Conditions Effecting the Nervous System and PharmacotherapyPart Six: Neurodegenerative DX- Parkinson’s Disease PD Flashcards
Exam 4 (Final)
Parkinson’s Disease (PD): What is it?
Chronic progressive neurodegenerative disorder
Parkinson’s Disease (PD): What is it a deficiency of?
Deficiency of NT dopamine (made by substania nigra in brain).
Parkinson’s Disease (PD):
Where is dopamine made?
(made by substania nigra in brain).
Parkinson’s Disease (PD):
When do symptoms appear?
Symptoms generally appear during middle age and progress
Parkinson’s Disease (PD):
Is there a cure for motor symptoms?
No cure for motor symptoms
Parkinson’s Disease (PD):
What can drug treatment do?
Drug tx can maintain functional mobility for years (ie, prolongs/improves QOL)
Parkinson’s Disease (PD):
What are cardinal motor symptoms of PD?
Cardinal motor sx:
tremor,
rigidity,
postural instability,
slowed movement (bradykinesia)
Parkinson’s Disease (PD):
What are nonmotor symptoms ?
Nonmotor sx:
sleep disturbances,
depression,
psychosis,
dementia,
autonomic disturbances
Parkinson’s Disease (PD):
When do early symptoms develop?
Early sx can develop years before function impairment (e.g. clumsiness, excessive salivation, worsening handwriting, tremors, slower gait, reduced voice volume)
Parkinson’s Disease (PD):
Secondary causes of Parkinson’s disease?
2° – caused by diagnosis other than PD (eg head trauma, infection, neoplasm, atherosclerosis, toxins, drug-induced EPS: neuroleptics, antiemetics, antihypertensives)
Patho of PD:
What is a probable cause?
Genetic-envi mutations probable cause
Patho of PD:
What is disrupted?
Neurotransmission is disrupted primarily in the brain’s striatum.
Patho of PD
What is misfolded?
Misfolded/dysfunctional alpha-synuclein
Patho of PD
Misfolded/dysfunctional alpha-synuclein:
What is it and what is it made by?
Toxic protein made by dopaminergic neurons accumulates
Patho of PD
Misfolded/dysfunctional alpha-synuclein:
What is it not broken down by?
Not broken down by 2 other proteins (parkin & ubiquitin)
Patho of PD
Misfolded/dysfunctional alpha-synuclein
What is defective?
Defective gene coding for all 3 proteins
Patho of PD
Misfolded/dysfunctional alpha-synuclein
What does it contribute to?
Contributes to neuron death/destruction of dopaminergic neurons
Patho of PD
Normally inhibitory actions of Dopamine are balanced by what?
Normally, inhibitory actions of Dopamine are balanced by excitatory actions of Ach –> controlled movement
Patho of PD
What is GABA?
GABA is an inhibitory NT blocking signals in nervous system
Patho of PD
Normally, inhibitory actions of Dopamine are balanced by excitatory actions of Ach –> controlled movement
In healthy people, what does GABA do?
In healthy individuals, GABA regulates movement by inhibiting certain brain signals.
Patho of PD
Normally,
Between do dopamine and GABA, what is needed?
Interplay between DA & GABA – need a balance
Patho of PD
Interplay between DA & GABA – need a balance
What does dopamine inhibit?
Dopamine inhibits the neurons that release GABA
Patho of PD
Interplay between DA & GABA – need a balance
What does acetylcholine excite?
Ach excites the neurons that release GABA
Patho of PD
In PD, what is there an imbalance between?
In PD – imbalance btwn DA & Ach
Patho of PD
What happens to neurons supplying DA
Neurons supplying DA to striatum degenerate
Patho of PD
Neurons supplying DA to striatum degenerate what does this lead to?
Excitatory effects of Ach go unopposed –> to excess stimulation of neurons that release GABA
Patho of PD
Excitatory effects of Ach go unopposed –> to excess stimulation of neurons that release GABA
What does this lead to?
Excess GABA interferes with motor function by blocking messages in movement centers
Patho of PD
Excess GABA interferes with motor function by blocking messages in movement centers
What is the result? (symptoms)
The result is difficulties with movement, such as stiffness, slowness, and tremors
Progression of Parkinson’s Disease:
What is it a degeneration of?
Degeneration of the dopamine-producing neurons in the substantia nigra of the midbrain
Progression of Parkinson’s Disease:
What balance is disrupted?
Disrupts the normal balance between dopamine and ACh in the basal ganglia
Progression of Parkinson’s Disease:
What dopamine normally essential for?
Dopamine is essential for normal functioning of the extrapyramidal motor system, including control of posture, support, and voluntary motion.
Progression of Parkinson’s Disease:
Manifestations of PD occur when how much of neurons are lost?
Manifestations of PD do not occur until 70-80% of neurons in the substantia nigra are lost.
Progression of Parkinson’s Disease:
WHen the amount og dopamine falls, how is acetylcholine?
When the amount of dopamine falls, ACh still functions. Its excitatory properties are responsible for the excess and exaggerated movements in PD.
Progression of Parkinson’s Disease
What is found in the brains of patients with PD?
Lewy bodies, abnormal accumulations of protein, are found in the brains of patients with PD.
Progression of Parkinson’s Disease
Lewy bodies, abnormal accumulations of protein, are found in the brains of patients with PD.
What causes these bodies to form? What does their presence indicate?
It is not known what causes these bodies to form, but their presence indicates abnormal functioning of the brain.
Progression of Parkinson’s Disease
How is onset?
How long does it take for loss of neurons to occur?
Onset insidious, loss of neurons takes place 5-20yrs, long before sx appear
Prevalence and Predisposing Factors of PD
Include what?
Genetic Link
Exposure to Chemicals and Drugs
Cellular Changes
Prevalence and Predisposing Factors of PD
Genetic Link: Approximately what % of patients with PD have a family history of PD?
Approximately 15% of patients with PD have a family history of PD.
Prevalence and Predisposing Factors of PD
Genetic Link: The most common genetic contributor to PD is what?
The most common genetic contributor to PD is the LRRK2 gene.
Prevalence and Predisposing Factors of PD
Genetic Link: Genes involved in familial PD are what?
What are mutations in these genes associated with?
Genes involved in familial PD are parkin (PARK2, PARK7), PINK1, and SNCA.
Mutations in these genes are often associated with a younger age of onset
Prevalence and Predisposing Factors of PD
Exposure to Chemicals and Drugs
Carbon monoxide
Metoclopramide (Reglan)
Antipsychotics
Prevalence and Predisposing Factors of PD
Exposure to Chemicals and Drugs:
Antipsychotics : What happens after stopping these drugs?
After stopping these drugs, symptoms of parkinsonism generally decrease or disappear
Prevalence and Predisposing Factors of PD
Cellular Changes
There are damaging effects of viruses or toxins on cells.
Prevalence and Predisposing Factors of PD
Cellular Changes: What does significant oxidative stress lead to?
Significant oxidative stress leads to the accumulation of free radicals within the cells in the brain.
Prevalence and Predisposing Factors of PD
Other causes of parkinsonism include?
Other causes of parkinsonism include infections, stroke, tumor, and trauma.
Clinical Presentation of PD
Motor Sx:
Resting tremors & Rigidity
Bradykinesia/akinesthesia
Postural disturbances
Dysarthria (difficulty with speech)
Dysphagia (difficulty swallowing)
Clinical Presentation of PD
How may symptoms develop?
Sx may develop isolated or in combination
All are present as dx progresses
Sx bilateral but usually involve 1 side early in dx
Clinical Presentation of PD
As disease progresses –> ?
As disease progresses –> postural abnormalities, diff walking, weakness, shuffling gait
Clinical Presentation of PD
Nonmotor sx:
sleep disorders,
sensory disturbances (loss of smell, vision),
urinary urgency,
difficulty concentrating,
depression,
hallucinations
Clinical Presentation of PD
Autonomic sx:
diaphoresis,
orthostatic hypotension,
drooling,
gastric/urinary retention,
constipation
Motor Symptoms of PD
Tremor
Rigidity
Akinesia
Postural Instability
Motor Symptoms of PD:
What is the first sign?
Tremor- 1st sign & may be mild initially
Motor Symptoms of PD:
How are tremors in PD?
More prominent at rest and is aggravated by emotional stress or increased concentration.
Pill-rolling
Motor Symptoms of PD:
Akinesia- What is it?
absence or loss of control of voluntary muscle movements
loss of automatic (blinking, swallowing)
Motor Symptoms of PD:
Akinesia- What else is involved?
bradykinesia (slowness of movement)
Motor Symptoms of PD:
Postural Instability
Stooped posture
Shuffling gait
Parkinson’s Rigidity: What is it?
Muscle resistance to passive movement of rigid limb in both flexion & extension
Parkinson’s Rigidity:
What are the two types?
Plastic or lead-pipe rigidity:
Cogwheel rigidity:
Parkinson’s Rigidity:
Plastic or lead-pipe rigidity: What is it?
Plastic or lead-pipe rigidity: increased muscle tone independent of force used in passive movement
Parkinson’s Rigidity:
Cogwheel rigidity: What is it?
uniform resistance maybe interrupted by a series of brief jerks
Parkinson’s Rigidity:
Complications
Dyskinesia (involuntary movements)
Weakness
Neuropsychiatric problems
Dysphagia
Infections
Skin breakdown
Orthostatic hypotension
Diagnosis & Management Overview for PD
Diagnostics:
⍉ definitive test
PMH
PE
Testing to R/O other DX
Diagnosis & Management Overview for PD
Diagnostics: PE includes?
Neuro assessment
Diagnosis & Management Overview for PD
TX?
⍉ PX or cure
⍉ reverse damage
⍉ delay progression
Symptom control, relief only!!!
Diagnosis & Management Overview for PD
Symptom control, relief only!!!- How do meds do this?
↑ DA & ↓ Ach to tx bradykinesia, gait disturbance, postural instability
Diagnosis & Management Overview for PD
What are limitations of meds?
Diminished effects over time
Control lost @ max dosing
Diagnosis & Management Overview for PD
SX options: What to do if unresponsive to drugs?
Deep brain stimulation - if unresponsive to drugs
Diagnosis & Management Overview for PD
Maximizing function
PT & OT
Assistive devices ~ wheelchairs, walkers, handrails
Diagnosis & Management Overview for PD
Overall health
Coping strategies & support
Proper nutrition
Adequate rest
Drug therapy!!!
PD Agent Classification:
What is targeted?
Target problem: ↓↓ striatal DA
Target problem: ↑↑ ACh
PD Agent Classification:
What drugs target ↓↓ striatal DA problem?
Dopaminergic meds
DA replacement
DA agonists
MAO-B inhibitors
DA releaser
COMT inhibitors??
PD Agent Classification:
Dopaminergic meds:
How often are they used?
What do they do?
DA activation ~ direct & indirect
More widely used
PD Agent Classification:
DA replacement includes?
Levodopa/Carbidopa
PD Agent Classification
DA agonists: What are the two groups?
Non-ergot
Ergot derivatives
PD Agent Classification
DA agonists:
Non-ergot includes?
Apomorphine
Pramipexole
Ropinirole
Rotigotine
PD Agent Classification
DA agonists:
Ergot derivatives includes?
Bromocriptine
Cabergoline (off-label)
PD Agent Classification
COMT inhibitors: How do they work?
By inhibiting COMT, plasma half-life of levodopa prolonged
PD Agent Classification
COMT inhibitors: What are the two?
Entacapone
Tolcapone
PD Agent Classification
MAO-B inhibitors: What do they do?
MAO-B inactivates dopamine
PD Agent Classification
MAO-B inhibitors: What are the two meds?
Selegiline
Rasagiline
PD Agent Classification
DA releaser: What is the med?
Amantadine
PD Agent Classification;
What meds Target problem: ↑↑ ACh?
Anticholinergic meds
PD Agent Classification;’
‘Anticholinergic meds
ACh receptor blockade
Benztropine
Trihexyphenidyl
Levodopa
MOA: How does it reduce symptoms?
Reduces symptoms by increasing dopamine synthesis in the striatum.
Levodopa
MOA: How does this med enter brain?
Enters brain via active transport across BBB
Levodopa
MOA: After entering brain, where does it go?
Taken up by nerve terminal in striatum
Levodopa
MOA: After being taken up by nerve terminal in striatum
Get converted into active form & released into synapse
Levodopa
MOA: Get converted into active form & released into synapse
What happens after this?
Binds to dopamine receptors on GABAergic neurons, causing them to fire at a slower rate
Levodopa
MOA: Binds to dopamine receptors on GABAergic neurons, causing them to fire at a slower rate
What does this help with?
Helps restore balance btwn DA & ACh
Levodopa
MOA:
What converts levodopa to dopamine? What is this enhanced by?
Decarboxylase (in brain, liver, intestine) converts levodopa to dopamine and is enhanced by Pyridoxine (vitamin B6)
Levodopa
Why can’t we just give dopamine by itself?
Dopamine can’t cross BBB
Dopamine has very short half-life in the blood
Levodopa:
What is the only way it is given?
Only given in combination with carbidopa or carbidopa/entacapone
Levodopa:
How effective is it?
Highly effective, but benefits diminish over time
Levodopa:
Highly effective, but benefits diminish over time
When do full effects develop?
Full effects take several months to develop, but it works
Levodopa:
Highly effective, but benefits diminish over time
How are symptoms controlled? For how long? Why?
Symptoms well controlled for first 2 years
But….return to pretreatment state at end of 5 years probably because of disease progression, not tolerance
Levodopa:
How is it administered?
Orally administered; rapidly absorbed from small intestine
Levodopa:
How does food effect absorption? Why?
Food delays absorption by slowing gastric emptying
Levodopa
Orally administered; rapidly absorbed from small intestine
What happens to levodopa (having to do with intestinal absorption)
Neutral amino acids compete with levodopa for intestinal absorption and for transport across blood-brain barrier
Levodopa
Orally administered; rapidly absorbed from small intestine
What has an effect on therapeutic effects of the drug? How?
High-protein foods reduce therapeutic effects by competing for intestinal absorption
What is Cornerstone of PD treatment!!!
Levodopa
Levodopa
Acute loss of effect – returns of sx
What happens
Gradual loss (wearing off) – drug levels decline to subtherapeutic
Levodopa
Gradual loss (wearing off) – drug levels decline to subtherapeutic
When does it develop?
Develops near the end of dosing interval
Levodopa
Gradual loss (wearing off) – drug levels decline to subtherapeutic
How can it be minimized?
Can be minimized by shortening dosing interval
Levodopa:
Gradual loss (wearing off) – drug levels decline to subtherapeutic
WHat do you do?
Give another PD (e.g entacapone) drug to prolong levodopa ½-life
Give direct acting dopamine agonist (e.g. pramipexole, ropinirole)
Levodopa:
Abrupt loss of effect (“on-off”) - sudden and unpredictable fluctuations in motor response, rapid transition between periods of improved mobility (“on” state) and worsened symptoms (“off” state).
When does this occur?
Occurs anytime during dosing interval, even if drug levels are high
Levodopa
This drug may go “on-off” What does this mean?
Abrupt loss of effect (“on-off”) - sudden and unpredictable fluctuations in motor response, rapid transition between periods of improved mobility (“on” state) and worsened symptoms (“off” state).
Levodopa:
Abrupt loss of effect (“on-off”) - sudden and unpredictable fluctuations in motor response, rapid transition between periods of improved mobility (“on” state) and worsened symptoms (“off” state).
How long is “off” time?
Off times may last minutes to hours
Levodopa:
Abrupt loss of effect (“on-off”) - sudden and unpredictable fluctuations in motor response, rapid transition between periods of improved mobility (“on” state) and worsened symptoms (“off” state).
Over course of treatment, what is likely to happen to off periods?
Over course of tx, off periods likely to increase, so many need add’l drugs (e.g COMT-I, MAO-I)
What is a precursor to dopamine?
Levodopa is a precursor of dopamine.
PD Pharmacology: Carbidopa
After oral administration, how is levodopa metabolized? Where? What is it converted to?
After oral administration, levodopa undergoes significant metabolism by decarboxylase in the GUT & blood vessels –> converted dopamine.
PD Pharmacology: Carbidopa
What happens to large amounts of levodopa before it reaches the brain?
Large amounts of levodopa are decarboxylated in the periphery before reaching brain & converted to dopamine
PD Pharmacology: Carbidopa
What does carbidopa enhance?
Carbidopa enhances effects of levodopa
PD Pharmacology: Carbidopa
What kind of effect does carbadopa have on its own?
What does it do to levodopa?
Carbidopa has no effect on it’s own but inhibits conversion of levodopa to dopamine by decarboxylase in the periphery, so it can reach the brain
PD Pharmacology: Carbidopa
Why does carbidopa not affect the levodopa’s conversion to dopamine in the brain?
Carbidopa does NOT cross BBB so it does not affect the levodopa ’s conversion to dopamine in the brain
PD Pharmacology: Carbidopa
Levodopa/Carbidopa (Sinemet)
How is it available? How is dosing?
Immediate or Continuous Release
Dose gradually increased from 1 tab daily –> 8 tabs daily
Levodopa ADRs
Nausea and vomiting
Dyskinesias
Cardiovascular
Psychosis from dopamine activation
Central nervous system (CNS) effects
Others
Levodopa ADRs
Nausea and vomiting: How can this be dealt with?
Low initial doses and administration with food….but food can reduce therapeutic effects by decreasing absorption, avoid if possible
Giving additional carbidopa (without levodopa) can help reduce nausea and vomiting
Levodopa ADRs
Nausea and vomiting: Why does this occur?
Activation of dopamine receptors in the chemoreceptor trigger zone of the medulla
Levodopa ADRs
Nausea and vomiting
By minimizing peripheral conversion, less levodopa is converted into dopamine outside the brain
Levodopa ADRs
What are the most troubling adverse effects?
Dyskinesias
Levodopa ADRs
Dyskinesias: Levodopa given to help with movement disorders it can cause What?
Although levodopa given to help with movement disorders it can cause movement disorders
Levodopa ADRs
Dyskinesias: What can be done about this
Reduce dose (but PD sx may emerge) or give Amantadine (dopamine releaser)
Levodopa ADRs
Dyskinesias: Reduce dose (but PD sx may emerge) or give Amantadine (dopamine releaser)
What does this do?
Regulates glutamate neurotransmission & NMDA receptors
Levodopa ADRs
Cardiovascular
What issues?
Postural hypotension – dopamine can cause vasodilation in periphery
Levodopa ADRs
Cardiovascular: Postural hypotension – dopamine can cause vasodilation in periphery
What should be done?
Increase intake of salt and water
Alpha-adrenergic agonist
Levodopa ADRs
Cardiovascular: Why do dysrhythmias occur?
Dysrhythmias from dopamine conversion in periphery – activation of beta1 receptors
Levodopa ADRs:
Psychosis from dopamine activation: WHat does this include?
Visual hallucinations
Vivid dreams or nightmares
Paranoid ideation
Levodopa ADRs:
Psychosis from dopamine activation: WHat is this caused by?
Caused by activation of dopamine receptors
Levodopa ADRs:
Central nervous system (CNS) effects
What does this include?
Anxiety and agitation
Memory and cognitive impairment
Insomnia and nightmares are common
Problems with impulse control
Behavioral changes associated with promiscuity, gambling, binge eating, and alcohol abuse
Levodopa ADRs
Others
Darken sweat/urine (harmless)
Drug interactions cont’d & Food interactions
Anti-psychotics that block receptors for dopamine in the striatum
MAO-Inhibitors
Anticholinergics
Pyridoxine (vitamin B6)
High-protein meals can reduce absorption
Drug interactions cont’d & Food interactions
Anti-psychotics that block receptors for dopamine in the striatum: What do they cause?
Anti-psychotics that block receptors for dopamine in the striatum
Drug interactions cont’d & Food interactions
MAO-Inhibitors: What do they cause?
Can cause hypertensive crisis from vasoconstrictive effects
Drug interactions cont’d & Food interactions
Anticholinergics: What do they cause?
By blocking cholinergic receptors, these agents enhance responses to levodopa
Drug interactions cont’d & Food interactions
Pyridoxine (vitamin B6): What do they cause?
Altho Vitamin B6 accelerates decarboxylation (conversion) of levodopa in periphery, no need to limit it since levodopa is taken with carbidopa
Carbidopa inhibits decarboxylase, so this eliminates concern about decreasing effects of levodopa by taking Vitamin B6
Drug interactions cont’d & Food interactions
High-protein meals can reduce absorption
Why does this happen?
Amino acids compete with levodopa for intestinal absorption & transport across BBB
Drug interactions cont’d & Food interactions
High-protein meals can reduce absorption
So what are patients advised to do?
Advise pts to spread protein consumption evenly throughout the day
Drug interactions cont’d & Food interactions
High-protein meals can reduce absorption
What does this do?
Could trigger an abrupt loss of effect
Levodopa/Carbidopa [Sinemet and Parcopa]
Advantages
Most effective therapy for PD
Levodopa/Carbidopa [Sinemet and Parcopa]
Mechanism of action
Carbidopa is used to enhance the effects of levodopa
Carbidopa has no therapeutic effects of its own
Carbidopa inhibits the decarboxylation (conversion) of levodopa in the intestine and the peripheral tissues
More levodopa is available to the CNS
Carbidopa is unable to cross the blood-brain barrier
Levodopa/Carbidopa [Sinemet] (Cont.)
Advantages:
By increasing the fraction of levodopa available for action in the CNS, what does carbidopa allow for?
By increasing the fraction of levodopa available for action in the CNS, carbidopa allows the dosage of levodopa to be reduced by about 75%
Levodopa/Carbidopa [Sinemet] (Cont.)
Advantages:
By causing the direct inhibition of decarboxylase, carbidopa does what?
By causing the direct inhibition of decarboxylase, carbidopa eliminates concerns about decreasing the effects of levodopa by taking a vitamin preparation that contains pyridoxine
Levodopa/Carbidopa [Sinemet] (Cont.)
Advantages:
By reducing the production of dopamine in the periphery, carbidopa does what?
By reducing the production of dopamine in the periphery, carbidopa reduces cardiovascular responses to levodopa as well as nausea and vomiting
