PD
- Promote activation of dopamine receptors
- Levodopa [Dopar]
• Anticholinergic agents
- Preventactivationofcholinergicreceptors
* Benztropine [Cogentin]
Levodopa
• Only given in combination with carbidopa or carbidopa/entacapone
• Highly effective, but benefits diminish over time
• Orally administered; rapidly absorbed from small intestine
• Food delays absorption
• Neutralaminoacidscompetewithlevodopaforintestinal
absorption and for transport across blood-brain barrier • High-protein foods reduce therapeutic effects
- Use in PD
- Diagnosis of PD questioned if levodopa fails
- Several months of treatment needed for full therapeutic response
- Symptomswellcontrolledforfirst2years
- Returntopretreatmentstateattheendof5years
- Acute loss of effect
- Gradualloss—“wearingoff”—developsneartheendof the dosing interval and indicates that drug levels have declined to a subtherapeutic value
- Wearingoffcanbeminimizedinthreeways:
- Shortening the dosing interval
- Giving a drug that prolongs levodopa’s plasma half-life (e.g., entacapone)
- Giving a direct-acting dopamine agonist
Mechanism of action
• Reduces symptoms by increasing dopamine synthesis in the striatum
• Levodopa,whichhasnodirecteffectsofitsown,isconvertedtodopamine, its active form
- Adverseeffects
- Nausea and vomiting
- Activationofdopaminereceptorsinthechemoreceptor trigger zone of the medulla
- Low initial doses and administration with food can reduce the therapeutic effects by decreasing levodopa absorption
- Giving additional carbidopa (without levodopa) can help reduce nausea and vomiting
- Thereasonthatcarbidopahelpsisunknown
- Adverse-effects • Cardiovascular
- Postural hypotension
- Increaseintakeofsaltandwater • Alpha-adrenergic agonist
Adverseeffects • Psychosis • Visualhallucinations • Vividdreamsornightmares • Paranoidideation • Causedbyactivationofdopaminereceptors • Symptoms can be reduced by lowering levodopa dosage • This will reduce beneficial effects as well
- Adverseeffects
- Central nervous system (CNS) effects
- Anxietyandagitation
- Memoryandcognitiveimpairment
- Insomnia and nightmares are common
- Problems with impulse control
- Behavioralchangesassociatedwithpromiscuity,gambling, binge eating, and alcohol abuse
- Adverseeffects
- Dyskinesias
- Levodopa is given to alleviate movement disorders, but it actually causes movement disorders in many patients
- Some dyskinesias are just annoying
- Others can be disabling
- Develop just before or soon after optimal levodopa dosage has been achieved
- Dyskinesias can be managed in three ways:
- Reduce dosage of levodopa
- Amantadine
- Surgery and electrical stimulation
Adverseeffects
• Darkens sweat and urine
• Activatesmalignantmelanoma:Importanttoperforma careful skin assessment of patients who are prescribed levodopa
- Drug interactions
- First-generation antipsychotic drugs (e.g., chlorpromazine, haloperidol) block receptors for dopamine in the striatum and decrease therapeutic effects of levodopa
- MAO inhibitors: Levodopa can cause a hypertensive crisis if administered to an individual taking a nonselective MAO inhibitor
- Anticholinergic drugs: Excessive stimulation of cholinergic receptors contributes to the dyskinesias of PD; by blocking these receptors, anticholinergic agents can enhance responses to levodopa
- Drug interactions
- Pyridoxine(vitaminB6)
- Stimulates decarboxylase activity
- Accelerationofdecarboxylationoflevodopainthe periphery; pyridoxine can decrease the amount of levodopa available to reach the CNS
- Therapeuticeffectsoflevodopacanbereduced
- Because levodopa is now always combined with carbidopa, a drug that suppresses decarboxylase activity, this potential interaction is no longer a clinical concern
Nonergot Dopamine Agonists
• Pramipexole[Mirapex]
- Used alone in early PD and with levodopa in advancing PD • Maximalbenefitstakeseveralweekstodevelop
- Adverseeffects
- Monotherapy: Nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations
- Combined: Orthostatic hypotension, dyskinesias, and increase in hallucinations
- Rareinstancesofpathologicgamblingandothercompulsive self-rewarding behaviors
Nonergot Dopamine Agonists
• Ropinirole [Requip]
• Ropinirole [Requip]
• HighlyselectiveforD2andD3receptors;bothdrugssharethesame
indications: PD and restless legs syndrome
• PD:RopinirolecanbeusedasmonotherapyforearlyPDandasan adjunct to levodopa for advanced PD
• Mostcommoneffectsarenausea,dizziness,somnolence,and hallucinations
• Rarely sleep attacks will occur
• When ropinirole is combined with levodopa, the most important side
effects are dyskinesias, hallucinations, and postural hypotension
• Compulsive gambling, shopping, eating, and hypersexuality
• Drug should not be used during pregnancy
Nonergot Dopamine Agonists (Cont.)
• Rotigotine[Neupro]
• ManagementofPDfromearlytoadvancedstages
• Management of moderate to severe primary restless legs syndrome
• Mostcommonadverseeffects:CNSandneuromuscular system effects, sleeping disorders, dizziness, headache, dose- related hallucinations, and dose-related dyskinesia
• Orthostatic hypotension and peripheral edema may occur
• Nauseaandvomiting,skinreactionsatthesiteofapplication,
and hyperhidrosis (excessive perspiration)
Nonergot Dopamine Agonists
• Apomorphine [Apokyn]
• Acute treatment of hypomobility during “off” episodes in
patients with advanced PD
• Notgivenbymouth
• NotindicatedforroutinePDmanagement
• Derivative of morphine but devoid of typical opioid effects (e.g., analgesia, euphoria, respiratory depression)
• Adverseeffects
Ergot Derivatives
• Bromocriptine
- When combined with levodopa, bromocriptine can prolong therapeutic responses and reduce motor fluctuations
- Bromocriptineallowsthedosageoflevodopatobereduced
- Theincidenceoflevodopa-induceddyskinesiasmaybereduced
• Adverseeffects
• Nausea
• Psychologicalreactions(e.g.,confusion,nightmares,agitation,
hallucinations, paranoid delusions)
• Retroperitonealfibrosis,pulmonaryinfiltrates,aRaynaud-like phenomenon, erythromelalgia, and valvular heart disease
Ergot Derivatives
Cabergoline
- OccasionallyusedforPD
- “Possiblyeffective”forimproving“off”timesduring levodopa therapy
- Hyperprolactinemia
COMT Inhibitors
Entacapone [Comtan]
• Inhibit metabolism of levodopa in the periphery
- Selective and reversible inhibitor of COMT
- Indicated for use with levodopa
- Inhibits metabolism of levodopa in the intestines and the peripheral tissues
- Prolongs time that levodopa is available to the brain
- Increases levodopa availability by inhibiting COMT, which decreases the production of levodopa metabolites that compete with levodopa for transport
- Adverseeffects
- Dyskinesias
- Orthostatic hypotension
- Nausea
- Hallucinations
- Sleep disturbances
- Impulse control disorders
- Managed by decreasing levodopa dosage
- Entacapone can cause vomiting, diarrhea, constipation, and yellow- orange discoloration of the urine
- Drug interactions
- IncreaseslevelsofdrugsmetabolizedbyCOMT,including levodopa as well as the following:
- Methyldopa (an antihypertensive agent)
- Dobutamine (an adrenergic agonist)
- Isoproterenol (a beta-adrenergic agonist)
Tolcapone [Tasmar]
• Used only in conjunction with levodopa
• Benefitsderivedfrominhibitinglevodopametabolisminthe periphery, which prolongs levodopa availability
• Improvesmotorfunctionandmayallowforareductionin levodopa dosage
• Reducesthe“wearing-off”effectthatcanoccurwithlevodopa, thereby extending levodopa “on” times by as much as 2.9 hours a day
• Deathsfromliverfailurehaveoccurred
• Treatmentshouldbelimitedto3weeksintheabsenceofa
beneficial response
Levodopa/Carbidopa/Entacapone
- Fixed-dose combinations sold as Stalevo
- More convenient than taking separate doses • Disadvantages
- Availableonlyinimmediate-releasetablets • Availableinonlythreestrengths
MAO-B Inhibitors
• Combination with levodopa can reduce the wearing- off effect
Selegiline [Eldepryl, Zelapar]
- Monotherapy or used with levodopa
- Modest improvement in motor function
- Causes selective and irreversible inhibition of MAO- B
- Can suppress the destruction of dopamine derived from levodopa and prolong the effects of levodopa
- Benefits decline dramatically within 12 to 24 months
