9/26/18. Objectives. Disclosures. Parkinson s Disease Update Clinical and Operational Considerations

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1 Parkinson s Disease Update Clinical and Operational Considerations Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO PharmaCare Strategies, Inc. September 2018 Objectives Describe epidemiology and pathophysiology of Parkinson s disease Evaluate management of early-stage and advanced stage Parkinson s disease Discuss current and emerging pharmacologic therapy and explore therapeutic challenges Describe the pharmacist's role in optimizing treatment benefits and ensuring treatment adherence Disclosures Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO PharmaCare Strategies Acadia Pharmaceuticals Consultant, speaker Astellas Pharmaceuticals Consultant Axovant Pharmaceuticals Consultant Mylan Pharmaceuticals Consultant Sunovion Pharmaceuticals Consultant, speaker 3 1

2 Diagnosing Parkinson s Disease (PD) Primary cause of PD is unknown. Genetic and environmental factors have been associated with PD. Recent findings suggest that Parkinson's disease can be transmitted via a prionlike mechanism and is associated with mis-folded alpha-synuclein. 4 Parkinson s Disease Risk Factors Age is the number one risk factor. Men are more likely than women to develop PD. 5 The Role of Genetics Eleven genes have been associated with PD. Genetic forms account for about 10% to 15% of PD. Having a first degree relative with PD increases your chances of getting PD perhaps 2- or 3-fold, which is perhaps a 3% lifetime risk (compared to 1%- 1.5% for the general population). Genetic testing is predominantly done in academic centers with very few commercially available tests. Parkinson's disease has been associated with: Increased oxidative stress Mitochondrial dysfunction Protein aggregation (alpha-synuclein) Proteasomal dysfunction 6 2

3 Pathophysiology Loss of dopaminergic neurons in the substantia nigra of the midbrain. Most symptoms will appear after 60% - 80% of the cells become impaired or die. The results of cell death cause abnormal activity in the basal ganglia and motor symptoms of the disease. The pathological hallmark of PD is the Lewy body Predominantly made of alphasynuclein and other ubiquitinated damaged proteins. Significant cholinergic and serotoninergic deficits may account for some non-motor symptoms (cognitive impairment/dementia and depression) that are common in PD as it progresses. 7 Pathological Changes in PD 8 Diagnosing Parkinson s Disease Key Facts Bradykinesia must be present, and At least one of the following: Muscular rigidity Tremor, or Postural instability. Diagnostic tests for PD do not exist. Tests may be necessary to rule out other conditions but not to confirm the diagnosis of PD. Non motor< symptoms are as important as motor symptoms<. If feasible, physicians should refer suspected PD untreated to a neurologist. Tremor Stooped posture Mask-like face Rigidity Hips and knees slightly flexed Tremor Short shuffling steps 9 3

4 Tremor Tremor Tremor is present in about 80% of PD cases. Typically asymetric and observed at rest. It usually improves when performing tasks. Transient upper-limb tremor may initially be subtle. PD tremor is characterized as slow, biplanar, pill-rolling tremor at 4-6 Hz. Higher frequency postural and kinetic tremors also occur. Tremor is rhythmic movement resulting from involuntary alternating or synchronous contractions of muscle antagonists. Clinical Info PD tremor and essential tremor (ET) may be confused. ET is much more prevalent and results in an action tremor, not a rest tremor, and often affects hands, head or voice; the latter two are not seen in PD. PD's resting tremors are observed with the body part completely at rest, and subsides with action or the assumption of a posture. Onset is typically asymetrically in one hand, although it may be observed elsewhere. Early in the disease, tremor may be intermittent and may be precipitated by axiety, stress, or clenching of the contralateral hand. 10 Bradykinesia Bradykinesia Slowness/poverty of movement. Look for reduced arm swing while walking. Bradykinesia is one of the most important symptoms in PD but may be hard to identify, especially in early stages. Initiation of movement may be difficult. Often identified by demeanor and overall gestalt. Clinical Info Unlike tremor, bradykinesia is present in all cases of Parkinson's. While sometimes subtle, Reduced arm swing Hesitation in initiating movement, Micrographia, and Reduced blink rate may be noticable and indicate the need for a focused motor exam. Hypomimia, hypophonia, and monotonous speech are also manifestations of bradykinesia. Bradykinesia can be mistaken for depression<. 11 Postural Instability and Rigidity Postural Instability One of the most common distressing factors for patients in later stages. Not frequent in early stages. Postural instability is one of the axial symptoms of PD and it is due to the loss of postural reflexes. Resultant loss of mobility becomes an important factor in the patient's quality of life. Falls resulting from balance impairment are common causes of hospitalization and mortality in PD. Postural instability is the least treatable of the major motor features of PD. Rigidity Present in about 90-99% of PD cases. Defined as increased resistance when stretching a muscle passively and is commonly associated with bradykinesias. Unilateral or bilateral. The cogwheel phenomenon is a particular type of rigidity occurring in PD. It is thought to be tremor superimposed on rigidity. Some patients refer to rigidity as tightness in their limbs. Treatment with levodopa and dopamine agonists works well with rigidity. 12 4

5 Gait Disorder Gait Disorder Changes in gait is one of the distinguishing symptoms in PD. Festinating or shuffling gait characterized by small shuffling steps. As the disease progresses, the normal heel strike is lost and the feet tend to slide along the floor. Freezing of gait is also very common in PD. Gait abnormality is one of the most important factors affecting the quality of life of affected patients. 13 Clinical Evaluation of Gait Raising from the chair: PD patients have difficuty standing up and may need to use arms of the chair to get up. First step: PD patients may have difficulties taking the first step. Posture when walking: PD patients may get stooped - more than expected for age. Arm swing is reduced. Speed: As described under bradykinesia<, PD patients move slower than expected for age. Stride length: Shortened in PD. Turning: PD patients take many steps to turn. Steadiness: As described in postural instability<, balance is mildly impaired. Gait improves with medication in later stages, gait problems become less responsive to medication. 14 Other Motor Symptoms Masked face Reduced blink rate Hypophonia Drooling Micrographia Hypokinetic dysarthriareduced spontaneous gesturing while talking Stooped posture Difficulty turning over in bed Dystonia Tremor Mask-like face Tremor Stooped posture Rigidity Hips and knees slightly flexed Short shuffling steps 5

6 Diagnosing Parkinson s Disease (con t) Clinical Best Practices Always ask for motor< and non-motor <symptoms. Rule out other neurological conditions: Alzheimer s or other dementias, Essential tremor, Progressive supranuclear palsy, Hydrocephalus, Psychosis, or Bipolar disorder. Significant, sustained response to dopaminergic therapy with a gradually progressive course is a hallmark of PD, as compared with other causes of parkinsonism. 16 Patient Medical History Occupation: Individuals who are health care workers, lawyers, accountants, teachers, or farm workers are more likely to develop PD. Environment: Exposure to herbicides/pesticides has been linked to PD. Other general conditions: Information on arthritis, depression, sleep disorders, orthostatic hypotension and constipation, among others, may help you in establishing your diagnosis. Medication intake: Medications that block dopamine receptors (such as antipsychotic drugs) and drugs used for nausea, vomiting, and GERD (such as prochlorperazine, promethazine, and metoclopramide) can cause parkinsonism. 17 Stages of PD (Hoehn Yahr Scale) Stage 0 Stage 1 No signs of disease Unilateral disease Stage 1.5 Unilateral disease plus axial involvement Stage 2 Bilateral disease, without impaired balance Stage 2.5 Bilateral disease, with impaired balance Stage 3 Stage 4 Stage 5 Mild to moderate bilateral disease, some postural instability; physically dependent Severe disability; still able to walk or stand unassisted Wheelchair-bound or bedridden 6

7 Goals of Treatment of Any Neurological Diseases: Fall prevention Correct deficits Transfers and bed mobility Strengthening of trunk, shoulders, hips Balance and coordination Swiss ball exercises Squats Reaching out beyond BOS Weight shifting marching, kicking ball Treatment for Parkinson s Disease Age < 50 years Start with dopamine agonist Age > 70 years Start with carbidopa/levodopa years Start with either option Physical therapy (PT), occupational therapy (OT), and speech therapy are as important as medication in the management of your patient. There are no products available to slow down the progression of PD Selegiline and rasagiline may impact the course of the disease for the first five years of therapy (controversial at this point in time). 20 Commonly Used Medications for Parkinson s Disease Levodopa Dopamine agonists MAO-B Inhibitors COMT Inhibitors Anticholinergics Other Medications 21 7

8 Levodopa Key Facts The central objective of using PD medication is to control or manage motor symptoms. Almost all patients will need levodopa in their management. In general it is recommended that you start with a dopamine agonist< if your patient is younger than 50 years; you should consider starting with carbidopa/levodopa if your patient is older than 70 years; either option is good if your patient is between 50 and 70 years old. All patients will eventually need levodopa in their therapeutic regimen as their PD progresses. Clinical Best Practices Levodopa should be titrated to severity of symptoms over several weeks. Levodopa/carbidopa is the main drug used for treatment of PD. While it can cause dyskinesias, all patients will eventually need levodopa in their therapeutic regimen as their PD progresses. 22 Levodopa (con t) Adverse Effects: Nausea, vomiting: Take pills on a full stomach to reduce nausea or use domperidone mg tid or trimethobenzamide hydrochloride 300 mg up to 4 times daily) Loss of appetite Orthostatic hypotension: Use lowest dose possible, improve hydrationreduce antihypertensive medications if possible, reduce alpha antagonists if possible (used to treat urinary incontinence or prostatic hypertrophy), consider midodrine (an alpha agonist) 2.5 half tab tid to start up to 15 mg tid Confusion/delirium: Reduce or withdraw anticholinergic medications; reduce or stop any medications that are sedating Dyskinesia Constipation Dry mouth Headache 23 Levodopa Formulations Presentation Carbidopa/levodopa immediate-release (Sinemet) Carbidopa/levodopa oral disintegrating (Parcopa) Carbidopa/levodopa extended-release (Sinemet CR) Carbidopa/levodopa extended-release capsules (Rytary) Carbidopa/levodopa enteral solution (Duopa) 10/100, 25/100, 25/250 10/100, 25/100, 25/250 25/100, 50/200 Dosages in Msilligram 23.75/95, 36.25/145, 48.75/195, 61.25/245 Clinician-determined Typical Treatment Regimens mg of levodopa total daily dose (divided 3-4 times) mg of levodopa total daily dose(divided 3-4 times) mg of levodopa total daily dose, (divided 2-4 times) mg of levodopa total daily dose. Up to 2000 mg of levodopa over 16 hours. Indications for Usage Monotherapy or adjunct therapy for slowness, stiffness, and tremor Same as above, plus need for dissolvable medication in mouth Monotherapy or adjunct therapy for slowness, stiffness, and tremor Monotherapy or adjunct therapy for slowness, stiffness, and tremor. Note that dosages of Rytary are not interchangeable with other carbidopa/levodopa products. For the treatment of motor fluctuations in patients with advanced Parkinson s disease. Carbidopa/levodopa/ 12.5/50/200, mg of Replacement for carbidopa/levodopa, for entacapone 18.75/75/200, levodopa total daily dose, motor fluctuations (benefit of entacapone) 25/100/200, dosed 2 3 times/day (Stalevo) 31.25/125/200, (divided 3-4 times) 37.5/150/200, 50/200/

9 Dopamine Agonists Key Facts Can be used as monotherapy or in combination with carbidopa/levodopa. Similar side effects as levodopa. Impulsive control disorder may be a serious side effect. Certain dopamine agonists are available in patch or in a self-injectable presentation. Dopamine agonists can be used as first line medication even before carbidopa/levodopa is started. Dopamine agonists have longer half lives than levodopa and for that reason can be helpful in reducing the intensity of the wearing-off reaction or to generally enhance the effect of levodopa. Watch for: Hypersomnia or daytime somnolence: Use levodopa rather than dopamine agonist, Reduce medication in evening before bed, Ensure that night time sleep is restorative, check for sleep apnea, consider modafinil or methylphenidate. Alert patient of this issue if patient drives 25 Dopamine Agonist Formulations Presentation Ropinirole (Requip ) (Requip XL ) Dosages in Msilligram 0.25, 0.5, 1, 2, 3, 4, 5 2, 4, 6, 8, 12 Typical Treatment Regimens 6-24 mg total daily dose, (divided 3-4 times) Indications for Usage Monotherapy or adjunct therapy for slowness, stiffness, and tremor Pramipexole (Mirapex ) 0.125, 0.25, 0.5, 0.75, 1, mg to 4.5 mg total daily dose, (divided 3-4 times) Same as above (Mirapex ER ) 0.375, 0.75, 1.5, 2.25, 3, 3.75, mg to 4.5 mg total daily dose Rotigotine (Neupro ) Apomorphine (Apokyn ) 2, 4, 6 Patch 4-6 mg once daily Monotherapy for slowness, stiffness, and tremor 10 mg/3 ml vial 2 6 mg Adjunct therapy for sudden wearing off 26 Rescue Meds for Severe Off-Episodes Apomorphine Self-injectable rescue drug for people with advanced PD and severe off episodes. Short half-life (average 40 minutes) and chemical structure make it difficult if not impossible to take by mouth. An anti-nausea medication (usually trimethobenzamide) is required prior to injection in the early phase of treatment but can be discontinued after the first week or two. Do not administer more than 5 times per day, and do not exceed 2 ml (20 mg) per day Carbidopa/levodopa Crushed in ginger ale, carbidopa/levodopa also provide a rescue-like effect, though not as fast as apomorphine. 27 9

10 MOA-B Inhibitors Key Facts Used as monotherapy for modest symptom control in early PD or in combination with other medications. Brain monoamine oxidase (MAO) converts dopamine into inactive substance. Blocking MAO makes more dopamine is available. MAO B inhibitors don t have the same side effects as MAO-A inhibitors, and therefore side effects associated with elevated concentrations of adrenaline-like substances as, for example, hypertension-are avoided. Used as an adjunct (add-on) to other medications, including levodopa. When used in combination with other medications, MAO-B inhibitors may reduce off time and extend on time. Watch for: Nausea Dry mouth Lightheadedness Constipation Agitation - Insomnia: common with selegiline (take only in the morning), - Vivid dreams and hallucinations 28 MOA-B Inhibitor Formulations Presentation Selegiline (l-deprenyl, Eldepryl ) Dosages in Msilligram Typical Treatment Regimens Indications for Usage 5 5 mg twice a day Monotherapy for slowness, stiffness, and tremor; adjunct therapy for motor fluctuations Rasagiline (Azilect ) Zydis selegiline HCL Oral disintegrating (ZELAPAR ) 0.5, mg once daily Same as above 1.25, mg once daily Same as above Interaction with new antidepresants and selegiline are rare. Monitor patients for serotonin syndrome (flushing, hypertension, agitation. Avoid meperidine in a patient taking selegiline. 29 COMT Inhibitors Key Facts Catechol-O-methyl transferase breaks down levodopa. COMT inhibitors extend the clinical benefit of levodopa Without levodopa COMT-inhibitors have no effect in PD. COMT inhibitors should not be used alone. Ttypically do not require dose escalation and are thus simple to administer. Used to enhance and prolong the effects of levodopa. Watch for: Watch for dyskinesias as often dose needs to be reduced Entacapone can turn the urine orange - this is a benign reaction and does not require treatment

11 COMT Formulations Presentation Entacapone (Comtan ) Dosages in Msilligram Typical Treatment Regimens mg 4 8 times daily (with each levodopa dose) Indications for Usage Adjunct therapy for motor fluctuations Tolcapone (Tasmar ) mg up to 3 times daily Carbidopa/levodo pa/entacapone (Stalevo ) 12.5/50/200, 25/100/200, 37.5/150/200, 50/200/ mg of levodopa total daily dose, dosed 2 3 times/day (divided 3-4 times) Adjunct therapy for motor fluctuations (second-line due to side effects) Replacement for carbidopa/levodopa, for motor fluctuations (benefit of entacapone) 31 Anticholinergics Key Facts Most useful in young people with tremor-predominant PD. ide effects may limit their usefulness. Use with caution in those older than 60 years due to risk of confusion. Acetylcholine and dopamine maintain a delicate equilibrium in the normal brain, which is upset by the depletion of dopamine and the degeneration of dopamine-producing cells. Drugs that block the effect of acetylcholine have the potential for restoring the normal balance of these two chemicals, thereby reducing the symptoms of PD. Good for refractory tremor but may result in anticholinergic side effects Watch for: Cognitive impairment Drowsiness Dry mouth Difficulty urinating Constipation 32 Anticholinergic Formulations Presentation Trihexyphenidyl (formerly Artane ) Benztropine (Cogentin ) Dosages in Msilligram Typical Treatment Regimens 2, mg 2 or 3 times daily Monotherapy or adjunct therapy, predominantly for tremor in younger people 0.5, 1, mg 2 or 3 times daily Indications for Usage Monotherapy or adjunct therapy, predominantly for tremor in younger people Same as above 33 11

12 Other Medications Amantadine Amantadine has mildly beneficial effect in PD. Primary role is to reduce levodopa dyskinesias. Provides immediate benefit for most PD symptoms. Effect frequently wanes after a few weeks or months. May be particularly beneficial in people who have prominent tremor or bothersome levodopa-induced dyskinesia. Watch for: Redness or reddish purple discoloration of the legs, often with swelling Hallucinations Confusion Droxidopa Used to treat neurogenic orthostatic hypotension. 34 Adjusting Pharmacotherapy as Motor Symptoms Worsen? ØIncrease dopaminergic medications as symptoms worsen Ø Dyskinesia q Don t treat if it doesn t disturb patient q Reduce levodopa, add amantadine or dopamine agonist q Carbidopa-levodopa: try decreased dose at shorter intervals Ø Wearing off q COMT inhibitors: prolong levodopa s therapeutic effect q Alternative: selegiline (MAO-B inhibitor) q Other strategies: add dopamine agonist, increase levodopa dosage or frequency of administration q Apomorphine: rescue therapy until next levodopa dose Managing the Adverse Effects of Pharmacotherapy? ØNausea (from carbidopa-levodopa, dopamine agonists) qoften mild; taking medication with food may alleviate qadditional carbidopa may help qif persistent, domperidone may be effective qmetoclopramide and prochlorperazine block dopamine receptors and worsen parkinsonism (don t use) Ø Excessive sleepiness (from dopamine agonists) q Discontinue all meds that may contribute to sleepiness q Teach good sleep hygiene q Evaluate patients for underlying sleep disorders more 12

13 Managing the Adverse Effects of Pharmacotherapy (con t)? ØPeripheral edema (from amantadine or dopamine agonists) qdoesn t always need treated, especially if mild qdisappears when offending medication discontinued; reducing dose won t help Ø Impulse control disorders (from dopamine agonists) q Occur in 14% of treated patients q Ask all patients about these behaviors q If treatment needed, reduce or discontinue offending medication (worsening motor symptoms may require return to original dose) Clinical Bottom Ling: Treatment v Refer patients to a neurologist for co-management v Begin drug Rx when symptoms cause functional impairment Start with levodopa / dopamine agonists / MAO-B inhibitors (depending on severity, motor complications, age, drug AEs) Adjust drug regimen + add other agents as PD progresses v Treat nonmotor symptoms Sleep disorders, neuropsychiatric complications, GI symptoms, autonomic dysfunction v Encourage regular exercise to maintain physical functioning v Consider deep-brain stimulation when substantial motor fluctuations, dyskinesia, or disabling tremor can t be managed QUESTIONS? 39 13