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210 Cards in this Set
- Front
- Back
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Epidemiology of AD (objective)
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Alzheimers in the Media
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Delirium
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acute confusional state; acute onset
with clouding of consciousness |
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Dementia
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intellectual deterioration severe
enough to impede social or occupational performance ……insidious onset with gradual deterioration over a slow period of time |
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Mild cognitive impairment
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“early dementia”
10-15% progress to dementia per year |
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Types of Dementia
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“Reversible” Causes of Dementia (objective)
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Risk Factors for AD
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two biggest risk factors of AD
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age
genetic factors |
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Genetic Influences of AD
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AD Pathophysiology (objective)
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Extracellular amyloid plaques
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Biochemical Changes in AD (objective)
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Clinical Presentation of AD (objective)
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Symptoms increase over time
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IADLs
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instrumental activities of daliy living
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Differences Between Normal Aging and
Alzheimer’s Disease (objective) |
Alzheimer's Disease
*Poor judgment and decision making *Inability to manage a budget *Losing track of the date or the season *Difficulty having a conversation *Misplacing things and being unable to retrace steps to find them Typical age-related changes *Making a bad decision once in a while *Missing a monthly payment *Forgetting which day it is and remembering later *sometimes forgetting which word to use *losing things from time to time |
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pic of pathophysiology of Ad
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Progression of Alzheimer’s Disease (obejective)
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early diagnosis
cognitive symtoms--> loss of ADL-->behavorial problems--> nursing home placement--> death |
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Diagnosis of AD (obejective)
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Definitive diagnosis can only be made with biopsy or at
autopsy |
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Exclusion of Other Conditions (objectives)
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Drug-induced Cognitive Impairment (know)
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Mental State Evaluation (know the scores)
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if AD is not treated how many points on the MMSE scale does it typically decrease
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2-4 per year
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MMSE questions
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AD Evaluations in Clinical Trials
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cognative tests (know)
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what cognitive test is used for mold to moderate Ad
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what cognitive test is used for severe AD
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Evaluation of Functional Status ADLs
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Evaluation of Functional Status IADLS
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A 78 y/o female dx with AD approx 4 yrs ago
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No cure, only supportive care
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An 82 y/o man with AD lives at home with his son
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No APAP pm,
benozos can worsen symptoms no-pharm such as better sleep habits: no stimulating activityi in the bedroom, sleep routine His sleep problems may be due to pain, so if treat the pain may begin to sleep fix sleep problems before phycosis |
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Clinical Management of AD (objective)
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No cure, only supportive care
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AGS Quality Indicators for AD
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AGS Quality Indicators
1. Medication review & adjustment 2. If mild-moderate, discuss use of cholinesterase inhibitors 3. Give information on dementia diagnosis, prognosis, associated behavioral symptoms, home occupational safety, and community resources 4. If behavioral problems, use nonpharmacologic interventions first and if using drugs, document risk/benefit discussion |
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ACP/AAFP Guidelines for AD
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1. Cholinesterase inhibitors or
memantine should be initiated based on individualized assessment 2. Drug choice should be based on tolerability, side effects, ease of use and cost 3. Insufficient evidence to compare effectiveness of agents 4. Urgent need for further research on clinical effectiveness of drugs |
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Pharmacologic Management of AD (objective)
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1. Cholinesterase Inhibitors
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Are NMDA antagonist good for mild AD
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NO, they are only beneficial in moderate-severe AD
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what happens if you stop AD meds
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the paitent will readily decline.
These meds are not used to imporve the paiteint just stablize |
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Acetylcholinesterase Inhibitors (objective)
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Efficacy of Cholinesterase Inhibitors
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Very modest improvement/stabilization in symptoms
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How are donepezila and galantamine metabolized (know)
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CYP2d6, and CYP3A4
More drug interactions |
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how is rigastigmine metabolized
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nonheopatically
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Donepezil (Aricept™)
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what is the effective dose of Donepezil (Aricept™)
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warnings of Donepezil (Aricept™)
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Warnings in patients with COPD/asthma (because increase in ACh causing bronchoconstriction), PUD (becasue increase in gastric acid secretions), sicksinus
syndrome (becasue vagal nerve stimualtion which decreases HR) |
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Rivastigmine (Exelon™)
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what is the effective dose of Rivastigmine (Exelon™)
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does Rivastigmine (Exelon™) have P450 interactions
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nope
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Galantamine (Razadyne/Razadyne ER™)
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what is the effective dose of Galantamine (Razadyne/Razadyne ER™)
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Donepezil 30-week Study (MMSE)
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showed very little difference in efficacy of 5 amd 10 mg
therefore 5 mg is the effective dose |
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Therapeutic Targets: NMDA
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the cortex and hippocampus release glutamate which binds the NMDA recptor causeing release of Ca which is involved in learning and memory and neuronal cell death
so blocking the NMDA receptor prevents the release of Ca and therefore neuronal cell death |
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Memantine (Namenda™)
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Memantine (Namenda™) dosing
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Dosing
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Memantine (Namenda™) metabolism
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Not largely metabolized, majority of drug excreted
unchanged in urine |
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Memantine (Namenda™) SE
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Usually well tolerated
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AD Treatment:
Memantine Combination |
with donepazil the results were much better there was less of a progression in AD
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Cost of AD Medications per month
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Donepezil $134
Rivastigmine $151 Galantamine $151 Memantine $136 vitamin E $17 gingo $10 |
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Gingko Biloba and AD
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Vitamin E and Selegiline and AD
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Other Options for AD
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Treatment
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Behavioral Therapy of AD
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are TCAs recommend to use in those with AD
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no because anticholinergic
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Psychotic symptoms of AD and how treated
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risks and benfits of anti psychotics in AD (objective)
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Antipsychotic Therapy in AD
Black Box Warning |
WARNING: INCREASED MORTALITY IN ELDERLY
PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL® is not approved for use in patients with dementia-related psychosis |
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Initiating Antipsychotic Therapy in AD patients
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Epidemiology PD
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Estimated prevalence: 329 per 100,0001
1 million in U.S. suffer from PD 3rd most common neurological disorder in elderly Average age of disease onset (clinical symptoms): 60 years Variable progression: 10-20 years or more |
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Burden of Parkinson’s Disease
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Reduced quality of life.1
Higher susceptibility to depression and cognitive impairments.2 Increased risk for comorbidities such as penumonia.2 Increased medical expenses (Physician visits and emergency care).2 Caregiver burden and risk of early nursing home placement.2, 3 |
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what is damaged in PD
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oxidative stress damages the mitochondria and complex I
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pathophysiology PD
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Depigmentation of dopamine producing neurons
Presence of Lewy bodies Brain Gastrointestinal tract Onset of clinically detectable symptoms occurs after 70-80% loss of dopamine producing neurons |
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path of damage in PD
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Degeneration of dopamine (DA) producing neurons in SNpc
Depletion of DA and reduction in nigrostriatal DA activity Imbalance of other neurotransmitters (Ach, GABA, glutamate, 5-HT) in the basal ganglia Impaired extrapyramidal tract function and symptoms of parkinsonism all of the above leading to tremor, rigidity, bradykinesia |
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D1-like receptor family (D1, D5)
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Found in brain, blood vessels and smooth muscle
Stimulatory Activation of D1: dyskinesia |
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D2-like receptor family (D2, D3, D4)
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Found in brain, smooth muscle and presynaptic nerve terminals
Inhibitory Agonist = Activation of D2 Clinical improvements Adverse effects |
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Regions of brain with a______density of D1-like receptors tend to have a l_____ density of D2-like receptors
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high
low |
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Primary Parkinson’s disease
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70%
Idiopathic (> 40 yrs old). Majority Young-onset (21 – 40 yrs old) Juvenile (< 21 yrs old) |
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Secondary parkinsonism
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10%
Drugs Toxins (MPTP, Mn, CO) Stroke related Others (brain tumor, Wilson’s disease) |
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Hereditary parkinsonisms
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< 5%
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Drugs likely to induce or exacerbate Parkinsonism
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Antinausea/antipsychotic - Chlorpromazine, promethazine, thioridazine, prochlorperazine, perphenazine, fluphenazine
Antipsychotics – Haloperidol (Haldol), olanzapine (Zyprexa), risperidone (Risperdal) Metoclopramide (Reglan) n-MPTP By-product of synthesis of street heroin |
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Drugs that should be used with caution in PD
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Amiodarone
Calcium Channel blockers Verapamil Diltiazem Nifedipine Amlodipine Lithium Valproate |
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Idiopathic Parkinson’s Disease
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A neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra as well as other dopaminergic and non-dopaminergic areas of the brain
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Primary clinical symptoms PD
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(TRAP)
Tremor Rigidity (muscular) Akinesia/bradykinesia Postural instability/gait dysfunction Initially, symptoms asymmetric and unilateral |
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Tremor of PD
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Commonly first obvious symptom
Begins unilaterally in the upper extremities Rapid and rhythmic Absent during sleep and slowed by sedation Increased when angry, upset, or tense More marked with time Can spread to lower extremities, face, jaw and tongue |
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Akinesia/bradykinesia PD
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Decrease or absence of normal automatic movements
Difficulty performing ADLs Development on dominant side affects handwriting Postural changes (bent forward, festination, freezing) Later stages: falls and injuries |
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Rigidity: cogwheeling PD
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Rigidity superimposed on tremor
Demonstrated by: Holding arm out with hand supporting elbow Moving arm towards and away from chest Rigidity felt through elbow and seen through movements in arm Reduced arm swing while walking rigidity superimmposed on the tremor failure of postural refelxes |
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Postural instability PD
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Failure of postural reflexes, which leads to impaired balance and falls
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Diagnosis of PD
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Bradykinesia and at least 2 of following:
Limb muscle rigidity Resting tremor abolished by movement Postural instability Unmistakable in advanced disease Other features supporting diagnosis of PD Unilateral onset w/persistent asymmetry of motor signs Progressive signs/symptoms with falls occurring later as disease progresses Significant loss of smell (becasue the olfactory area of the brain region is affected) Excellent response to levodopa challenge |
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Non-Motor Features of PD
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Cognitive/ Psychiatric
Anxiety Depression Fatigue Slow thinking Sleep fragmentation Hallucinations Autonomic Drenching sweats Dyspnea Orthostatic hypotension Sexual dysfunction Constipation Incontinence Sensory/ Pain Tingling sensation Akathisia Olfactory deficit Diffuse pain |
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other Non-Motor Features of PD
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Others
Masked face (loss of facial expresions) Less blinking/staring Salivation and drooling (not producing more saliva just not swallowing as much) Declining intellect Begins early and is progressive Hallucinations common later in course Delusions Dementia Anxiety and confusion |
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what is the only neoroprotective treatment that has been proven to slow the progression of PD (know)
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exercise
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Need for Neuroprotective Therapies
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Agents that slow disease progression
The ability to prevent the degeneration of neurons during the progression of the disease Potentially, this strategy could also restore lost function Motor complications of current therapies Non-motor symptoms related to disease progression (depression, dementia, psychosis) None of the current therapies have been proven to be neuroprotective |
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______ of the current therapies have been proven to be neuroprotective
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NONE
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Dopamine replacement for PD
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Immediate release (Sinemet)
Sustained release (Sinemet CR) Orally disintegrating tablet (Parcopa) |
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Dopamine agonists for PD
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Non-ergot derived
Ropinirole (Requip, Requip XL) Pramipexole (Mirapex, Mirapex ER) Rotigotine TD (Neupro) Apomorphine (Apokyn) Ergot derived Rarely used in clinical practice Bromocriptine |
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COMT-inhibitors
for PD |
Entacapone (Comtan)
Tolcapone (Tasmar) |
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NMDA receptor antagonist
for PD |
Amantadine (Symmetrel)
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Anticholinergics
for PD |
Trihexiphenidyl (Artane)
Benztropine (Cogentin) Diphenhydramine (Benadryl) |
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MAO-B inhibitors
for PD |
Selegiline (Eldepryl, Zelapar)
Rasagiline (Azilect) |
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Carbidopa/Levodopa MOA
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Carbidopa inhibits dopa-decarboxylase to prevent peripheral conversion of levodopa to dopamine
Levodopa crosses BBB and is converted to dopamine Binds to D1 and D2 Overall effect: amounts to brain and peripheral side effects |
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Carbidopa/Levodopa indications
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Most effective drug for motor symptom management.
Traditionally used 1st line - “Gold Standard” Indications: bradykinesia, rigidity and tremor, some antidepressant effects |
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Response to Levodopa & Progression of Parkinson’s Disease
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Early PD:Long duration motor response
Low incidence of dyskinesias Moderate PD: Shorter duration motor response Increased incidence of dyskinesias advanced PD;Short duration motor response “On” time consistence associated with dyskinesias |
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Carbidopa/Levodopa: Dosing Immediate Release/ODT (know dose and with or without food)
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Immediate Release/ODT
Initial – 25/100 mg daily x 3 days; BID x 3 days; TID x 3 days Increase dose by 1 tablet every other day Titrate dose to symptom relief Absorption better on empty stomach |
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Carbidopa/Levodopa: Dosing CR (know with or without food)
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Initial 50/200 mg daily x 3 days; BID
Increase dose by 1 tablet every 3 days Titrate dose to symptom relief Absorption better with food (low protein < 2mg/kg) Tablets can be cut in half Less effective in moderate to late stage disease due to erratic absorption. tablets can be cut |
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what is the ratio of carbidopa to levodopa
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4/1 in each dose
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Carbidopa/Levodopa: Dosing ODT (Parcopa)
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Place on tongue, no water needed.
Good for patients with: Swallowing difficulties Morning rigidity Compounding liquid C/L Stable for 72 hours at room temp Compound 10 IR tablets (10/100 mg or 25/100 mg); 2 g crystalline ascorbic acid and 1 L of water |
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Carbidopa/Levodopa Formulations
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Onset
IR/ODT 30 min(quick) with peaks and troughs CR 60 min (slow) smooth response F: IR/ODT: 99% (w/o food) CR: 70% (w/ food IR/ODT duration of action: 3 hours CR: 4-5 hours dosing and frequency IR/ODT: TID CR: BID (both can be more) |
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Carbidopa/Levodopa absorption affected by
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Absorption affected by:
H2 blockers/PPIs (increase) Dietary protein (decrease) Protein – large neutral amino acids – compete for BBB transport Drugs that increase gastric emptying (increase) Pharmaceutical iron binds to C/L in GI tract. (decrease) Separate by >2 hours. |
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where is Carbidopa/Levodopa absorbed
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duodenum that is why drugs that increase gastric emptying increase the absorption
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Carbidopa/Levodopa contraindications
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Hx of melanoma, narrow-angle glaucoma
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Carbidopa/Levodopa cautions
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Psychoses, cardiac, pulmonary, renal hepatic, or endocrine disease
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SE Carbidopa/Levodopa
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GI: Nausea/vomiting
Cardiovascular: Orthostatic hypotension; dizziness Psychiatric: Euphoria, hallucinations, psychosis Motor complications (long-term): Dyskinesias Wearing-off, on-off phenomena Oxidation - Black discoloration of tongue or teeth; dark urine; black residue around sink/toilet ? Long-term use may lead to degeneration of neurons (NIH study ELLDOPA) |
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PD and Melanoma
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Patients with PD have a 2 to 4 fold higher risk of developing melanoma than the general population
Self and physician exams of skin on regular basis |
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Managing Side Effects of Carbidopa/Levodopa Nausea
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Titrate dose slowly
Take with small snack (low protein) Take with carbonated beverage Extra carbidopa (Lodosyn) 25mg |
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Managing Side Effects of Carbidopa/Levodopa dyskinesia
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Use smaller, more frequent doses of levodopa
Decrease levodopa, increase dopamine agonist Amantadine Deep brain stimulation |
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Management of Motor Complications of Carbidopa/Levodopa delayed on
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Delayed On” - Due to delayed gastric emptying or decreased absorption in the duodenum
Crush or chew a IR tablet and take with a full glass of water Switch to ODT formulation End of dose wearing off - Due to increasing loss of neuronal storage capability for dopamine and short half-life of levodopa Increase frequency of dosing Adjunctive therapy which extend the action of L-dopa Add dopamine agonist C/L solution |
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Management of Motor Complications of Carbidopa/Levodopa freezing
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Difficulty initiating movement
Physiotherapy Specialized assistive walking devices Sensory cues |
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Management of Motor Complications of Carbidopa/Levodopa off period
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Sustained muscle contractions
Bedtime administration of sustained release products Baclofen Botulinum toxin usually occurs at night because not taking meds |
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Dopamine Agonists
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Pramipexole (Mirapex*, Mirapex ER) Ropinirole (Requip*, Requip XL), Rotigotine (Neupro), Apomorphine (Apokyn)
Indications: bradykinesia, rigidity and tremor Used 1st line; alternative to levodopa (levodopa sparing) Not as effective as levodopa; Can be used in combination with levodopa MOA: Directly bind to D2 and D3 receptors Dosing Initial - titrate weekly to max therapeutic effect or intolerable side effects Pramipexole: 0.125 mg TID Pramipexole ER: 0.375mg daily Ropinirole: 0.25 mg TID Ropinirole XL: 2 mg daily Rotigotine: 2 mg/24 hours Max Pramipexole: 4.5 mg/day Ropinirole: 24 mg/day Rotigotine: 6 mg/day |
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SE Dopamine Agonists
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Nausea, vomiting
Postural hypotension Peripheral edema (can occur at any time during therapy) Confusion Hallucinations (highest with ropinirole) Somnolence Obsessive-compulsive behaviors Motor complications less than with levodopa/carbidopa Dyskinesias less than with levodopa/carbidopa Additional side effects w/bromocriptine |
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Rotigotine TD Patch
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May return to market in 2010??
Approved in 2007 Withdrawn 4/08, due to manufacturing issues Dosing: Initially 2 mg/day increase weekly by 2 mg intervals Needs to be refrigerated Advantages Delivery system Less hallucinations Disadvantages Somnolence Nausea and vomiting Caution in patients with sulfite sensitivity Metabolite (sodium metabisulfite) may cause allergic-type reactions |
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Apomorphine (Apokyn™)
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Treatment of acute, intermittent “off” episodes associated with advanced PD
Non-ergot dopamine agonist with high affinity for D4, and moderate affinity for D2, D3,& D5 Given subcutaneously at a starting dose of 2mg (0.2ml) Use as needed up to 5x per day |
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SE Apomorphine (Apokyn™)
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Dizziness, severe nausea & vomiting, syncope, hypotension, falls, hallucinations, drowsiness
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with Apomorphine (Apokyn™) what MUST you pretreat with
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MUST pretreat with trimethobenzamide (Tigan®)
Start 3 days prior to first dose Continue for 2 months |
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can you get Apomorphine (Apokyn™) at any pharmacy
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Only available thru a specialty pharmacy provider - $$$
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Catechol-Omethyl Transferase (COMT) Inhibitors
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Entacapone (Comtan), Tolcapone (Tasmar)
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Catechol-Omethyl Transferase (COMT) Inhibitors indications
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Indications: May decrease “wearing off,” on-off times, and motor fluctuations
2nd line used only in combination with levodopa/carbidopa |
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Catechol-Omethyl Transferase (COMT) Inhibitors MOA
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Inhibit COMT, decreasing breakdown of levodopa and increase availability to brain
Results in smoother levodopa plasma levels |
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Catechol-Omethyl Transferase (COMT) Inhibitors dosing (know)
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Tolcapone: 100-200mg tid
Entacapone: 200mg with each levodopa/carbidopa dose (max 8/day) May need to decrease levodopa dose |
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COMT Inhibitors SE
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Orthostatic hypotension, somnolence, dyskinesia
Explosive diarrhea, less frequent with entacapone Can occur at any time Discontinue medication and do NOT use again Urine and body fluid discoloration (orange) Liver failure, less frequent with entacapone Must monitor LFTs with tolcapone (baseline, Q2wks X1yr, then Qmo X6mo, then Q8wks) |
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Stalevo®
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3 drugs in 1 tablet
Approved by FDA 6/03 Carbidopa/levodopa/entacapone 12.5 mg / 50 mg / 200 mg (Stalevo 50) 18.75 mg / 75 mg / 200 mg (Stalevo 75) 25 mg / 100 mg / 200 mg (Stalevo 100) 31.25 mg / 125 mg / 200 mg (Stalevo 125) 37.5 mg / 150 mg / 200 mg (Stalevo 150) 50 mg / 200 mg / 200 mg (Stalevo 200) Appropriate for those with: Total daily levodopa dose 600 mg No dyskinesias Concurrent IR carbidopa/levodopa + entacapone IR Carbidopa/levodopa and end-of-dose “wearing off” |
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MAO-B Inhibitors
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Selegiline* (Eldepryl), rasagiline (Azilect)
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MAO-B Inhibitors indications
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Indications: 1st line in patients with mild disease to slow progression and delay need for levodopa
As adjunctive therapy to decrease “wearing off” |
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MAO-B Inhibitors MOA
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Decrease breakdown of dopamine
? Neuroprotective effects by reducing oxidative metabolism of dopamine |
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MAO-B Inhibitors dosing (know frequency)
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Selegiline 5 mg BID (QAM and QNoon)
ODT: 1.25 – 2.5 mg daily Rasagiline monotherapy: 1 mg daily Adjunctive: Start at 0.5mg daily; may increase to 1mg daily |
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Adverse Effects of MAO-B Inhibitors Selegeline
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Insomnia – Amphetamine metabolites
Hallucinations Dizziness Nausea/abd pain Dry mouth Potential tyramine reaction and serotonergic syndrome |
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Adverse Effects of MAO-B Inhibitors Rasagiline
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Generally well tolerated
Headache Hallucinations Dizziness N/V Orthostatic hypotension Dyskinesias Potential tyramine reaction and serotonergic syndrome |
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MAO-B Inhibitors and the “Cheese Reaction”
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Warning listed in package insert
Hypertensive crisis resulting from lack of dietary tyramine metabolism (due to MAO-A inhibition) Recommendation to restrict foods containing tyramine MAO-A is primarily responsible for tyramine metabolism (not MAO-B) “Cheese reaction” is rarely seen in MAO-B inhibitors when taken at recommended doses All MAO-B inhibitors inhibit MAO-A at doses beyond the threshold for selectivity |
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MAO-B Inhibitors and the “Cheese Reaction” and food content
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Can occur within minutes or hours after ingestion of tyramine containing food products results in:
Increase blood pressure, heart rate, fever, disorientation, headache, sweating, flushing Tyramine content in food Ingestion of 6-8 mg tyramine can trigger an increase in blood pressure in patients taking a nonspecific MAO inhibitor Foods considered “dangerously high” in tyramine contain 6 mg/serving High-tyramine content foods: Soy sauce: 14 mg/serving Sauerkraut: 7.8 mg/serving Air-dried sausage: 7.6 mg/serving Gorgonzola cheese: 7 mg/serving |
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MAO-B Inhibitors & Dietary Tyramine
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Take Home Message:
NON-SELECTIVE MAO inhibitors + 8mg tyramine = hypertensive crisis SELECTIVE MAO-B inhibitors: Up to 75mg tyramine is SAFE. |
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Serotonin Syndrome
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Excessive amounts of serotonin
Can be life threatening Can occur within minutes or hours Increased risk when MAO-B inhibitors are used in combination with some medications hypertension |
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Serotonin Syndrome and absolute contraindicaitons
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Meperidine (Demerol)
General anesthesia |
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Serotonin Syndrome and realtive contraindicaitons
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Fluoxetine (Prozac)
Fluvoxamine (Fluvox) Venlafaxine (Effexor) Amitriptyline (Elavil) Dextromethorphan St. John’s Wort Tramadol (Ultram) Methadone Mirtazapine (Remeron) Cyclobenzaprine (Flexeril) Pseudoephedrine (Sudafed) |
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S/S Serotonin Syndrome
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Agitation
Uncoordinated movements (ataxia) Heavy sweating not due to activity (diaphoresis) Diarrhea Overactive reflexes (hyperreflexia) Fever Mental status changes (confusion or hypomania) Muscle spasms (myoclonus) Shivering Tremor |
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Amantadine (Symmetrel)
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NMDA Receptor Antagonists
? 1st line agent for younger patients or as adjunctive therapy in those with akinesia, rigidity, and tremor Duration of benefit <1 year If effects wane, need to D/C and start levodopa or dopamine agonist |
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Amantadine (Symmetrel) indications
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Indications: Useful for mild symptoms of akinesia, rigidity, tremor and levodopa induced dyskinesias
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NMDA Receptor Antagonists MOA
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Stimulates dopamine receptors
Increases dopamine release Reduces dopamine uptake Mild anticholinergic activity ? Neuroprotective (NMDA antagonism) |
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NMDA Receptor Antagonists dosing (PD) Amantadine
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100-300mg/day divided BID-TID
Dose adjust in renal impairment Abrupt withdrawal: Small risk of encephalopathy |
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NMDA Receptor Antagonists SE
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Dry mouth
Hallucinations Dizziness Nightmares Confusion Blurred vision Depression Insomnia Livedo reticularis |
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Anticholinergics nemes
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Trihexiphenidyl (Artane), Benztropine (Cogentin), Diphenhydramine (Benadryl)
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Anticholinergics indications
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Adjunctive therapy for tremor
Useful for sialorrhea |
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Anticholinergics dosing
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start low & go slow
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Anticholinergics MOA
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Reduce relative excess ACh in basal ganglia
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Anticholinergics SE
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Cognitive impairment
Urinary retention Constipation Dry mouth Blurred vision Flushing |
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Coenzyme Q10 (ubiquinone) and PD
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Coenzyme Q10 well tolerated at all doses
Adverse events not different than placebo Only 1200mg/d showed a better UPDRS score change compared to Placebo (p = 0.04) Greatest effect in activities of daily living |
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Coenzyme Q10 (ubiquinone) and PD dose
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Coenzyme Q10 was safe and well tolerated by PD patients. Worsening of PD was slowed significantly by 1200mg/d.
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Creatine and PD
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MOA: Enhances mitochondrial function and reduces oxidative stress by stabilizing mitochondrial creatine kinase
Possible anti-apoptosis effects Less need for levodopa dose increases Improved mood and mentation No benefit in disability scores Currently being investigated in a large, multi-center clinical trial (NET-PD LS1) |
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Excessive daytime sedation treatiment in PD
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Selegiline, amantadine, modafinil, methylphenidate
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insomnia and PD
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hypnotics
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Rapid eye movement sleep behavior disorder
om PD treament |
Clonazepam
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Restless leg syndrome treatment in PD
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Dopamine agonists
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bladder dysfunction treatment in PD
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Anticholinergics
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Cpmstipation treatment in PD
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Exercise, increase fluid & fiber intake, stool softeners, osmotic laxatives (polyethylene glycol)
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Erectile dysfunction treatment in PD
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Phosphodiesterase inhibitors
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treamtment of falls in PD
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Minimize orthostatic hypotension, calcium, vitamin D, prevent/treat osteoporosis
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treatment of hypotension in PD
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Evaluate antihypertensive meds, if present; increase salt and fluid intake; compression stockings; fludrocortisone, midodrine
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treatment of Depression in PD
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SSRI’s, SNRI’s, TCA’s, pramipexole, exercise
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treatment of Dementia in PD
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Donepazil, rivastigmine or galantamine1,2
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Psychosis and PD
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Alterations in thoughts or perception
Visual Non-threatening Less likely to be delusions and paranoia Associated with PD (17%) Prevalence: Non-demented PD pts: 10% Cognitive impairment: 70% Strong predictor of nursing home placement1 Can be related to drug therapy |
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Psychosis and PD contributing factors
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Dopamimetic agents: dopamine agonists > levodopa > selegiline = anticholinergics = amantadine
Visual color & contrast deficits (sensory deprivation) Daytime sleepiness (sensory deprivation) Depression; dementia (attention deficit) Rapid eye movement sleep behavior disorder |
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Psychosis and PD management
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Rule out dehydration & infection.
Evaluate Rx profile. Reduction of anti-PD agents based on risk/benefit. Start with “little guns” (e.g., antichol, selegiline, amantadine) Attempt with “big guns” (e.g., dopamine agonists, levodopa) May not be helpful Likely to worsen PD symptoms Consider antipsychotic as last line option: Quetiapine Clozapine |
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JBD is a 62 y/o WM presents to clinic with a chief complaint of a mild resting hand tremor, left side worse than right. He is able to function at home and is not having difficulties at work.
PMH: Hypertension, osteoarthritis FH: Non-contributory Medications: Lisinopril 10mg daily, HCTZ 25mg daily, celecoxib 200 mg daily, multi-vitamin daily Allergies: NKDA Social Hx: (-) Tobacco, (-) illicit drug, (+) ETOH socially VS: BP 128/76, P 69, wt: 204 lbs, Ht: 74” PE: Mild resting hand tremor (L > R), moderate cogwheel rigidity in left upper extremity and mild rigidity in lower extremity. Normal gait except for a reduced left arm swing. What stage of PD is JBD (early, moderate, advanced)? List non-pharmacological therapies for JBD. What pharmacological therapy could be initiated at this stage? |
What stage of PD is JBD (early, moderate, advanced)?
Early List non-pharmacological therapies for JBD. Education Support services Exercise Nutrition Speech Therapy What pharmacological therapy could be initiated at this stage? Rasagaline 1 mg qd |
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3 months later JBD returns to clinic for a follow-up visit. He is having more difficulty functioning at work and at home. His wife sometimes has to help him get dressed and he has difficulty writing and typing. He is concerned that he may lose his job.
What would you recommend for this patient? Recommend a treatment plan |
What would you recommend for this patient?
Carbidopa/Levodopa or dopamine agonist Recommend a treatment plan Increase dose or frequency of dopamine therapy Adjunctive therapy (selegiline, rasagaline, COMT inhibitor) Long acting formulation (CR) |
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Two weeks later, JBD’s wife calls the clinic and states that JBD has been having nightmares and is “seeing things”.
Recommend a plan for this patient. |
Evaluate current medications, since hallucinations started after a recent dose increase, it is likely related to drug.
Decrease dopaminergic therapy Consider discontinuation of rasagiline Once hallucinations have resolved re evaluate patient and medications |
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Huntington’s Disease
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Incidence: 4-10 per 100,000
HD is due to a mutation in a gene that is transmitted as an autosomal dominant trait Inherited, progressive neurodegenerative disorder |
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what is Huntington’s Disease
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Loss of neurons in certain areas of the brain, including the basal ganglia and cerebral cortex
Characterized by the development of emotional, behavioral, and psychiatric abnormalities Loss of previously acquired intellectual or cognitive functioning; and movement abnormalities (motor disturbances) |
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Tetrabenazine (Xenazine)
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First drug approved by FDA for the treatment of chorea associated with HD
12.5 mg and 25mg tabs Black box warning for depression and suicidality |
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Tetrabenazine (Xenazine) MOA
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Interferes and depletes central monoamine neurotransmitters in presynaptic vesicles in the basal ganglia
Inhibits presynaptic dopamine release Blocks CNS dopamine receptors |
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Tetrabenazine (Xenazine)
dosing (know dose for slow and fast metabolizers) |
Initial: 12.5 mg po Daily; titrate by 12.5 mg weekly
Maximum single dose of 25mg Daily doses > 37.5 mg should be divided into 3 doses Doses > 50 mg/day genotype for CYP2D6 Fast metabolizers max 100mg/day; 37.5 mg/dose Slow metabolizers: Max 50 mg/day; 25 mg/day Concomitant use with CYP2D6 inhibitors; reduce dose of TB by 50% If treatment is interrupted: > 5 days re-titration is recommended < 5 days resume at previous maintenance dose |
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Tetrabenazine (Xenazine) SE
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Most are dose related
CNS – Extrapyramidal symptoms, sedation, somnolence, fatigue, insomnia, akathisia, depression, anxiety, parkinsonism, irritability, dizziness headache, obsessive reaction Dermatologic - Bruising GI – Nausea, dysphagia, vomiting, anorexia, diarrhea Genitourinary - dysuria NM/skeletal – Falls, balance difficulties, bradykinesia, dysarthria, gait disturbance Respiratory – Upper respiratory tract infection, bronchitis, dyspnea Rare (but serious) – Aspiration pneumonia, hyperprolactinemia, orthostatic hypotension, neuroleptic malignant syndrome, QTc prolongation, restlessness, suicidal ideation, suicide, syncope, elevated transaminases |
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Tetrabenazine (Xenazine) PK
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Duration of effect: 16 -24 hours
Protein binding: 82-85%; metabolites 59-68% Metabolism: Hepatic, to alpha and beta hydroxytetrabenazine (HTBZ) via CYP2D6 Active metabolites Bioavailability: Low and erratic due to extensive first pass metabolism; unaffected by food Half-life: Alpha-HTBZ: 4-8 hrs; Beta-HTBZ: 2-4 hours Time to peak plasma: 1-1.5 hours Excretion: Urine (~85%) feces (~15%) |
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Is Tetrabenazine (Xenazine) available at any poharmacy
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Only available through a specialty pharmacy $$$$$$
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Tetrabenazine (Xenazine contraindications
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Suicidality, untreated or inadequately treated depression
Hepatic impairment Concurrent or recent use of a monoamine oxidase inhibitor or reserpine |
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Restless legs syndrome (RLS)
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Common, under-diagnosed, treatable condition
Symptoms are most consistent with sensory-motor feelings Neurological movement disorder associated with sleep disorder Prevalence 2 - 15% Incidence increases with age Most common in women 2:1 Diagnosis is based on clinical features |
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RLS: Diagnostic Criteria
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NIH characteristics of RLS
Urge to move the limbs with or without sensations Worsening at rest Improving with activity Worsening in the evening or night Validated diagnosis is based on these criteria |
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Terms used to describe RLS by patients
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Creeping
Crawling Itching Burning Searing Jimmy legs The gotta moves Tugging Indescribable Pulling Drawing Aching Flowing water Elvis legs |
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RLS: Evaluation
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General
Sleep history, symptoms Look for secondary etiologies CBC, Fe, Ferritin, RF, BUN, SCr, Hgb A1C Folate, Mg, TSH (hypothyroidism), B12 Medications Other Electrical studies, polysomnogram (sleep study), electromylogram (EMG) |
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RLS: Associated Conditions
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Attention deficit disorder
Adults and children Anxiety ~ 13 times the risk of panic attacks Depression ~ 5 times the risk in RLS |
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Evidence suggests that patients with long standing RLS leads to chronic sleep deprivation and may be at higher risk for:
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Cardiovascular disease
Hypertension |
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RLS: Clinical Course
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Chronic condition
Occasional remissions Exacerbations Onset at any age Severity increases with age Most common disorder in people >65 yo |
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QOL RLS
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General discomfort
Sleep problems – getting to sleep and staying asleep Cognitive dysfunction Emotional dysfunction |
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Exacerbation of Symptoms of RLS
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Triggers or worsening of conditions
Antihistamines (cold/sinus medicines) Chlorpheniramine (Coricidin®) Diphenhydramine (Benadryl®) Brompheniramine (Dimetapp®) Caffeine, nicotine, alcohol, lack of exercise, lack of sleep, long flights or meetings, low iron stores Sympathomimetics (cold medicines) Tyramine Amphetamine Dopamine Antagonist (Anti-nausea) Metoclopramide (Reglan®) Prochlorperazine (Compazine®) Droperidal (Inapsine®) Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRI’s) (in some individuals) Mirtazapine (Remeron®) |
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RLS: Etiology
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Primary RLS
A CNS disorder, not caused by psychiatric factors/stress Dysfunction of the dopamine receptor in the basal ganglia, perhaps Imbalance of neurotransmitters in the dorsal horn of the spinal cord or spinal excitability Genetic-Evidence to suggest it is hereditary > 40% have a family history Three main chromosome defects: This accounts for 70% of RLS cases MEIS1 on chromosome 2p BTBD9 on chromosome 6p MAP2K5 and LBXCOR1 on chromosome 15q Secondary RLS Non-genetic causes |
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Periodic Limb Movements in Sleep (PLMS)
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Muscle jerks at night
Repetitive, periodic Occurs during lighter sleep stages Prevalence increases with age 80 to 90% of RLS individuals have PLMS, however 20% of PLMS individuals have RLS |
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Secondary RLS
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Iron deficiency anemia
Iron is the cofactor for the rate limiting step in production of levodopa End-stage kidney disease 6-60% Peripheral neuropathy, Parkinson’s Disease (~ 21%) Pregnancy Risk increased up to 27% Diabetes Type II DM a risk factor Other: Folate and Mg deficiencies, vitamin E, C, B12 deficiencies, hypothyroidism |
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Iron and RLS
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Measuring iron deficiency
Ferritin is a good predictor of iron stores Can be falsely elevated with inflammation % iron saturation and TIBC can be helpful Normal is ~ 11 to 30% Low normal is not good enough for RLS Treatment goal of ferritin > 50ng/ml |
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Treating Iron Deficiency in RLS
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Oral iron
Ferrous sulfate 325 mg, one 2 to 3 x/day Slow Fe 160 mg, one 2 to 3 x/day Ferro-sequels – contains a laxative Absorption enhanced Take each dose with 250 mg of vitamin C, empty stomach, no calcium with the dose, avoid tea IV iron for severe unresponsive iron deficiency Treat constipation with stool softener |
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RLS Treatment: Pregnancy
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Non-pharmacologic first line
Hot baths, massage, elastic stockings, sleep Iron replacement Opiate medications Methadone safest 3rd trimester safest for drug treatment |
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Primary RLS: Therapy
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Non-medical
Lifestyle changes Medical Primary therapy Secondary therapy |
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RLS: Non-Medical Therapies
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Good sleep hygiene
May change sleep time Moderate physical activity (e.g. walking, stationary bike riding, kickboxing, etc.) Hot or cold packs, baths, massage Rubbing or pressure, stretching Engage the mind (yoga, meditation) |
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RLS: Medical Therapy
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Dopaminergic agonists
Benzodiazepines Opioids Antiepileptic drugs Iron Levodopa/carbidopa Other |
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RLS Treatment: Dopaminergics
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Requip® (ropinirole)
0.75mg daily-24mg daily for Parkinson’s disease 0.25mg daily week 1 (typical starting dose for RLS) and increase to relief of symptoms (max dose 3 mg/daily) Requip XL total daily ropinirole dose given once daily Mirapex® (pramipexole) 1.5 – 4.5 mg daily for Parkinson’s disease 0.125mg-1.5mg daily (in 2-3 divided dose) for RLS Mirapex ER would consider for severe RLS, given daily Sinemet® (carbidopa/levodopa) Parkinson’s Disease dose varies 50 - 200 mg hs or 25/100 given 30 to 60 minutes before bedtime and may repeat once Controlled Release (CR) may be best in RLS Rotigotine (Neupro® patch) Currently not on the market |
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Dopaminergic Agent Withdrawal
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Symptoms occur after sudden discontinuation of drug
Symptoms include anxiety, panic attacks, depression, sweating, nausea, dizziness, generalized pain, and drug cravings Only occurs in patients with Impulse Control Disorders (ICDs) Possible solutions: Avoid high doses of dopamine agonists Closely monitor patients for symptoms of ICDs Warn patients of risks Taper off drug at first sign of ICDs Closely monitor patients when tapering off dopamine agonists |
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Symptom Augmentation
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Increased symptom intensity related to increased dosage of medications
There is a lag to beneficial symptom relief Duration of treatment benefit is shorter Symptoms extend to previously unaffected body parts (arms, etc.) Symptoms begin presenting earlier in day More patients on levodopa have augmentation than those on a dopamine agonist start treatment at night then the patient needs them during the day too |
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Treating Augmentation
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Lack of controlled trials with evidence to guide
Possible strategies Decrease or split dose and increase non-medicine treatments Treat to ferritin above 50 ng/ml Consolidate sleep Discontinue levodopa Change dopamine agonist Change to a different class of medication Drug holiday Combination of agents with different mechanisms of action |
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RLS Treatment: Sedative Hypnotics
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Benzodiazepines (BZD’s)
Improves sleep Off label use Clonazepam (Klonopin®) 0.5 to 4 mg/day Temazepam (Restoril®) 15-30 mg/day Side Effects Constipation, urinary complications, cognitive dysfunction |
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RLS Treatment: Opioids
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Codeine 15 to 120 mg/day
Oxycodone 2.5 to 20 mg/day Methadone 5 to 30 mg/day Side Effects Constipation, tolerance or loss of effect |
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RLS Treatment: Antiepileptic drugs
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Valproic Acid (Depakote®)
Carbamazepine (Tegretol®) Lamotrigine (Lamictal®) Gabapentin (Neurontin®) Pregabalin (Lyrica®) Side effects Sedation, blood count abnormalities, rash, weight gain, edema, tremor, cognitive dysfunction |
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Other RLS Medications
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Liorasel® (baclofen)
Catapres® (clonidine) Ambien® (zolpidem) Ultram® (tramadol) Side effects Constipation, sedation, seizures (rare), cognitive dysfunction Amantidine – non-dopamine agonist Selegiline – MAO–B inhibitor indirectly effects dopamine Bupropion – weak blocker of serotonin and norepinephrine and reuptake inhibitor of neuronal dopamine Apomorphine – dopamine system Intrathecal pumps – helpful in pain syndromes Acupuncture Estrogen Ketamine (NMDA receptor antagonist) CPAP for sleep apnea Cognitive behavioral therapy |
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On The Horizon/Future Research RLS
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BGP15 – heat shock protein, just completed phase IIb studies in DMII
Aplindore/Neurogen - Wyeth - Phase II clinical trials - better efficacy than placebo Ropinirole gel (topical)/Jazz pharmaceuticals – plans to restart clinical trials in the future Rifaximin (Xifaxan®) – approved by the FDA for travelers diarrhea - may improve IRLS Carbergoline (Dostinex®) – approved by the FDA for hyperprolactinemia Histamine and orexin (hyperarousal) Heat shock proteins |
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Conclusion RLS
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RLS is a common and an underdiagnosed treatable condition that can have significant effect on quality of life
Onset can occur in childhood, although prevalence increases with age Numerous secondary causes treated the same as primary Dopamine agonists are 1st line therapy The availability of generic medications could dramatically increase the number of patients who get treatment for RLS |
