Parkinsons + Drugs Flashcards
rigidity, bradykinesia (slowed movements), tremor (usually resting), mask facies, stooped posture, festinating gait (progressively shortened accelerated steps)
Parkinsonism
DDX for Parkinsonism
– Parkinson’s disease (idiopathic) – most common cause
– Multiple system atrophy
– Progressive supranuclear palsy
– Corticobasal degeneration
– Intoxication with MPTP
– Post-encephalitic Parkinson’s disease
Prevelance of Parkinsons Disease
Prevalence:500,000-1,000,000patientsinU.S.
– 1-in-40 lifetime risk of having PD
– Slight male predominance
– Prevalence increases with age (peak onset: 55-65 yrs)
• Age is the strongest risk factor
– Positive family history in 6-16% of PD cases: If have 1 first degree relative with PD, 3 times greater risk for getting PD and If have 2 or more: 10 times the risk
Possible mechanism for Parkinsons
*Misfolded protein/stress response triggered by protein aggregation
*Defective proteosomal function
*Altered mitochondrial function
PD genetics: most are sporadic, but there is some familial cases that are the _____gene thats located on chromosome ____ and seen in YOUNGER people with parkinsons
Parkin gene
chromosme 6
Very rare mutation present in families with auto. dom. familial PD and subsequently discovered to be a major component of Lewy bodies
***NOT present in sporadic PD
α-synuclein
POssible Environment and pestacides involved in PD
Manganese
Carbon monoxide
Rural living
– Well-water drinking
Paper mills
Hydrocarbons (petroleums, plastics)
Residential use of pesticides
Symptoms of Parkinsons
TRAPS body
Tremor (at rest; pill rolling)
Rigidity (cogwheeling)
Akineisa or Bradykinesia
Postural instability
Shuffling gait
Most common presenting syndrome in Parkinsons
Tremor
It is typically **asymmetric and low frequency **( 4Hz to 6 Hz)
Pill-rolling type of movements
Most often affects the distal upper extremities
Chin tremor specific for PD
• Slowness or lack of movement
- Micrographia
- Hypophonia
- Hypomimia
• Decreased blink rate
• Decreased arm swing with walking
**• Shortened stride length **
Bradykinesia
Increased resistance to passive movement of skeletal muscle across a joint
Rigidity seen in Parkinsons
How does posturea and gait present in parkinsons early and late?
- Early on, it can manifest as dragging of one leg or stooped posture
- Later in the course of the disease gait problems can be severe
What are some nonmotor symptoms seen during the PREmotor phase of PD
• Sleep: REM behavior disorder
- Olfactory Loss
- Dysautonomia
What are some supportive criteria for a Parkinsons Dx?
• Unilateral onset
• Rest tremor present
• Excellent response to levodopa
• Clinical course for 10y or more
How do we confirm dx of Parkinsons?
• No lab tests
• No blood tests
• No x-rays or MRI scans
_• Must be a response to L-DOPA _
What is the pathology we see in the brain associated with Parkinsons?
– Pallor of substantia nigra
– Neuronal loss and Lewy bodies in substantia nigra
– Lewy bodies - Eosinophilic cytoplasmic neuronal inclusions • Contain alpha-synuclein
What is this indicitivie of?
Lewy body seen in Parkinsons:
• Eosinophilic cytoplasmic neuronal inclusions • Contain alpha-synuclein
characterized by dementia associated with any two the following three core clinical features:
• Fluctuating cognition or level of consciousness
- Visual hallucinations
- Parkinsonian motor signs
Dementia with Lewy Body (DLB)
What are ‘suggestive’ features for DLB diagnosis?
Rapid eye movement (REM) sleep behavior disorder
Neuroleptic sensitivity
Low dopamine transporter uptake in the basalganglia
*If one or more of these suggestive features is present along with one or more core features, a diagnosis of probable DLB can be made *
How are Parkinsons and dementia with Lewy Body simular and different?
Both have substantia nigra degeneration and Lewy bodies
Different clincal presentaiton:
PD
– Patients present with parkinsonism signs and symptoms
– Most eventually develop dementia – 5x more frequent than in controls (age-matched)
– Pathologic correlate of dementia is Lewy body presence in cortex (cortical Lewy bodies)
Neuronal loss and Lewy bodies in substantia nigra AND
Lewy bodies in the cerebral cortex
Lewy Body Dementia has LB in the subnigra + cerebral cortex
*this image is of a Lewy body in cortex (note there is none of the brown shit you see in substantia nigra)
Focus of Pharmacotherapy in Parkinsons
Primarily targeted to restoring the neurotransmission in the circuit that regulates the extrapyramidal system
Understanding role of dopamine in parkinsons
the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement
Why are dopaminergic cells vulnerable?
Due to MAO breakdown of dopamine; we end up with OH and OH- free radicals and iron; as cellls age, they accumulate free radicals and reduce number of DA cells
What is the lifecycle of Dopamine
Tryosine –> tyrosine hydroxylase–> DOPA–> (L-AAAD)–> DA
DA gtes a methyl group added via COMT
then broken down by MAO
OR uptake back into the terminal
What is Levadopa and why do we give it to pts with Parkinsons?
Restore levels of DA in the basal ganglia via using amino acid transporters to enter the brain
*Decarboxylated to DA in DA cells, other neurons that express L-aromatic amino acid decarboxylase (L-AAAD)
What is a pharmakokintetic concern with Levadopa?
At most 2% of an oral dose of L-DOPA gets into the brain
Because most L-DOPA is metabolized to dopamine by peripheral L-AAAD or COMT (in the liver and gut, respectively)
THUS: lots of DA where we don’t need it with not enough getting into brain
What is given along with L-Dopa to prevent activation to DA in the periphery
Carbidopa: work to inhibit L-AAAD (can’t cross BBB so no worries it will inhibit drug from wokrin in the brain)
thus get more CNS dose and less peripheral sides
What is co-administerd with L-Dopa ot increase it’s action in the brain
entacapone COMT inhibitor to prevent breakdown
Half-life of L-DOPA is _____ and absorption is dependent upon ______, it is taken up by amino acid transporters that can be **saturated after a high protein meal **
very short (1-3 hours)
GI contents
What do we know about the effectiveness and clinical usefullness of L-Dopa
Very effective, in fact, if it doesn’t help, it probably wasn’t Parkinson’s Disease to begin with
Effective against all of the symptoms, esp. bradykinesia
Early disease, beneficial effects outlast half-life which suggests that the DA vesicles are filled; effects are sustained and smooth
When is the best time to prescribe L-Dopa to pts?
Best results are obtained in the first few years of treatment; then effectiveness is lost or becomes erratic (regardless of disease intensity)
THEREFORE: Is _not used until symptoms cause functional impairment _
Side effects of L-Dopa due to it’s conversion to DA
CNS effects-_Not alleviated by co- administration with carbidopa_
Wearing off; due to L-DOPA loss from the body
Dyskinesias: Too much movement
Dementia, confusion: treat with atypical antipsychotics (clozapine and quetiapine) z
What side effects are greatly reduced when L-Dopa is co-administered with Carbidopa (L-AAAD inhibitory)
Peripheral side effects-greatly reduced by carbidopa
- GI: nausea
- Cardiovascular: postural hypotension (common) arrhythmias (rare)
hypertension
What drugs interact with L-Dopa?
- Pyridoxine (Vit B6; increases metabolism ot DA in periphery)
- MAO inhibitors (except selegiline; can cause hypertension)
- Halothane (sensitizes the heart to arrhythmias)
- Antipsychotics that are _DA receptor antagonists _
Contraindications to L-Dopa use
- Glaucoma
- Psychosis
- Cardiac disease that involves arrythmias
- Malignant melanoma
Rationale: Mimic dopamine without need for intact nerve terminals
Mechanism: Agonists of DA receptors in the striatum
Dopamine receptor agonists
Advantages of dopamine R agonists over L-DOPA
- No enzymatic conversion is needed
- Selectivity for receptor subtypes
- Longer half-life
- Less DA-dependent oxidative stress?
****we can use these drugs earlier! and are effective much longer then L-DOPA is
Selective D2 agonists
Most commonly used currently for tx of Parkinsons
Pramipexole and ropinerole
High affinity D4 agonist; moderate affinity for D2, D3, and D5
Used by subcutaneous injection for **immediate therapy of an “off” episode **
Dopamine agonist: Apomorphine
What restores activity in the indirect pathway
D2/D4 agonists:
Pramipexole and ropinerole = Selective D2 agonists
Apomorphine = High affinity D4 agonist
Pramipexole and ropinerole can be_____ to therapeutic doses over a week or less
titrated
Direct agonists are used as the first line treatment over L-DOPA because:
- Longer duration of action (half-life) than L- DOPA results in fewer end-of-dose problems; less hyperactivity
- Better than L-DOPA because they reduce DA synthesis; less oxidative toxicity
- Direct agonists are the initial therapy in young patients; L-DOPA in elderly
- Apomorphine is reserved for patients refractory to other treatments
Side Effects of direct DA agonists
Nausea (esp. bromocriptine)
Fatigue
Sudden attacks of daytime sleep
CNS toxicity
Apomorphine can cause increased QT prolongation and injection site reactions
Describe CNS toxicity seen from direct DA agonists
a. Confusion is worse than L-DOPA (hence the avoidance of use in elderly pts)
b. Dyskinesia is not as bad as L-DOPA
Rationale for MAO inhibitors: inhibit MAO will increase amount of DA and decrease the amount of oxidative stress: the issue is
BUT: MAO inhibitors are a therapeutic nightmare because MAO in the liver is essential to metabolize tyramine that is ingested; tyramine is a sympathomimetic
HOWEVER: There are two forms of MAO
MAO-A: major form found in the human GI tract and liver
MAO-B: major form found in the brain
Rationale and mechanism of MAO-B inhibitors
MAOinhibition will prolong the action of dopamine; and may also reduce oxidative stress on neurons
Mechanism: Selective, irreversible inhibition of MAO-B
What are our two MAO-B inhibitors?
selegiline
**rasagiline **
When do we prescribe MAO-B’s to pts?
- Disease onset; will see modest benefit
- IN more advanced disease, provide with L-DOPA to prolong its 1/2 life
- works as anti-depressant
- Modest effects on diesease progression
Side effects of MAO-B inhibitors Selegiline and Rasagiline
- Generally well tolerated in early disease
- In advanced disease, worsens the side effects of L-DOPA (too much dopamine?)
- Is metabolized to amphetamine and methamphetamine; cause anxiety and insomnia
Reduced when administered as an orally- disintegrating tablet or as a patch (these avoid first-pass metabolism)
Adverse drug reactions of MAO-B inhibitors Selegiline and Rasagiline
When administered in combo with:
meperidine
tricyclic antidepressants
serotonin reuptake inhibitors—can lead to Serotonin Syndrome (stupor, rigidity, agitation, hyperthermia)
Rationale for using COMT inhibitors
COMT metabolizes dopamine so its inhibition will prolong the action of dopamine; COMT inhibition will also decrease L-DOPA metabolism to non-dopamine metabolites
What are the 2 COMT inhibitors we would use and which would we use more often
Tolcapone (causes significant hepatotoxicity, limits usefulness)
Entacapone –use more often bc doesn’t have hepatotoxiciy
What is Tolcapone and what are its pros and cons
COMT inhibitor: tolcapone has a relatively long half life and inhibits both peripheral and central COMT (therefore, has all of the benefits)
but causes hepatotoxicity
COMT inhibitor that has a short half life and does not get into the CNS well; therefore is usually co- administered with L-DOPA to eliminate peripheral metabolism (just like carbidopa)
Entacapone
Side effects of COMT inhibitors Tolcapone and Entacapone
- Common (due to increased dopamine) nausea, orthostatic hypotension, vivid dreams, confusion, hallucinations
- Tolcapone can produce liver toxicity; not used except as a last resort and with hepatic monitoring
Rationale for using antimuscarinics for Parkinsons
** Cholinergic interneurons** in the striatum are normally inhibited by dopamine. The loss of dopamine results in overactivity of these excitatory neurons. This is blunted by the anticholinergics
What antimuscarinics are used to tx parkinsons
trihexyphenidyl
benztropine
Clincal effectiveness and usefullness of antimuscarninics : trihexyphenidyl and
benztropine to tx Parkinsons
- Modest efficacy; not good against the bradykinesia
2. Third choice (after L-DOPA and dopamine agonists), used when dopaminergic therapy is contraindicated; early disease; elderly
- Can be used in combination with L-DOPA/DA agonists so that their dose can be lower
Side effects of antimuscarinics to tx PD
Side effects
- Sedation, mental confusion
- Atropine-like side effects in the periphery
Anti-viral agent that works to Increases dopamine release; is mildly anticholinergic; blocks NMDA receptors
AMANTADINE
Clincal effectiveness and usefullness of Amantadine
- Less effective, short-lived benefits
- Often given with L-DOPA (esp. if there are end-of-dose problems) or with anticholinergics
- Not useful when L-DOPA is ineffective
Side effects of Amantadine
Dizziness, lethargy, sleep disturbances
Can cause peripheral edema
Sympathomimetic effects due to effects on catecholamine release
**Contraindicated in patients with congestive heart failure **
