Transcript file (Parkinsons Disease Topic

PARKINSON’S DISEASE
Stefanie L. Drahuschak
PharmD Candidate 2014
OBJECTIVES




Describe the etiology, epidemiology, and clinical
manifestation of Parkinson’s Disease (PD)
Determine appropriate first-line therapy for
Parkinson’s Disease
Determine appropriate adjunct therapeutic
agents for Parkinson’s Disease
List treatment complications and understand
how to augment therapy accordingly
EPIDEMIOLOGY

~2% lifetime risk of PD


4% if positive family history
The number of patients diagnosed with PD per
year ranges from 10 per 100,000 people aged 5059 and 120 per 100,000 people aged 80-89

Prevalence of PD increases with age
Usual age at time of diagnosis ranges between 55
and 65 years old
 A higher incidence is reported among males


Male to female ratio of 2:1
EPIDEMIOLOGY

Risk factors (possible)


Protective factors (consistent evidence)


Living in rural area, drinking well water, chronic
exposure to pesticides and/or heavy metals (iron and
manganese)
Cigarette smoking, caffeine consumption
Genetic factors

More likely play a role if develop PD before age 50
GENETICS
A growing number of single gene mutations have
been identified
 Six genes have been identified (11 mapped)


SNCA, UCH-L1, PRKN, LRRK 2, PINK 1, DJ-1
genes
With the exception of LRRK 2, these genes only
account for a small number of PD patients
 LRRK 2 gene is the most common cause of
familial or “sporadic” PD
 Identification of these genes have allowed for
further insight into disease mechanisms

ETIOLOGY
Not fully understood
 Likely involves interactions between aging,
genetic makeup, and environmental factors
 Two hallmark features:

1) Cell death in the substantia nigra affecting
dopaminergic neurons  decreases dopamine levels
 symptoms occur
 2) Lewy bodies are present in the remaining neurons


PD is usually clinically detectable when ~70-80%
of neurons are depleted
CLINICAL PRESENTATION

Symptoms start insidiously and unilaterally
T - tremor (at rest)
 R - rigidity (of muscles)
 A - akinesia/bradykinesia (no/slow movement)
 P – postural changes

Probable PD can be diagnosed when at least two
of these symptoms are present
 For proper diagnosis other causes must be ruled
out, such as medication-induced parkinsonism

CLINICAL PRESENTATION

T – tremor
Usually in arms/hands
 Patients make a pill-rolling movement with fingers
and hands
 May subside when patient is mobile or while sleeping


R – rigidity of muscles

Hypomimia – mask-like appearance of face
CLINICAL PRESENTATION

A – akinesia/bradykinesia
Slow movement throughout action/task
 Micrographia – writing progressively smaller
 Gait issues


P – postural changes
Most common in advanced stages of PD
 Increases risks of falls to patients

MEDICATION-INDUCED PARKINSONISM
Must rule out before proper PD diagnosis
 Most likely to occur with medications that act on
dopamine-2 receptors


Antipsychotics


Antiemetics (dopamine antagonists)


Phenothiazines, olanzapine, risperidone, haloperidol
Metoclopromide (BBW), prochlorperazine
Etc

Methyldopa
TREATMENT GOALS
Preserve motor and non-motor functions
 Be able to perform activities of daily life
 Improve mobility
 Minimize adverse effects of PD treatment
 Improve non-motor issues such as cognitive
impairment, depression, fatigue, and sleep
disorders.


IMPROVE QOL!
PD TREATMENT
PD
Physical and Mental
Therapy
MAO-B Inhibitors
Pharmacotherapy
Dopamine agonists
Surgery
Carbidopa/Levodopa
MAO-B INHIBITORS

Agents
Rasagiline (Azilect®)
 Selegiline (Eldepryl®)
 Selegiline ODT (Zelapar®)


MOA

Selectively and irreversibly inhibitions MAO-B in the
brain, which interferes with the degradation of
dopamine leading to prolonged dopaminergic activity
MAO-B INHIBITORS
Duration of
Action
Metabolism
Bioavailability
Rasagiline
(Azilect®)
~1 week
CYP1A2
36%
Primarily
renally
Selegiline
(Eldepryl®)
24-72 hours
CYP2B6
25-30%
delivered
over 24h
10% renal
2% fecal
Selegiline
ODT
(Zelapar®)
24-72 hours
CYP2B6 and
3A4
>> capsule /
tablet
Primarily
renally
Drug
Excretion
RASAGILINE (AZILECT®)
Effective as monotherapy for early PD or as addon therapy for managing motor fluctuations in
advanced PD
 Dose



Adverse effects


0.5 to 1 mg once daily
Generally well tolerated with minimal GI or
neuropsychiatric side effects
Second generation, not as well studied as
selegiline
SELEGILINE (ELDEPRYL®)
Early PD – monotherapy can provide modest
motor function improvments
 Advanced PD – adjunctive use can add 1 hour of
“on” time
 Dose



5 mg PO BID
Adverse effects
minimal; insomnia, hallucinations, jitteriness
 Can worsen preexisting dyskinesias or psychiatric
symptoms such as delusions
 Second dose given in afternoon to avoid insomnia

SELEGILINE ODT (ZELAPAR®)
Avoids first pass hepatic metabolism  increased
bioavailability
 Use as adjunctive therapy
 Decreases “OFF” time
 Dose



1.25 mg PO daily for at least 6 weeks; can increase to
2.5 mg PO daily based on response
Adverse effects

Oral irritation (10%), insomnia
DOPAMINE AGONISTS

Directly stimulate dopamine receptors

Two subtypes

1) Ergot-containing agonists
Bromocriptine (Parlodel®)
 Pergolide (Permax®) – no longer available


2) Nonergot agonists
Pramipexole (Mirapex®)
 Ropinirole (Requip®)
 Rotigotine (Neupro®)

DOPAMINE AGONISTS
Nonergot dopamine agonists are useful as
monotherapy in mild-mod PD or adjunct therapy
to L-dopa
 Reduce frequency of “off” periods
 May allow reductions in L-dopa dose



Longer half lives than L-dopa
Adverse effects
Nausea, confusion, hallucinations, light-headedness,
lower-extremity edema, postural hypotension,
sedation, vivid dreams
 Compulsive behaviors (gambling, hypersexuality)

DOPAMINE AGONISTS
Drug
Initial Dose
Max Dose
Pramipexole
0.125 mg TID
1.5 mg TID
Renal dosing:
CrCl 35-59 mL/min
CrCl 15-34 mL/min
0.125 mg BID
0.125 mg daily
1.5 mg BID
1.5 mg daily
Pramipexole ER
0.375 mg daily
4.5 mg daily
Renal Dosing:
CrCl 30-50 mL/min
CrCl <30 mL/min
0.375 mg every other day
NOT recommended
2.25 mg daily
NOT recommended
Ropinirole
0.25 mg TID
24 mg/day
Ropinirole XL
2 mg daily
24 mg/day
Bromocriptine
1.25 mg BID
40 mg/day
LEVODOPA (L-DOPA)
Most effective drug for symptomatic treatment of
PD  drug of choice
 Is an immediate precursor to dopamine
 Able to cross the blood brain barrier


Other drugs for PD are not able to
Very short half-life
 Undergoes rapid peripheral conversion of L-dopa
to dopamine



Used in combination with other agents to reduce the
conversion peripherally and increase L-dopa
concentration centrally
Regardless of initial therapy, all patients will
eventually require L-dopa
CARBIDOPA
Peripherally-acting L-amino acid decarboxylase
inhibitor
 Decreases the peripheral conversion of L-dopa to
dopamine

Increases L-dopa transported into brain
 Decreases peripheral side effects of dopamine
(nausea)

Unable to cross blood brain barrier
 Never used as monotherapy
 Increases half-life of L-dopa to 1.5-2 hours

CARBIDOPA/LEVODOPA COMBINATIONS

Carbidopa/Levodopa immediate release
(Sinemet®)


Carbidopa/Levodopa sustained release (Simemet
CR®)


10mg/100mg; 25mg/100mg; 25mg/250mg
25mg/100mg; 50mg/200mg
Carbidopa/Levodopa ODT (Percopa®)

10mg/100mg; 25mg/100mg; 25mg/250mg
CARBIDOPA/LEVODOPA (SINEMET®)

Dosing

Start with 25mg/100mg one tablet TID
75 mg carbidopa/300 mg levodopa per day in divided doses
 75 mg of carbidopa per day is required to sufficiently inhibit
peripheral activity of L-amino acid decarboxylase


Titrate up slowly based on symptoms

No true maximum dose of Levodopa

200 mg carbidopa and 2,000 mg levodopa is a common
maximum dose
CARBIDOPA/LEVODOPA (SINEMET®)

Adverse effects
“Sin-emet” = without vomiting
 Nausea, postural hypotension, sedation, vivid
dreams, dyskinesias


Counseling
Should be initially taken with food for a few weeks
 Then take 30 mins before or 60 mins after meals to
avoid competition for absorption with other amino
acids
 Move carefully from supine position (postural
hypotension)

MOTOR COMPLICATIONS OF L-DOPA

Approximate risk of developing complications is
10% per year of L-dopa therapy


Can occur as early as 5-6 months after starting
therapy, especially with higher doses
Possible complications
End-of-dose “wearing off”
 “Delayed on” or “no on” response
 Start hesitation (“freezing”)
 Peak-dose dyskinesia

END-OF-DOSE “WEARING OFF”

Phenomenon of experiencing motor fluctuations
before the next dose is due


With advancing PD, duration of action of single
dose shortens progressively


Due to decreasing neuronal storage capability and
short half-life of levodopa
Therefore needs to eventually be dosed more
frequently
Can also add another agent (MOA-B
inhibitor/DA) to help help control “off” time
“DELAYED-ON” OR “NO ON” RESPONSE
A delayed or completely absent onset of drug
 Due to delayed gastric emptying or decreased
absorption in the duodenum
 Intervention:

Take medication on an empty stomach
 Chew tablet or crush and drink with full glass of
water
 Use ODT formulation
 “Drug holidays” may be used rarely to modify
dopamine receptors


Unpleasant for patient, not commonly done
START HESITATION (“FREEZING”)
A sudden, episodic inhibition of lower extremity
motor function
 Interferes with ambulation and increases risk of
falls/injuries
 Patients feel as if they are “stuck to the floor”
 Can be exacerbated by anxiety or obstacles
(doors, turns)
 Intervention


Could increase dose +/- add medication, but physical
therapy/walking devices are more helpful generally
PEAK-DOSE DYSKINESIA
Involuntary movements usually involving the
neck, trunk, and lower/upper extremities
 Associated with peak concentrations of dopamine
 Using lower doses of L-dopa dyskinesias will
improve


But PD symptoms may return  increasing dosing
interval or addition of another chemical
Addition of an NMDA receptor antagonist
(amantadine) may be helpful
 For severe dyskinesias, surgery may be
considered

ADJUNCTIVE PD THERAPY

Amantadine

Apomorphine

Anticholinergics

COMT Inhibitors
AMANTADINE

MOA
Not fully understood
 Inhibits glutamate NMDA receptors  releases
dopamine from nerve terminals

Onset of action within 48 hours
 Excreted unchanged in urine
 Provides modest early PD benefit



Useful for decreasing L-dopa induced dyskinesias
Dose
200-300 mg/day in early PD
 200-400 mg/day in divided doses for dyskinesias

AMANTADINE

Adverse effects
Confusion, dizziness, dry mouth, hallucinations
 Elderly are prone to develop confusion


Counseling
Take without regards to food
 Take early in day to avoid sleep disturbances

APOMORPHINE

Subcutaneous nonergot dopamine agonist

Extensive first pass metabolism from SQ
administration

Duration of effect is ~100 minutes

Creates an “on” response within 20 minutes

Dose


2-6 mg per injection (about 0.06 mg/kg)
$$$$$
APOMORPHINE

Adverse effects

Nausea/vomiting and hypotension
Premedication with antiemetic is necessary
 Contraindicated with 5HT3-receptor blockers (ondansetron,
etc)
 Dopamine antagonists should be avoided (metoclopromide,
prochlorperazine)
 Trimethobenzamide would be antiemetic of choice

ANTICHOLINERGICS

Dopamine inhibits acetylcholine neurons
Therefore, when dopamine is depleted in PD
cholinergic activity increases
 Increased cholinergic activity is believed to
contribute to tremors
 MOA: decrease cholinergic activity

Same effectiveness at treating tremors as
dopamine agonists
 Limited use from adverse effects



Dry mouth, blurred vision, urinary retention,
constipation, confusion, sedation
On Beers Criteria for elderly patients to avoid
ANTICHOLINERGICS

Agents:

Benztropine


Trihexyphenidyl


0.5 to 2 mg BID
0.5 to 1 mg BID; slowly titrate to 2 mg TID
Indications
Treatment of tremors in patients < 65 yo
 To decrease rigidity
 To manage drooling

COMT INHIBITORS (CATECHOL-OMETHYL-TRANSFERASE)

MOA
Reduce peripheral conversion of L-dopa to dopamine,
which enhances central dopamine bioavailability
 Similar to carbidopa




Can decrease off-time significantly by increasing
L-dopa AUC by ~35%
Considered more effective than SR
carbidopa/levodopa in extending L-dopa effect
Agents: tolacpone and entacapone
TOLACAPONE (TASMAR®)

First COMT Inhibitor available in US

Dose


100-200 mg TID
Black box warning
Fatal liver injury
 Reserved for inadequate symptom control
 Need informed consent
 Liver function monitored q 2 weeks x 1 week, then q
4 weeks thereafter

ENTACAPONE (COMTAN®)





Has a shorter half-life than tolcapone
Dose: 200 mg needs to be given with each dose of
carbidopa/levodopa up to a maximum of 8
times/day
Increase total daily “on” time by 1-2 hours
Adverse effects: Brownish-orange urine, delayed
onset diarrhea (no liver issues)
Available in combination tablet with carb/levo
SURGERY
Currently considered an adjunct to
pharmacotherapy for patients with uncontrolled
symptoms despite an appropriate medication
regimen
 Deep-brain stimulation (DBS) is preferred
surgical method

A battery-powered neurostimulator is implanted
subcutaneously below clavical
 Provides constant electrical stimulation
 Very effective for suppressing tremors, but not as
helpful for other PD symptoms

COST CONSIDERATIONS


In US, direct costs associated with PD range from
$4-$8 billion per year
The more severe the disease, the higher it costs
to manage


Falls, dementia issues, nursing facilities
Minimizing costs
Should use lowest effective dose
 Try single agents before adjunctive therapy
considered

NON-MOTOR COMPLICATIONS OF PD

Autonomic


Sleep disturbances


Daytime somnolence, insomnia, RLS, fatigue, REM
sleep disorder
Mood issues


Sexual dysfunction, orthostatic hypotension, urinary
incontinence, constipation
Anxiety, depression, psychosis
Cognitive dysfunction

Dementia
SEXUAL DYSFUNCTION

Occurs in both men and women with PD

Less studied in women

Sildenafil (Viagra®) 50 mg has been effective in
the treatment of ED in PD patients
ORTHOSTATIC HYPOTENSION



A drop of 20 mmHg in SBP or 10 mmHg in DBP
Determine if any other agents could be
contributing  d/c if possible
Use support stocking, stand up slowly, decrease
L-dopa dose if possible
DAYTIME SOMNOLENCE

Can be multifactoral


Due to PD, medications, underlying sleep issues,
mood issues
Modafinil may be beneficial in improving
patient’s perception of wakefullness during the
day
RESTLESS LEG SYNDROME



Occurs in up to 20% of patients with PD
Dopamine agonists (ropinirole and pramipexole)
are only FDA-approved agents for RLS
Carbidopa/levodopa may decrease the incidence
of nighttime leg movements
DEMENTIA


Unknown if the etiology is similar or different in
patients with PD
Donepezil (Aricept®) or rivastigmine (Exelon)
could be considered
DEPRESSION



Occurs in ~40% of PD patients
Depression may be exacerbated by PD issues
such as insomnia, psychomotor changes, weight
changes, fatigue/loss of energy, feelings of losing
control of body
Selective serotonin reuptake inhibitors can be
used to help improve QOL
CONCLUSION




A cause or cure for PD still does not exist
Many treatment options exist with wide patient
intervariability
An appropriate medication regimen can
significantly improve QoL
Goal of therapy continues to be maintaining
functional control with minimal complications
REFERENCES







1) Davie CA. A review of Parkinson’s Disease. Br Med Bull.
2008; 86: 109-127.
2) Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease.
In: Dipiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy.
8th ed. New York, NY: McGraw-Hill; 2011: 1033-1044.
3) Jankovic J. Parkinson’s disease: clinical features and
diagnosis. Neurol Neurosurg Psychiatr. 2008; 79(4): 368-76.
4) Chen JJ. Anxiety, depression, and psychosis in
Parkinson’s Disease: Unmet needs and treatment
challenges. Neurol Clin. 2004; 22(3): 63-90.
5) Obeso JA, Rodriguez-Oroz MC, Goetz CG, et al. Missing
pieces in the Parkinson’s disease puzzle. Nat Med. 2010;
16(6): 653-61.
6) Lees AJ, Hardy J, Revesz T. Parkinson’s Disease.
Lancet. 2009; 373: 2055-66.
7) Rihmer Z, Seregi K, Rihmer A. Parkinson’s disease and
depression. Neuropsychopharmacol Hung. 2004; 6(2): 82-5.
QUESTIONS?