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PARKINSON’S DISEASE Soheyla Mahdavian, Pharm.D. Assistant Professor of Pharmacy Practice DEFINITION A neurodegenerative disorder of the Central Nervous System. It results from the death of dopaminergic cells in the nigrostriatal, a region of the brain. EPIDEMIOLOGY More common in the elderly over 60 years of age. 5–10% of cases, classified as young onset, begin between the ages of 20 and 50. More common in men than women. RISK FACTORS Exposure to environmental toxins Herbicides Pesticides Heavy metal exposure Formed deposits in the substantia nigra Head trauma (rare) Genetics PATIENT CASE CC: “My left hand won’t stop twitching.” HPI: DD is a 66-year-old male who recently retired from Corny Fields Corn Farm. He comes to the clinic today because he has noticed over the past month he’s been having a slight tremor in his hand. He reports the tremor only occurs when he is relaxing. He also mentioned experiencing some fatigue, constipation and an increase in anxiety. PMH: Asthma, MI, obesity SH: Recently retired, married, and is the caregiver of his father who has late stage PD, smokes 1 pack/day, currently on a high protein diet for weight loss. Medications: Advair HFA 250/50, Toprol XL 50mg, Aspirin 81mg What are the risk factors this patient has? PARKINSON’S DISEASE PATHOPHYSIOLOGY DOPAMINE TRACTS Dopamine Tract Origin Function Nigrostriatal Substantia Nigra Movement Mesolimbic Midbrain Arousal, memory, stimulus processing, motivational behavior Mesocortical Midbrain Cognition, social function, communication, response to stress Tuberofundibular Hypothalamus Regulates prolactin release DOPAMINE IN THE BODY Dopamine is responsible for many functions in the body, including: Cognition Voluntary movement Motivation The brain’s reward system Sleep Mood Attention Memory Learning NORMAL BALANCE OF DOPAMINE AND ACETYLCHOLINE 5/25/2017 IMBALANCE OF DOPAMINE AND ACETYLCHOLINE IN PD 5/25/2017 MOTOR SYMPTOMS • Classic Motor Symptoms Resting Tremor • Limb Rigidity • Akinesia or bradykinesia • Postural Instability • • Other motor symptoms Hypomimia Hypophonia Micrographia Decreased coordination, dexterity No arm swing when walking Shuffling gait Dysphagia NON-MOTOR SYMPTOMS Autonomic/sensory disturbances Bladder problems Constipation Sexual dysfunction Impaired smell or vision Pain Fatigue Psychiatric issues Depression Anxiety Cognitive dysfunction Dementia (late stages) Sleep Disturbances PATIENT CASE CC: “My left hand won’t stop twitching.” HPI: DD is a 66-year-old male who recently retired from Corny Fields Corn Farm. He comes to the clinic today because he has noticed over the past month he’s been having a slight tremor in his hand. He reports the tremor only occurs when he is relaxing. He also mentioned experiencing some fatigue, constipation and an increase in anxiety. PMH: Asthma, MI SH: Recently retired, married, and is the caregiver of his father who has late stage PD, smokes 1 pack/day, currently on a high protein diet for weight loss. Medications: Advair HFA 250/50, Toprol XL 50mg, Aspirin 81mg Identify the patient’s motor and non-motor symptoms. SECONDARY PARKINSONISM USUALLY REVERSED IF THE CAUSE IS DISCONTINUED AND NO PERMANENT DAMAGE CAUSED Pharmacotoxicity Antiemetics (e.g., metoclopramide, prochlorperazine) Antipsychotics (e.g., phenothiazines, haloperidol, olanzapine, risperidone) Environmental (drug-induced) toxicity Carbon monoxide poisoning Manganese Methanol Organophosphates DIAGNOSIS No true diagnostic procedure Medical history Rule out medications causing secondary parkinsonism Rule out family history Neurological exam Walking and coordination, as well as some simple hand tasks “Levodopa Test” 5/25/2017 HOW DO WE CORRECT THIS IMBALANCE OF DOPAMINE AND ACETYLCHOLINE IN PD? CORRECTING THE PROBLEM 5/25/2017 PHARMACOLOGIC APPROACHES Dopamine replacement therapy Dopamine releasing therapy Dopamine conservation therapy Blocking acetylcholine Additional therapies DOPAMINE REPLACEMENT THERAPY 5/25/2017 DOPAMINE REPLACEMENT THERAPY MOA: Levodopa is metabolized to dopamine for utilization in the body Sinemet® (Levodopa/carbidopa) Parcopa® (Levodopa/carbidopa ODT) Adverse events Wearing off affects Dose adjustment Postural hypotension Visual disturbances Dose adjustment Nausea and/or vomiting Carbohydrate snack can alleviate Insomnia Mood Changes Smell and taste abnormalities Brownish bodily secretions DOPAMINE REPLACEMENT Brand Name Generic Name Sinemet® Sinemet® CR Levodopa/Ca Tablet rbidopa Extended Release Tablet ODT Parcopa® Stalevo® Formulation Comments s Levodopa/Car Tablet bidopa/Entac aone Used as last line therapy. May color bodily secretions brown. Nausea and vomiting can be alleviated with carbohydrate snack. High protein diet and pyridoxine reduces efficacy. Carbidopa >75mg per day to be affective. KEY POINTS WHEN USING CARBIDOPA/LEVODOPA • In order for levodopa to be effective, >75 mg of carbidopa should be received with levodopa in a day. When patients are switched from immediate-release to sustained-release formulation, the dose should be INCREASED and vice-versa. ‘Wearing off’ affects are dose dependant ‘On-off’ affects have no known cause, but it is thought to be because of several factors: disease progression, end of dosing, and the body’s response to medication. Apomorphine** (Apokyn) is used for on-off periods in patients with optimized levodopa/carbidopa therapy Because of oxidative properties, Carbidopa/levodopa should be used as LAST LINE therapy!! KEY POINTS WHEN USING CARBIDOPA/LEVODOPA Protein-based foods should not be administered with levodopa-based therapies. Vitamin B6 should not be coadministered with levodopa-based products. High fat meals delay drug absorption. Carbohydrates taken at the same time decrease nausea and vomiting Drug interactions: Selegilene, Rasagilene Vitamin B6 High protein/fat meals PATIENT CASE DD was first prescribed Sinemet® 25/100 twice daily. Do you agree with this? Why or Why not? After about a week of use, he began experiencing “wearing off affects.” What should we look at before making medication changes? DD begins to develop a tremor in his right hand. What stage is he in? DOPAMINE RELEASING THERAPY 5/25/2017 DOPAMINE AGONISTS MOA: Stimulates dopamine receptors Bromocriptine (Parlodel) Ropinerole (Requip) Pramipexole (Mirapex) **Apomorphine (Apokyn)- used for onoff treatment Adverse events: Dyskinesias Visual disturbances Impulse behaviors Mental disturbances DOPAMINE AGONISTS Brand Generic Formulations Parlodel ® Bromocriptin Tablet e Comments Ergot derived agonist. Not used widely because of pulmonary fibrosis Apokyn® Apomorphin Subcutaneous e injection ONLY USED for “ONOFF” episodes Requip® Requip® XL Ropinerole Non-ergot derived. substrate of CYP1A2 Mirapex ® Mirapex ® ER Pramipexole Tablet Extended Release Tablet Tablet Extended Release Tablet Non-ergot derived. KEY POINTS WITH DOPAMINE AGONISTS Is usually FIRST LINE Therapy Adverse reactions: Ropinerole/Pramipexole Sleep attacks Impulse behaviors (Gambling, shopping) Vivid dreams Hallucinations Drug interactions: Inducers/Inhibitors of CYP 1A2 (Ropinerole) Charbroiled foods Smoking Zafirlukast Zilueton Carbemazepine MAOIs PATIENT CASE DD was take off Sinemet® and prescribed Requip® Are there any drug interactions that can occur with this patient? What side effects should he be aware of? Are there any food restrictions? He continues this medication for 5 years. DOPAMINE CONSERVATION THERAPY 5/25/2017 COMT INHIBITORS MOA: Inhibits catechol-O-methyltransferase Tolcapone (Tasmar®) Entacapone (Comtan®) Entacapone/Carbidopa/Levodopa (Stalevo®) Adverse events: Hypotension Diarrhea Orange colored urine Sleep disturbances COMT INHIBITORS Brand Generic Formulations Comments Tasmar® Tolcapone Tablet Associated with hepatotoxicity, has BOTH peripheral and central effect, orange-brown urine, used with levodopa/carbidopa products, use reserved for those not responsive to entacapone. Comtan® Entacapone Tablet NOT associated with hepatotoxicity, ONLY peripheral effect, orange-brown urine, used with levodopa/carbidopa products Stalevo® See side effects/comments associated with all three agents Levodopa/C Tablet arbidopa/En tacapone MONOAMINE OXIDASE INHIBITORS MOA: Inhibits MAO Selegiline (Eldepryl®) Rasagilene (Azilect®) Adverse events: Hypertensive crisis (food restrictions) - Orthostatic hypotension - Insomnia - Hallucinations - MAOIS Brand Generic Formulation Comments Eldepryl® Zelapar® Selegilene Tablet ODT Tablet Selective for MAO-B, but inhibits MAO-A at higher doses Azilect® Rasagilene Tablet Selective for MAO-B, more potent than Selegilene, preferred over selegilene. CYP1A2 Substrate KEY POINTS FOR MAOIS • Eat in moderation Tyramine containing foods • Drug interactions: Cheeses Wines Sour cream Yogurt Caffeine Salami/Cold cuts Sauerkraut Fermented or aged foods Other MAOIs COMT Inhibitors CYP1A2 inhibitors/inducers (Rasagilene) Charbroiled foods Smoking St. John’s wort Zafirlukast Zilueton Carbamazepine Fluvoxamine* Psuedoephedrine PATIENT CASE BB is given Azilect® later. After looking at his profile, identify everything he should be aware of? Anticholinergics MOA: Antagonizes acetylcholine receptors to block acetylcholine to restore the balance between acetylcholine and dopamine. Benztropine (Cogentin®) Trihexyphenidyl (Artane®) NOT a good option for patients>65 years old!! Adverse events: Anti-SLUD Sedation Confusion Increases IOP ANTICHOLINERGICS Brand Generic Formulations Comments Cogentin® Benztropine Tablet Intramuscular Injection IV Because of side effects, NOT the best choice for patients >65yo Artane® Trihexyphenidyl Tablet Solution Same as above KEY POINTS WITH ANTICHOLINERGICS NOT a first choice for tremors in PD, but can be used to treat medication induced tremors NOT the best choice in elderly patients Other medications with anticholinergic properties used for PD Diphenhydramine (Benadryl®) Can DD be given these medications for his tremors? ANTIVIRALS MOA: Unknown, but thought to potentiate dopaminergic function Brand Generic Symmetrel® Amantadi ne Formulations Comments Tablet Oral Solution Not used much. Can cause: Visual disturbances, Sleep disturbances, Anti-SLUD affects, GI disturbances, Hypotension, Caution in patients with seizures or heart failure PATIENT CASE DD has been taking Stalevo® and Amantadine for two years. He begins developing these ‘freezing’ attacks, or ‘On-Off periods.’ How can this be managed? DD develops the inability to stand alone, or walk without assistance. What stage has he progressed to? CRITICAL THINKING QUESTIONS What role does dopamine play in the symptoms of Parkinson’s Disease? Besides movement issues, happens when there is too little dopamine? What role does dopamine play in the common side effects of the medications? Does dopamine cross the blood brain barrier? Why would the levodopa/carbidopa products be last line treatment? Which enzymes break down dopamine? Which medications should we be aware of that have drug-food interactions? What is the difference between ‘wearing off’ affects and ‘on-off’ periods? How are the above treated? Which medications for PD should we really not use in elderly patients? Why? What is the rule for changing from IR Sinemet® to Sinemet® CR? What role does pyridoxine play with these medications? Please review the formulations of the Parkinson’s Disease treatment options. What other diseases/disorders can these medications treat? Which medications can cause Parkinson’s disease LIKE symptoms? QUESTIONS Soheyla Mahdavian, Pharm.D. Assistant Professor of Pharmacy Practice Office #347 850-599-8186