Term
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Definition
• Unclear etiology, likely combination of genetic and environmental factors
• Proposed mechanisms: oxidative stress, mitochondrial dysfunction, protein aggregation and misfolding, inflammation, excitotoxicity, apoptosis
• Progressive loss of dopaminergic neurons à symptoms only appear after significant (>60%) loss
• Non-motor symptoms often precede classic motor symptoms
• First symptoms may be hyposmia/anosmia and constipation |
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Term
Parkinson’s Disease: Symptoms
Motor symptoms |
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Definition
• Tremor at rest
• Bradykinesia
• Rigidity
• Postural instability
• Gait impairment |
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Term
Parkinson’s Disease: Symptoms
Non-Motor symptoms |
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Definition
• Cognitive impairment
• Depression
• Psychosis
• Autonomic dysfunction
• Sleep disorders
• Pain and paresthesias |
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Term
| Parkinson’s Disease etiology |
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Definition
• Second most common neurodegenerative disease
• Male predominance, usually appears in advanced age
• May be multitude of disorders with similar symptomatology
• No agent has been proven to be neuroprotective |
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Term
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Definition
• Rhythmic oscillatory movement around a joint
• Essential tremor is most common
• Postural tremor
- Occurs at rest
- Associated with benign essential tremor, Parkinson’s disease
• Intention tremor
• Occurs with movement
• Often drug- or alcohol-induced |
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Term
| Essential Tremor: Treatment |
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Definition
• Inderal (propranolol) and Mysoline (primidone) are first-line
• 30–50% of patients will not adequately respond to first-line therapies
• Oral therapies preferred over injectables (botulinum toxin)
• Surgical intervention last-line |
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Term
| Essential Tremor: Treatment agents |
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Definition
Effective: propranolol, primidone
Probably effective: alprazolam, atenolol, gabapentin, sotalol, topiramate |
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Term
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Definition
• Irregular, unpredictable, involuntary muscle jerks which impair voluntary activity
• May be induced by certain medications (antipsychotics, copper toxicity)
• May be hereditary (Huntington’s disease |
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Term
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Definition
• Treatunderlyingdisorderifpresent (thyrotoxicosis, systemic lupus erythematous, hepatic cirrhosis, etc.)
• Discontinuationofoffendingagent(levodopa, antimuscarinics, amphetamines, lithium, phenytoin, oral contraceptives)
• Dopamineantagonists(haloperidol,olanzapine, perphenazine)
• Central monoamine depleting agents(reserpine) |
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Term
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Definition
• Sudden, brief, coordinated, often repetitive abnormal movements or sounds
• Temporarily suppressible by patient
• Often associated with Tourette’s syndrome |
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Term
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Definition
• Reduce dose of stimulant
• Neuroleptics (haloperidol, risperidone, aripiprazole, fluphenazine)
• Catapres® (clonidine)
• Tenex® (guanfacine)
• Botox ® (Botulinum toxin A) for motor tics
• Pimozide (rarely used due to significant adverse effects) |
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Term
| Drug-Induced Dystonia/Dyskinesia |
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Definition
• Induced by dopamine antagonists such as antipsychotics and some antiemetics
• Dose-related, usually appears within first three months
• May appear with first dose of phenothiazine antipsychotics |
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Term
| Drug-Induced Dystonia/Dyskinesia: Management |
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Definition
• Discontinue or reduce dose of causative agent
• Anticholinergic medications (example: benztropine)
• Antihistamines (diphenhydramine)
• Valium® (diazepam) |
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Term
|
Definition
• Appearafterprolongeduseofdrugssuchas neuroleptics or metoclopramide
• Avoidconcomitantuseofneurolepticsand antimuscarinics
• Atypicalantipsychoticspreferredovertypical antipsychotics
• Generallyirreversible,difficulttotreat
• Withdrawal of offending agent may worsen symptoms while increasing the dose may suppress them |
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Term
| AJ is a 34-year-old female with severe nausea. After a dose of Reglan (metoclopramide) 10 mg, she develops an acute dystonic reaction. How would you treat AJ? |
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Definition
Benztropine 1–2 mg by slow intravenous injection. Most patients respond within 5 minutes and are symptom-free by 15 minutes. If there is no response the dose can be repeated after 10 minutes, but if that does not work then the diagnosis is probably wrong.
Other options: diphenhydramine, promethazine, diazepam. |
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Term
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Definition
• Able to cross blood-brain barrier where it is metabolized to dopamine
• Always given with dopa decarboxylase inhibitor (carbidopa) to reduce peripheral metabolism of levodopa, thereby making more levodopa available to reach CNS
• Limited by tolerance and development of levodopa-induced dyskinesias
-for parkinsons |
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Term
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Definition
| Administration of levodopa is often limited by tolerance and development of levodopa-induced dyskinesias. So as you can see here, on the base of the screen, levodopa is highlighted in the periphery. You can see the enzyme that's responsible, dopa decarboxylase, for a breakdown of levodopa and peripheral inhibition of levodopa by carbidopa, which we will discuss on the subsequent slides, makes it available more readily in the central nervous system. |
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Term
Has ADE:
• Wearing-off
• On-off phenomenon
• Dyskinesias
• Anorexia/nausea/vomiting • Orthostatic hypotension
• Mood changes
• Dyskinesias
• Rare arrhythmias |
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Definition
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Term
|
Definition
• Peripheral dopa decarboxylase inhibitor
• Always co-administered with levodopa
• Reduces peripheral metabolism of levodopa so that lower levodopa doses can be administered with equal effect
-for parkinsons |
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Term
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Definition
• Sinemet® (carbidopa/levodopa)
• Sinemet® CR (carbidopa/levodopa)
• Rytary® ER (carbidopa/levodopa)
• Parcopa® orally-disintegrating tablet (carbidopa/levodopa)
• Stalevo® (carbidopa/levodopa/entacapone) |
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Term
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Definition
| So as you can see here, the action of carbidopa includes inhibition of the enzyme that's responsible for breaking down of levodopa in the peripheral nervous system here, which, in turn, allows for more drug to be available to cross the blood brain barrier for the effects of levodopa up on conversion of dopamine. |
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Term
| Catechol-O-Methyltransferase (COMT) Inhibitors |
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Definition
• Mechanism: reduces peripheral metabolism of levodopa and decrease concentration of 3-O-methyldopa which may compete with levodopa for transport across BBB
• Entacapone, tolcapone (rarely used due to hepatotoxicity)
• Only tolcapone can cross BBB, which theoretically may confer additional benefit through more complete COMT inhibition
• Reduce off time, reduce required levodopa dose
• Must be given with levodopa
-for parkinsons |
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Term
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Definition
| Administration of concomitant COMT inhibitors also has been shown to reduce off time reduction of the required levodopa dose that often has to be administered. This is often given with levodopa as described in previous slides, and it's actually commercially available in concomitant formulations of levodopa and carbidopa. As you can see here on this figure is the action of C-O-methyl transferase inhibition allowing less available end products to compete otherwise with levodopa, thereby increasing the concentrations of levodopa in the brain and subsequent conversion into dopamine. |
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Term
Has ADE:
• Diarrhea, abdominal pain
• Orthostatic hypotension
• Sleep disturbances
• May cause urine to turn orange
• Tolcapone requires signed patient consent due to hepatotoxicity |
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Definition
| COMT inhibitors • Entacapone, tolcapone (rarely used due to hepatotoxicity) |
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Term
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Definition
• Adenosine antagonist->may decrease D2 receptor inhibition
• Most effective agent to reduce levodopa- induced dyskinesias
• Modest and brief effect on motor symptoms
-parkinson's treatment |
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Term
Has ADE:
• Restlessness,irritability,agitation,hallucinations, confusion, psychosis
• Insomnia
• Depression
• Peripheraledema,heartfailure
• Livedoreticularis
• Posturalhypotension
• Urinaryretention
• Anorexia,nausea,constipation,xerostomia
• Rare:seizures |
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Definition
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Term
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Definition
• Commonlyusedfirst-lineasmonotherapy for parkinsons,canalso be used as adjunct to levodopa-based regimen
• Primaryagents:Requip(ropinirole),Mirapex (pramipexole)
• Othertherapies:bromocriptine,cabergolinerarely used due to poor adverse effect profile
• Reducesofftimeandmaybeabletoreduce levodopa dose
• Convenientextended-releasepreparationsare available |
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Term
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Definition
These agents are known to reduce the off time and are able to potentially reduce the amount of levodopa that we are prescribing to the patient so that we can prevent some of those levodopa described toxicities that we highlighted in the previous slides. It is convenient to prescribe some of these agents because they are often available in extended release preparations. So that's something to consider, especially in patients that are not amenable to taking medication therapies that have increased frequencies.
So here, you see the dopamine receptors in the central nervous system and the agonistic activity of these dopamine agonists as we described in the previous slide. |
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Term
Has ADE:
• Adverse effects of pramipexole/ropinirole:
• Constipation, dyspepsia, N/V, anorexia
• GI bleed from peptic ulcer
• Peripheral edema, postural hypotension
• Dose-related dyskinesias
• Confusion, hallucinations, delusions
• Impulse control disorders
• Rare: sleep attacks |
|
Definition
Dopamine Agonists
• Primaryagents:Requip(ropinirole),Mirapex (pramipexole)
• Othertherapies:bromocriptine,cabergolinerarely used due to poor adverse effect profile |
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Term
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Definition
• Eldepryl(selegiline),Zelaparorally- disintegrating tablet (selegiline), Azilect (rasagiline)
• Usuallyusedasadjuncttolevodopa-based regimen
• Reduceofftimeandwearingoff,maybeableto reduce levodopa dose
• Patientsmustadheretotyramine-restricteddiet
• Numeroussignificantdruginteractions
-for parkinsons |
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Term
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Definition
| As you can see here, this schematic highlights the central nervous system's action of these monoamine oxidase B inhibitors and its role and effects in the setting of Parkinson's disease. |
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Term
Has ADE:
• Headache
• Nausea
• Hypotension
• Hallucinations
• Dyskinesia
• Rhinitis
• Xerostomia
• Weightloss
• Insomnia |
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Definition
MAO-B Inhibitors:
-Insomnia(selegiline)
• Eldepryl(selegiline),Zelaparorally- disintegrating tablet (selegiline), Azilect (rasagiline) |
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Term
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Definition
• Cogentin (benztropine), Artane (trihexyphenidyl)
• Improve tremor and rigidity by reducing levels of acetylcholine
• Ineffective for other symptoms, generally used in combination with other therapies |
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Term
Has ADE:
• Agitation, confusion, hallucinations/delusions
• Tachycardia
• Constipation
• Xerostomia
• Glaucoma, vision problems
• Urinary retention
• Rash |
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Definition
Anticholinergics
• Cogentin (benztropine), Artane (trihexyphenidyl) |
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Term
|
Definition
• Dopamineagonist
• Effective,fastactingagentforofftime
• Onlyavailablethroughspecialtypharmacy
• Associated with profound emesis à must administer Tigan (trimethobenzamide) three days before initiating apomorphine and continue for at least the first two months of therapy
• Mustadministertestdoseandmonitorsupine and standing blood pressure and pulse pre-dose and at 20, 40, and 60 minutes post-dose |
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Term
Has ADE:
• Nausea
• Dyskinesias
• Hypotension
• Chest pain, diaphoresis
• Drowsiness
• Injection site pain and bruising |
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Definition
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Term
|
Definition
• Implantableimpulsegeneratorwithadjustable amplitude, frequency, width
• Levodopa-responsivepatients,youngerpatients, and shorter disease duration more likely to respond to deep brain stimulation
• Reduces“offtime”andprovidesbettertremor control than with medications
• Reduce motor fluctuations, dyskinesias comparable to medications |
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Term
Has ADE:
• Paresthesia
• Dysarthria
• Dizziness
• Dyskinesia
• Facial contractions
• Rare: surgical complications |
|
Definition
|
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Term
|
Definition
vector-based gene therapy for parkinson's
• Viral vector containing three genes allowing local and continuous dopamine production
• Injected bilaterally into putamen of 15 patients with Parkinson's disease
• All patients experienced improvement in motor function during 12-month follow-up and there was no evidence of antibody response to viral vector
• Most common adverse effects were dyskinesias and “on-off” symptoms |
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Term
| ST is a 78-year-old male with Parkinson’s disease treated with Sinemet (carbidopa/levodopa) 25 mg/250 mg three times daily. During today’s visit, he reports that his symptoms get worse approximately an hour before the next dose is due. What would you recommend? |
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Definition
| There are several ways to approach this case: you can change to a controlled-release formulation; switch to a combination product such as Stalevo, which includes a COMT inhibitor; or add a MAO-B inhibitor or dopamine agonist. |
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Term
| Antipsychotics for movement disorders |
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Definition
• Clozaril (clozapine) has best evidence supporting its use, however limited by adverse effects (agranulocytosis)
• Seroquel (quetiapine) also recommended; better tolerated
• Avoid Zyprexa (olanzapine), ineffective and may worsen motor symptoms |
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Term
|
Definition
for pts w parkinson's disease psychosis
• Atypical antipsychotic agent, selective serotonin 5-HT2A inverse agonist
• Only FDA approved treatment (in 2017) of hallucinations and delusions associated with PD
• Randomized 200 patients with mild-moderate psychosis to six weeks treatment with pimavanserin or placebo
• Improved psychosis symptoms without worsening motor symptoms
• Post marketing surveillance: suspected increased rates of death since 2017 approval |
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Term
| Antidepressants for movement disorders |
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Definition
• Elavil (amitriptyline) has best evidence to support its use
• Due to improved tolerability, SSRIs more commonly used |
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Term
| Cognitive Decline treatment for parkinsons |
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Definition
• Exelon (rivastigmine) may improve cognitive function, however it may worsen tremor
• Aricept (donepezil), Namenda (memantine), Razadyne (galantamine) may have benefit, limited data |
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Term
| pain treatment for parkisons |
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Definition
• Levodopa through improved motor symptoms
• Neurontin (gabapentin), Lyrica (pregabalin)
• Cymbalta (duloxetine) |
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Term
| Fatigue treatment for parkinsons |
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Definition
• Ritalin (methylphenidate)
• Provigil (modafinil), Nuvigil (armodafinil) |
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Term
| Sexual Dysfunction treatemnt for parkinsons |
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Definition
| • Viagra (sildenafil) may be effective for erectile dysfunction in Parkinson’s disease |
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Term
| Sleep Disorders treatment for parkisons |
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Definition
• Sinemet (levodopa/carbidopa) and dopamine agonists reduce sleep- associated motor symptoms including restless leg syndrome, which may reduce insomnia
• Provigil (modafinil) may improve patient perception of wakefulness
• Melatonin improves patient perception of sleep quality |
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Term
| DS is a 69-year-old male with long-standing Parkinson’s disease. Recently, he started using an Exelon (rivastigmine) patch, but his hand tremor has noticeably worsened. As a result, he is no longer able to feed himself most days. His wife would like to know if there is a different medication he can use for his moderate dementia. |
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Definition
| Aricept® (donepezil), Namenda® (memantine), Razadyne® (galantamine) may have benefit, limited data. |
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