PARKINSON’S DISEASEPARKINSON’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 CASECC: “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, obesitySH: 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

Cognition Voluntary

movement Motivation The brain’s reward

system

Sleep Mood Attention Memory Learning

Dopamine is responsible for many functions in the body, including:

NORMAL BALANCE OF DOPAMINE AND ACETYLCHOLINE

04/19/23

IMBALANCE OF DOPAMINE AND ACETYLCHOLINE IN PD

04/19/23

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

Psychiatric issuesDepressionAnxietyCognitive

dysfunctionDementia (late

stages)Sleep Disturbances

Autonomic/sensory disturbancesBladder problemsConstipationSexual dysfunction Impaired smell or

visionPainFatigue

PATIENT CASECC: “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, MISH: 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 PARKINSONISMUSUALLY REVERSED IF THE CAUSE IS DISCONTINUED AND NO PERMANENT DAMAGE CAUSEDPharmacotoxicity (drug-induced)

Antiemetics (e.g., metoclopramide, prochlorperazine)

Antipsychotics (e.g., phenothiazines, haloperidol, olanzapine, risperidone)

Environmental toxicityCarbon monoxide poisoningManganeseMethanolOrganophosphates

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”

HOW DO WE CORRECT THIS IMBALANCE OF DOPAMINE AND ACETYLCHOLINE IN PD? 04/19/23

CORRECTING THE PROBLEM

04/19/23

PHARMACOLOGIC APPROACHES

Dopamine replacement therapy Dopamine releasing therapy Dopamine conservation therapy Blocking acetylcholine Additional therapies

DOPAMINE REPLACEMENT THERAPY

04/19/23

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

Formulations

Comments

Sinemet®Sinemet® CR

Parcopa®

Levodopa/Carbidopa

TabletExtended Release TabletODT

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.

Stalevo® Levodopa/Carbidopa/Entacaone

Tablet

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

04/19/23

DOPAMINE AGONISTS

MOA: Stimulates dopamine receptors Bromocriptine (Parlodel) Ropinerole (Requip) Pramipexole (Mirapex) **Apomorphine (Apokyn)- used for on-

off treatment Adverse events:

Dyskinesias Visual disturbances Impulse behaviors Mental disturbances

DOPAMINE AGONISTSBrand Generic Formulations Comments

Parlodel®

Bromocriptine

Tablet Ergot derived agonist. Not used widely because of pulmonary fibrosis

Apokyn®

Apomorphine

Subcutaneous injection

ONLY USED for “ON-OFF” episodes

Requip®Requip® XL

Ropinerole TabletExtended Release Tablet

Non-ergot derived. substrate of CYP1A2

Mirapex®Mirapex® ER

Pramipexole

TabletExtended 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

04/19/23

COMT INHIBITORS MOA: Inhibits catechol-O-methyltransferase Tolcapone (Tasmar®) Entacapone (Comtan®) Entacapone/Carbidopa/Levodopa (Stalevo®) Adverse events:

HypotensionDiarrheaOrange 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® Levodopa/Carbidopa/Entacapone

Tablet See side effects/comments associated with all three agents

MONOAMINE OXIDASE INHIBITORS

MOA: Inhibits MAOSelegiline (Eldepryl®)Rasagilene (Azilect®)Adverse events:

- Hypertensive crisis (food restrictions)- Orthostatic hypotension- Insomnia- Hallucinations

MAOIS

Brand Generic Formulation Comments

Eldepryl®Zelapar®

Selegilene TabletODT 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 Cheeses Wines Sour cream Yogurt Caffeine Salami/Cold cuts Sauerkraut Fermented or aged foods

• Drug interactions: 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-SLUDSedationConfusionIncreases IOP

ANTICHOLINERGICS

Brand Generic Formulations Comments

Cogentin® Benztropine TabletIntramuscular InjectionIV

Because of side effects, NOT the best choice for patients >65yo

Artane® Trihexyphenidyl

TabletSolution

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

Brand Generic Formulations

Comments

Symmetrel®

Amantadine

TabletOral Solution

Not used much. Can cause: Visual disturbances, Sleep disturbances, Anti-SLUD affects, GI disturbances, Hypotension, Caution in patients with seizures or heart failure

MOA: Unknown, but thought to potentiate dopaminergic function

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