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Epidemiology
• Prevalence is 160 in 100,000
• Onset usually at 40-70 years of age, with peak onset in
sixth decade
Parkinson’s Disease • Slightly more common in men
• Incidence 20 cases/100,000 annually
John Hwang, PharmD, BCPS • Caucasians > AA = Asians
• Slightly more common in men
• Protective: cigarette smoking, ibuprofen, statins, and
caffeine
• Risk factors: hx of traumatic brain injury, low vitamin D,
use of well water, etc.

Etiology Pathophysiology
• Degeneration in DA-
• Cause is unknown producing neurons leads to
depletion of DA in the
• Multifactorial
substantia nigra
• Aging
• Genetics • Onset of clinical detection is
• Most cases appear to be sporadic typically apparent when 70—
• Some genetic forms of parkinsonism have been found related 80% of neurons are lost
to nuclear and mitochondrial genes
• Environment
• Lewy bodies are the
pathologic hallmark of PD
Round eosinophilic
neuronal inclusions
containing alpha-
synuclein

Diagnosis Clinical Manifestations

• Step 1: Presence of bradykinesia and at least one of the following • Main features
• Resting tremor • Tremor
• Presenting symptom of 70-80% of patients
• Rigidity
• “Pill-rolling”
• Postural instability • May be intermittent in early PD starting unilaterally
• Step 2: Exclude other types of parkinsonism or tremors disorders • Bradykinesia
• Step 3: Presence of at least 3 supportive positive criteria • ~80% of patients
• Generalized slowness of movement
• Asymmetry of motor signs/symptoms
• Difficulty initiating voluntary movement
• Unilateral onset
• Rigidity
• Progressive • 75-90% of patients
• Resting tremor • Resistance to passive movement about a joint
• Excellent response to L-dopa/carbidopa • Affects lower and upper extremities
• L-dopa response for 5 years or longer • Postural instability
• Presence of L-dopa dyskinesis • Most disabling
• Develops late in disease course
• Poor response to drug therapy

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Clinical Manifestations Treatment

• Neuropsychiatric abnormalities • Desired outcomes
• Cognitive dysfunction • Improve motor and nonmotor symptoms so that
• Dementia patients are able to maintain the best possible quality of
• Psychosis life
• Depression • Preservation of ability to perform ADLs
• Anxiety • Improvement of mobility
• Apathy • Minimization of ADRs
• Sleep disturbances • Improvement of non-motor features
• Fatigue • Cognitive impairment
• Depression
• Autonomic dysfunction
• Sleep disorders
• GI dysfunction

Treatment
• Generally treatment should be initiated when symptoms
start to interfere with ADLs, employment or QOL
• Non-pharmacologic
• Pharmacologic
• Anticholinergics
• Amantadine
• Carbidopa/levodopa
• Selegiline
• Dopamine agonists
• COMT inhibitors
• Surgical ‐ pallidotomy, thalamotomy, deep‐brain stimulation,
transplantation of dopamine‐producing cells
Source: Chapter 43. Parkinson's Disease, Pharmacotherapy: A Pathophysiologic Approach, 9e
Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014 Available
at: http://accesspharmacy.mhmedical.com/content.aspx?sectionid=45310493&bookid=689&Resultclick=2 Accessed: August 10, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved

Monoamine Oxidase-B Inhibitors Monoamine Oxidase-B Inhibitors

• MAO
• MAO-A: metabolizes NE, HT, and DA • Well tolerated in younger patients and primarily
used in early or mild PD
• MAO-B: metabolizes DA selectively*
• Useful as adjunctive therapy
• Rasagiline, selegiline, and safinamide are primarily • Reduces levodopa-related wearing off symptoms
MAO-B inhibitors • Sparing effect of levodopa
• Selective for MAO-B at therapeutic doses* • MAO-B inhibitors typically do not substantially
• Irreversibly binds to MAO-B inhibit the peripheral metabolism of
• Prevents degradation of DA
catecholamines
• Synthesis of MAO-B is slow  long duration of action • Use within 10 days prior to elective surgery is
contraindicated
• Effects of MAO-Bs are modest
• Avoid tyramine-rich foods

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Monoamine Oxidase-B Inhibitors MAO-B: Adverse Drug Reactions

• Drug interactions • Nausea
• Take with food
• Serotonin Syndrome
• Meperidine • Confusion
• Tramadol • Monitor mental status
• Methadone • Reduce dose
• Dextromethorphan • Insomnia
• St. John’s wort • Administer early in day
• SSRI • Hallucinations
• SNRI • Reduce dose
• TCA
• etc.
• Orthostatic hypotension
• Monitor BP, dizziness on standing
• Avoid concomitant use with serotonergic drugs • Reduce dose
• May cause/exacerbate hypertension

Amantadine ADRs
• Antiviral agent with mild antiparkinsonian activity • Confusion
• Unknown mechanism • Dizziness
• Inhibit DA reuptake? • Insomnia
• Stimulate DA receptors?
• Inhibits NMDA  decrease glutamate? • Anxiety
• May also have anticholinergic effects • Livedo reticularis
• Stop amantadine
• Effective for mild symptoms
• Most effective for tremor relief • Peripheral edema
• Can alleviate bradykinesia and rigidity • Use with caution in heart failure
• Used short term due to transient efficacy • Use with caution in patients with history of seizures

Anticholinergics ADRs: Anticholinergics

• Centrally-acting anticholinergics • Confusion
• Benztropine • Monitor mental status
• Trihexyphenidyl • Reduce dose
• Effective for rigidity, dystonia and tremor • Dry mouth, Sedation, Urinary retention
• Monitor for constipation, urinary retention
• NOT helpful for bradykinesia
• Reduce dose
• Older patients sensitive to ADRs • Avoid in:
• Preferred in patients < 65 y/o • Elderly
• Hx of constipation
• Can switch between drugs in this class if one not
• Hx of memory impairment
effective • Hx of urinary retention

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Dopamine Agonists Dopamine Agonist: Bromocriptine

• Agents • Bromocriptine
• Ergoline • Uncommonly used due to newer agents available
• Bromocriptine • Requires slow titration over 2-3 monts to offset side effects
• Non-Ergoline • ADRs
• Apomorphine • Confusion
• Reduce dose
• Pramipexole (ER available)
• Drowsiness
• Ropinirole (ER available) • Reduce dose
• Rotigotine (transdermal only) • Hallucinations/delusions
• Reduce dose
• MOA: directly stimulates DA receptors • Nausea
• Used as monotherapy or adjunct • Titrate slowly
• Take with food
• No evidence of superiority between agents but patients • Orthostatic hypotension
• Monitor BP, Dizziness upon standing
may respond differently • Reduce dose
• Ineffective in patients who have shown no therapeutic • Pulmonary fibrosis (rare)
• Monitor Chest X-ray at baseline and annually
response to levodopa • Raynaud’s phenomenon

Dopamine Agonists ADRs: Pramipexole, Ropinirole, Rotigotine

• Confusion
• Ropinirole, pramipexole, rotigotine • Monitor mental status
• Reduce dose
• Long duration of action (8-24 hours) • Drowsiness
• Useful in patient with “on-off” phenomena which occurs • Reduce dose
with L-dopa • Hallucinations/delusions
• Monitor mental status
• Preferred in younger patients due to more motor • Reduce dose
complications in older patients • Impulsivity
• Monitor behavior
• Used for L-dopa sparing effects as well • Reduce dose
• Nausea/vomiting
• May be useful in delaying the need to initiate • Titrate up slowly
levodopa therapy • Take with food
• Orthostatic hypotension
• Same agents used for restless leg syndrome • Monitor BP/dizziness upon standing
• Reduce dose

Apomorphine
• SQ injection
• Potent non-ergoline
• Used for temporary “rescue” of severe rigidity or
inability to move (“off” episodes)
• Fast distribution to brain (onset~10 mins, lasts ~2 hrs)
• Pretreatment with antiemetic necessary
• Trimethobenzamide
• Test dose is necessary to ensure tolerability
• Hypotension
• Titrate to effective dose (max 6 mg) 3-5 times a day
• If there’s an interruption > 1 week, re-titration required
Levodopa (L-DOPA)
• Metabolic precursor of DA
• Single most effective agent for treatment of PD
• Reserved for when symptoms become intrusive
with daily activity or are uncontrolled by other anti-
PD drugs
• Eventually all patients will require treatment
• More effective rigidity and bradykinesia but less
effective for postural instability and tremor
• Preferred in patients >65 years
• May cause more dyskinesia in young-onset PD

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L-DOPA
Levodopa-Carbidopa
• Quickly absorbed in small intestines but is sensitive
to pH, food, metabolism, gastric emptying • L-DOPA has the ability to
• ~1% of drug reaches the brain cross the BBB
• Most of the drug is undergoes decarboxylation • Converted by striatal
outside of the brain to DA enzymes to DA
• Therefore, must be given with a DA-decarboxylase
inhibitor that does not penetrate the BBB • Interacts with D2 and D3
receptors
• Carbidopa is a peripherally-acting L-amino acid
decarboxylase inhibitor • SinemetⓇ contains fixed 1:4
• Reduces the daily requirements of L-DOPA by ratio of carbidopa/levodopa
approximately 75% • e.g 25 mg/100 mg
• Decrease peripheral ADRs of dopamine such as N/V,
hypotension, arrhythmias

Levodopa-Carbidopa ADR: L-DOPA

• Drowsiness
• Effects are best during the first few years of • Reduce dose
treatment • Dyskinesias
• Adverse effects will eventually force the need to • Reduce dose
decrease dose • Add amantadine
• Loss of DA-nigrostriatal nerve terminals • Nausea/vomiting
• May have mortality benefit • Take with food
• The decision to start therapy must be determined • Do not give phenothiazines
individually • Cardiovascular
• Hypotension
• Available as immediate release, controlled-release, • Arrhythmia
and extended-release • Behavioral
• Depression, anxiety, insomnia, hallucinations, confusion,
agitation

Fluctuations in Clinical Response Fluctuations in Clinical Response

of L-DOPA of L-DOPA
• Wearing-off phenomenon • On-off phenomenon
• AKA “end-of-dose” effect • Profound, unpredictable return of PD symptoms without
respect to dosing interval
• Usually occurs 3-5 years after starting L-DOPA
• “Off” periods of marked akinesia alternate over the
• May need to adjust diet, use long-acting formulations, course of a few hours with “on” periods of improved
increase frequency mobility BUT often with disabling dyskinesias
• May need to add DA-agonist, MAO-B inhibitor, COMT- • Treatment: COMT-I, DA-agonist
inhibitor • Dyskinesias: involuntary movements e.g. chorea and
• Increasing doses/frequency limited by development of dystonia
dyskinesias, excessive and abnormal involuntary • Treatment: decrease L-DOPA or add amantadine
movements • Severe off-periods require apomorphine rescue
• Mechanism is unknown

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Levodopa-Carbidopa
COMT-Inhibitors
• Drug Interactions
• Phenytoin • Catechol-o-methyltransferase inhibitors
• Phenothiazine • Tolcapone
• Pyridoxine (B6) increases peripheral conversion • Entacapone
• Catechol-o-methyltransferase inhibitor
• Drug-food interactions • Inhibits L-dopa metabolism  more L-DOPA to cross
BBB
• Protein • Entacapone does not cross BBB well
• Same active transport carrier as AA in diet
• Tolcapone also inhibits central COMT
• Compete for absorption
• High protein diets decrease absorption • Useful for managing L-DOPA fluctuations
• Vitamin B-6 (same as above) • No effect when given alone
• Increases “on” time by 1-2 hours per day

ADRs: COMT Inhibitors

• Augmentation of L-dopa effects (see
Levodopa/Carbidopa)
• Need to lower L-DOPA dose by 30% for first 48
hours to avoid AE Alzheimer Disease
• Tolcapone John Hwang, PharmD, BCPS
• Liver toxicity
• Monitor LFTs especially during 1st 6 months of therapy and at
dose increase

Epidemiology Pathophysiology
• Neuropathologic changes
• Neuritic plaques  neuronal injury
• Most important risk factors are age >70 and +FH • Neurofibrillary tangles
• Prevalence increased with each decade of adult life, • Located in the cortical areas and the medial temporal lobe
reaching 20-40$ of the populations aged >85 structures of the brain
• Degeneration of neurons in the cortex and limbic structures of the CNS
• Autosomal dominant inheritance occurs in ~2% of • Areas associated with higher functions
• Learning
patients • Memory

• Females more at risk •

•
Reasoning
Behavior
•
• Estimated annual cost of caring for a single patient Emotional; control

• 4 major alterations
with advanced disease > $50,000 1. Cortical atrophy
2. Degeneration of cholinergic neurons
3. Presence of NFTs
4. Accumulation of neuritic plaques

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Diagnosis
Risk Factors
• Definitive diagnosis of AD requires histopathologic
• Genetic factors exam (rarely done)
• Inherited forms < 1% of cases • Diagnosis depends on clinical criteria
• More than 50% of young onset (<65 yrs)
• Insidious onset
• Environmental factors • Progressive decline in memory
• Age
• At least one other cognitive domain leading to impaired
• Decreased reserve capacity of the brain functioning
• Reduced brain size
• Low educational level • National Institute on Aging and the Alzheimer's
• Reduced mental and physical activity in later life
• Head injury
Association Criteria
• Downs syndrome • Interference with ability to function at work or at usual
• Depression activities
• Mild cognitive impairment • A decline from a previous level of functioning
• Risk factors for vascular disease • No explained by delirium or major psychiatric disorder

Dementia Clinical Manifestations

• Memory impairment  language and visuospatial deficits
• Most common causes  executive dysfunction
• Alzheimer’s disease • 50% of patients with mild cognitive impairment will progress to
• Vascular dementia AD over 4 years
• Parkinson’s (Lewy body) • Cognitive problems interfere with daily activities
• Alcoholism • Keeping track of finances, driving, housekeeping, etc.
• Drug intoxication
• Less common causes • Middle stages: patients become unable to work, easily
• Vitamin deficiencies e.g. B12, B1
confused and lost, requiring supervision, word finding,
• Head trauma apraxia
• Endocrine e.g. hypothyroid • Late stages: patients may wander aimlessly; loss of
• Neoplastic judgment/reasoning; delusions; passivity and withdrawal;
• Psychiatric e.g. depression development of Parkinsonian rigidity with shuffling gait
• Degenerative disorders e.g. Huntington’s disease
• End stages: rigid, mute, incontinent, bedridden requiring
constant care

Symptoms Treatment
Cognitive Behavioral Mood Changes • Current therapy does not cure or stop the disease
Memory loss Easy distractibility Apathy • Therapy focuses on 3 domains
Aphasia Demanding Anger 1. Cognition
Agnosia Stubborn Paranoia 2. Behavioral and psychiatric symptoms
Disorientation Uncooperative Delusions 3. Functional ability
Impairment of abstract Losing/hoarding/hiding Depression
thinking things Irritability • Mini-Mental State Examination (MMSE) scores
Apraxia Wandering Aggression • Mild: 19-26
Hallucinations Repetitive speech or • Moderate: 10-18
action
Agitation • Severe: <10
Sleep disturbances • Scores based on degree of impairment to memory,
orientation, judgment, personal care, etc.

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Nonpharmacological Approach Pharmacologic

• Consider vision, hearing, or other sensory impairments • Mild to moderate disease  cholinesterase
• Find optimal level of autonomy and adjust expectations for inhibitor
patient performance over time
• Avoid confrontation. Remain calm, firm, and supportive if • Donepezil (IR, ER)
the patient becomes upset • Rivastigmine (IR, patch)
• Maintain a consistent, structured environment with • Galantamine (IR, ER)
stimulation level appropriate to the individual patient
• Provide frequent reminders, explanations, and orientation • Moderate to severe disease  consider adding
cues. Employ guiding, demonstration, and reinforcement anti-glutamatergic therapy
• Reduce choices, keep requests and demands of the patient • Memantine
simple, and avoid complex tasks that lead to frustration
• Bring sudden declines in function and the emergence of • Agents can be used monotherapy or in combination
new symptoms to professional attention

Cholinesterase Inhibitors Cholinesterase Inhibitors

• AD is associated with reduced activity of cholinergic
neurons
• Decrease in cerebral choline acetyl transferase --> decreased
acetylcholine synthesis --> impaired cholinergic function
• Cholinesterase inhibitors prevents Ach degradation in
the synaptic cleft
• Hydrophobicity --> cross BBB
• Provides only modest symptomatic relief
• No neuroprotective effects and does not affect course
of illness
• No significant different between agents
• Donepezil (Aricept)
• 5 mg to 10 mg per day
• A 23 mg once-daily formulation available but clinically
not shown to be superior (more side effects)
• Rhabdomyolysis (rare), vivid dreams/nightmares
• Galantamine (Razadyne)
• 8 mg to 16 mg per day
• More GI side effects than donepezil
• Avoid in ESRD or severe hepatic impairment
• Short half-life (requires re-titration if interrupted)

Cholinesterase Inhibitors ADR: Cholinesterase Inhibitors

• Rivastigmine (Exelon) • Dizziness • Nausea
• Patch has better tolerability and similar efficacy
• Syncope • Vomiting
• Short half-life (requires re-titration if interrupted)
• Has been associated with mortality • Atrial arrhythmias • Diarrhea
• Hasn't been studied in severe hepatic impairment • MI • Anorexia/weight loss
•Initiation/interruptions of therapy • Angina • PUD/GI bleed
•All CIs should be started at lowest dose and titrated • AV block • Caution with NSAID
•Interruption for >3 days requires re-titration (for • Seizures use
galantamine and rivastigmine)
•Abrupt discontinuation may worsen symptoms • Insomnia

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NMDA Receptor Antagonist
• Memantine (Namenda), IR and XR formulation
• Glutamate binds to N-methyl-D-aspartate receptors
• Glutamate is a neuroexcitatory transmitter
• Suggested to have neuroprotective effect but not
proven
• Indicated for moderate to severe stages of AD
• Benefits are modest with moderate to severe AD
• Fewer side effects than CIs
• Can be added to CIs or used monotherapy when CIs
are intolerable
Depression
• Depression
• Common in patients with AD
• Apathy is seen in 48% to 92%
• Clinically significant depression occurs in approximately
32% with mild dementia, 23% with moderate disease,
and 18% in the severe stage of the dementia
• Treatment with selective SSRIs most common
• Good side-effect profile and evidence of efficacy
• Serotonergic function may also play a role in some of
the other behavioral symptoms
• SSRIs may be used in absence of depression
• Avoid TCAs due to anticholinergic activity
Benzodiazepines
• Aggression and disruptive behavior
• Benzodiazepines
• Used to treat anxiety, agitation, and aggression
• Modest benefit
• Routine use not advised
• PRN for infrequent agitation only
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ADR: Memantine
• Dizziness
• Headache
• Confusion
• Usually seen during dose titration and is transient
• Hallucinations
• Constipation
• May mitigate diarrhea
Antipsychotics
• Use of antipsychotics should be reserved when
symptoms are dangerous, severe, or cause
significant patient distress
• No FDA approved drugs for treatment of behavioral
disturbances in dementia patients
• BBW Antipsychotics are associated with increased
mortality in elderly patients with dementia-related
psychosis
• Use low doses and at short durations, as last option
after addressing causative factors and using
psychosocial interventions
Unproven Treatments
Estrogen
• Lower incidence of AD in women who took ERT post-menopausally
• Prospective clinical trials have not supported the use of estrogen as a treatment
for cognitive decline and longer trials tend to suggest harm
Anti-inflammatory agents
• Retrospective epidemiologic studies suggest a protective effect against AD in
patients who have taken NSAIDs
• In prospective clinical trials NSAIDs have had no cognitive benefit in AD patients
or else benefits so minimal the risk of harm exceeds the potential benefit
Lipid-lowering agents
• Longitudinal epidemiologic studies suggest an association between elevated
midlife total cholesterol levels and AD
• Increased risk of dementia does not appear to be associated with
hypercholesterolemia in late life
• RCTs of statin therapy given in late life to patients at risk for vascular disease
indicate that statins do not prevent AD
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Dietary Supplements
Vitamin E
• Based on pathophysiologic theories involving
oxidative stress and the accumulation of free radicals
in AD, significant interest has evolved regarding the
use of antioxidants
• A meta-analysis found that high-dose vitamin
E increases mortality in supplemented subjects
• No benefit in patients with mild cognitive
impairment in the progression to AD
• No longer recommended for AD treatment
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Dietary Supplements
Gingko Biloba
• Proposed mechanisms for Ginkgo’s use in AD include its potential
to increase blood flow, decrease blood viscosity, antagonize
platelet-activating factor receptors, increase anoxia tolerance,
inhibit monoamine oxidase, and serve as an antioxidant
• A large trial did not reduce either the overall incidence rate of
dementia or AD incidence in elderly individuals with normal
cognition or MCI
• Another recent large trial found that the long-term use did not
reduce the risk of progression to AD among older adults
suffering from memory complaints compared with placebo
• Antiplatelet effect
• Use with caution with NSAIDs and antiplatelets
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