Parkison's Disease Flashcards
what is the 2nd most prevalent neurodegenerative disorder?
parkison’s disease
what are the diff pathogenesis of parkisons?
- impaired degradatio of proteins, intracellular protein accumulation & aggregation, oxidative stress, mitochondrial damage, inflammatory cascades, apoptosis
- Prion diseaes -> presence of Lewy bodies
- Genetic factors
- Environmental & endogenous toxins
what are the 2 parts of substantia nigra & their functions?
- pars reticulata = receives signals from another part of the basal ganglia (stratum)
- pars compacta = sends messages to the striatium
what is the structure that receives nadequat eamount of nigrate cells which impairs person’s ability to control movement?
striatum portion of basal gangli
what is the pathophysiology of parkinons dis?
- loss of dopaminergic neurons in substantia nigra
- presence of Lewy body
- Cholinergic & serotenergic deficits
what are important neurotransmitters affected in Parkinsons disease?
- Dopamine
- Acetylcholine
what will happen if there is no dopamine?
excess muscle tone, tremors, & rigidity
when will symptoms of PD show?
if there is >60-80% dopamine lost
what are motor & non-motor symptoms of parkinsons disease?
Motor symptoms
* resting tumor
* rigidity
* bradykinesia
* postural instability
Non-motor symptoms
* autonomic: GI, urinary, & sexual, orthostatic hypotension, hyperhidrosis
* sleep disorders
* cognitive decline
* sensory problems (pain, visual)
* neuropsychiatric comorbidity (depression, dementia, psychosis)
what are other symptoms of PD?
- “pill-rolling” tremor = repetitive invluntary rubbing of the thumbn and index finger
- rigidity
- stooped posture
- expressionless, mask-like face
what is the tx goal of PD?
- alleviate motor and nonmotor symptoms
- limit complications
- slow down, stop, or modify disease progression
what is used to see if there are any improvements in the drug efficacy and symptom control?
rating scales: Hoehn & Yahr scale & Unified Parkinson’s disease rating scale
what is the simplest treatment of PD?
Dopamine
however, it cannot cross the BBB
what are the different dopamine receptors?
D1 reeptors: D1 & D 5
D2 receptors: D2, D3, D4
What happens with stimulation of D2 receptors?
Antiparkinsonism
What dopamine receptors are targeted by drugs?
D2
D1
D3
What are the 4 pathways for production of Dopamine?
Nigostrial pathway
Mesolimbic and mesocortical pathways
Tuberoinfundibular pathway
What are the 4 pathways for production of Dopamine?
Nigostrial pathway
Mesolimbic and mesocortical pathways
Tuberoinfundibular pathway
What are the functions of these pathways of Dopamine production?
- Nigostrial pathway = responsible for movement & coordination
- Mesolimbic & Mesocortical pathway = controls motivation, emotion, desire
- Tuberoinfundibular pathway = inhibits the secreiton of prolactin
What is the intendd target pathway for Anti-parkinson medication?
Nigostrial pathway
what are diff drugs used to tx motor sympotoms in px with parkinsons diseases?
- Levodopa = dopamin precursor
- Dopamine precursor combination
- Dopamine receptor agonists
- Monoamine oxidase B inhibitors
- COMT inhibitors
- Anticholinergics
- Others: Amantadine, Apomorphine
What is the gold std for Parkisons dis?
Levodopa
IT CAN CROSS THE BBB
what phenomenon has symptoms of rigidity and hypokinesia improve when they take the med but effects wear of AFTER 1-2 HRS?
wearing-off phenomenon
what phenomenon has off periods of marked akinesia alternate over the course of few hrs with on-periods of improve mobility but often marked dyskinesia?
On-off phenomenon
what are important AEs of Levodopa?
- dyskinesias (chronic use) -> apomorphine (emergency drug tx for overdose)
- depression, anxiety, agitation
what are are the clinical uses for Levodopa?
- used during first few yrs
- motor features of PD, bradykinesia
what are C/Is of Levodopa?
- not for psychotic px
- peptic ulcer disease
what happens to the effects of Levodopa admin from early stages to chronic use?
- early stage = almost complete improvement
- advanced stage of the disease = partial imprtovement of motor symptoms
- longer stage = partial improvement with dewveloping dyskinesia
what happens if DOPA decarboxylase exits outside the CNS?
INC dopamine levels in the rest of the body -> nausea, vomiting, anorexia, and orthostatic hypotension
what is the more problematic side effect of L-dopa?
can cause tachycardia and arrhythmia
what are advantages of Levodopa combinations?
- prevents peripheral side effects (nausea, vomiting)
- more Levodopa available for use byu the brain
- GI effects are less bothersome
- CV effects are reduced
what are the diff Levodopa combinations?
- Sinemet (Levodopa + Carbidopa)
- Stalevo (Levodopa + Carbidopa + Entacapone)
what is a DOPA decarboxylase inhibitor of Sinemet?
Carbidopa
does not enter CNS
What is Entacapone in Stalevo?
COMT inhibitor
reduyces metabolism of L-dopa
What is Entacapone in Stalevo?
COMT inhibitor
reduyces metabolism of L-dopa; prolonging action of the drug
what are alternative first line drugs of PD?
Dopamine receptor agonsits
what are advantages of Dopamine receptor agonists?
- reduced risk of dykinesias & motor fluctuations
- indicated for those who cannot tolerate high doses of L-dopa
what is the MOA of Dopamine receptor agonsits?
- diretly asks on postsynaptic dopamine reeptors
- no toxic metabolites
- do not compete
what are important AEs of Dopamine receptor agonsits?
- impulse control disorders are enhanced
- GI: anorexia, nausea, vomiting
- CV: postural hypotension, painless digital vasospasm
- Dyskinesias
- Mental: hallucinations, delusions, impulse control
- Bromocriptine: nasuea, vomiting, somnolence, pulmonary fibrosis
- Pergolide: valvular heart disease
what are ergot derivatives that can be used in Dopamine receptor agonists?
Bromocriptine: D2 agonist
Pergolide: D1 & D2 agonists
What are C/Is of Dopamine receptor agonists?
- Ergot derivatives = peripheral vascular disease
- Pergolide = valvular <3 disease
what are diff tx for motor symptoms?
- levodopa
- levodopa combinations
- dopamine receptor agonists
- COMT inhibitors
- Monoamine oxidase inhibitors
- acetylcholine blocking agents
- Amantadine
what are the 2 Monoamine oxidase inhibitors used for PD?
Selegiline
Rasagiline
what are the MOA of Selegiline & Rasagiline?
- retards breakdown of dopamine
- enhances effect of LD
- reduce on-off phenomenon
what are important AEs?
- Selegiline = insmonia & hallucinations
- MAO-A or MAO-B = tachycardia, vomiting, headache
what drugs are not supposed to be taken w/ MOAIs?
- Meperidine
- Tramadol
- Methadone
- Propoxyphene
- Cyclobenzaprine
- St. John’s wort
- Dectromethorphan
What are other COMT inhibitors?
Tolcapone
Entacapone
what do these COMT inhibitors do?
- prevent peripheral enxyme from degrading L-dopa
- More L-dopa to get into the brain
- only Tolcapone can cross BBB
- given as adjunct
what are AEs of COMT Inhibtors?
- dyskinesia
- nausea
- confusion
- diarrhea
- abdominal pain
- orthostatic hypotension
- sleep disturbances
- orange discoloration of urine
- Tolcapone
what PD drugs are used to improve tremor and rigidity more than bradykinesia?
Acetylcholine blocking agents
What are the diff Ach Blocking agents?
Benzotropine
Biperiden
Trihexyphenidyl HCl
what are significant AEs?
- dry mouth
- blurred vision
- difficulty with micturition/constipation
what is the clinical use of Ach blocking agents?
monotherapy later on as adjunct therapy
what is an antiviral agent that has potentiate dopaminergic functions that influence synthesis, release and reuptake of dopamine?
Amantadine
what are important AEs of Amantadine?
Restlessness
confusion
irritability
insomnia
depression
hallucinations
confusion
seizures
what are other treatment approaches?
- neurosurgery: Pallidotomy & deep brain stimulation
- neuroprotective therapy
- gene therapy
- deep brain stimulation
what tx approach involves an implantable device that directly sends elecrtical signals to the basal ganglia and coutneract the signaling in PD?
Deep brain stimulation
what is used as tx for Dementia?
Rivastigmine
What is used as tx for Psychosis?
Atypical antipsychotics = Clozapine, Quetiapine
DO NOT USE TYPICAL ANTIPSYCHOTICS
What is used as tx for Psychosis?
Atypical antipsychotics = Clozapine, Quetiapine
DO NOT USE TYPICAL ANTIPSYCHOTICS
What is the tx for mood disorders?
antidepressants
what is the tx for sleep disorders?
Melatonin
what are txs for Autonomic dysfunction?
- avoid preceipitating factors of orthostatic hypotension (sudden changes in posture, large meals, vasodilators)
what are general rules in prescribing levodopa?
- use of this should be delayed until there is signficant disability
- to delay long-term side effects -> dopamine agonist or a slow-release levodopa
what are other anti-PD used if there is functional impairment?
- anticholinergic = for tremors
- Amantadine = drug-induced dyskinesias
- Apomorphine = freezing “off” episodes or “on-off” phenomenon
what anti-PD is given if age is >60yo or <60yo?
- <60 yo = Dopamine receptor agonists
- > 60 yo = Levodopa
