Parkinson Disease Management and Pharmacotherapy

Parkinson Disease Management and Pharmacotherapy N A D I A K H A R T A B I L , P H A R P H A R M D , 8 3 5 , F A L L B C G P , 2 0 2 4 A P H , M A S 29 0828 Learning Objectives 1 2 Recommend an initial treatment plan for a patient with PD based on patient-specific factors. Recognize the type of levodopa motor complication a patient is experiencing based on history and symptoms. complications movement 3 Develop a treatment plan for a patient experiencing levodopa-associated motor complications. scination 4 Develop a treatment plan for a patient with PD who is experiencing hallucinations and psychosis motor c p psychosis to Ipod hasMotors Depression g pDoiffectmore menon thenFemale Parkinson Disease (PD) more 155 6 PD is a progressive movement disease characterized by the loss of dopaminergic neurons of the substantia nigra and presence of Lewy Bodies. • The nigrostriatal pathway is most affected, leading to loss of neurons from the substantia nigra to the dorsal striatum. • Lewy bodies = clumps of misfolded -Synuclein protein •Pathology spreads up the brainstem and laterally into higher cortical areas. The cause of neuronal death is not fully understood, but is multifactorial: • Age • Genetics • Race, geography, and environmental factors are less clear A Clinical Presentation Idiopathic PD: signsisaryptons major Cardinal symptoms of Parkinson’s Disease TRAP motor symptoms: Tremor Rigidity no inabilitytomove Akinesia/Bradykinesia so slownessinthemovement Postural Instability is w 5 micrographia (diminution of handwritten Other motor features: letters), shuffling gait, stooped posture, masked faces, decreased blinking, hypophonia ( reduced voice volume), freezing, dysarthria (slurred speech). https://stanfordmedicine25.stanford.edu/the25/parkinsondisease.html Clinical Presentation: Non-Motor Symptoms Autonomic and Sensory Symptoms • Bladder and anal sphincter disturbances • Constipation • Diaphoresis • Fatigue • Olfactory disturbance • Orthostatic BP changes • Pain • Paresthesia • Paroxysmal vascular flushing • Seborrhea • Sexual dysfunction • Sialorrhea toomuchsativa Mental Status Changes • Anxiety • Apathy • Bradyphrenia • Confusional state • Dementia • Depression • Hallucination/psychosis • Sleep disorders GET Clinical Presentation: Non-Motor Symptoms Sleep Disturbances Lab Tests • Excessive daytime sleepiness • Insomnia • Obstructive sleep apnea • REM sleep behavior disorder • No labs to diagnose PD Other Diagnostic Tests • Genetic testing is not routinely helpful • Neuroimaging for exclusionary diagnoses • Medication history to rule-out druginduced parkinsonism The hallmark of Parkinson’s Disease pathophysiology is degradation of acetylcholine pathways in the nigrostriatal pathway of the midbrain F it'sdopomenerigicin substinalnigra Start presenting to display the poll results on this slide. Diagnostic Criteria Step 1: • Presence of bradykinesia and at least one of the following: resting tremor, rigidity, or postural instability Step 2: • Exclude other types of parkinsonism or tremor disorders (see Differential diagnosis) Step 3: • Presence of at least three supportive positive criteria: • Asymmetry of motor signs/symptoms • Unilateral onset • Progressive disorder • Resting tremor • Excellent response to carbidopa/L-dopa • L-dopa response for five years or longer • Presence of L-dopa dyskinesias moat involuntarymuscle Differential Diagnosis PPHDMRO gig Essential tremor Drugs that can induce or worsen Parkinson Disease Drug-induced: antiemetics, antipsychotics, other drugs Metoclopramide (specially in elderly), prochlorperazine InEnvironmental Iss toxicity antinasua Infections 2 Ey Metabolic disorder Neoplasms, strokes, traumatic lesions involving nigrostriatal pathways Normal-pressure hydrocephalus First , second generation antipsychotics ( high dose risperidone, high dose olanzapine, paliperidone) prep Haloperidol, Droperidol Issa Theyarengtoronly Assessment Tools: UPDRS (Unified Hoehn and Yahr 0= No visible signs I = Mentation, Behavior, Mood 1= Unilateral disease II= Activities of Daily Living 2= Bilateral disease 3= Bilateral disease with mild postural instability 4=Bilateral disease with marked postural instability 5=No independent ambulation UPDRS III (motor Parkinson’s Disease Rating Scale) (ADLs) III= Motor Scale IV= Complications of therapy scale) • • • • • • • • • • • • • • • Speech Facial expression Rest tremor Rigidity Intention tremor Finger taps Open-close Rapid Alternating Movements Heel taps Toe taps Rising from chair Gait Retropulsion Body Bradykinesia Desired Outcomes Improve motor and non-motor symptoms activitiesofdaily living has who hedppt actually Exergise PB on Preservation of ADLs, employment, improvement in motility, minimization of AE’s/treatment complications, putative disease modification gig Improvement of non-motor features such as cognitive impairment, depression, fatigue and sleep disorders Pharmacological Agents ( Motor symptoms) MeDOBBY'fsinffopass Dopamine : 1. Dopamine precursor: • Levodopa (L-Dopa) 2. Dopamine receptor agonist: • Pramipexole ax • Ropinirole • Apomorphine 3. Reduce dopamine degradation: • COMT inhibitors • Entacapone tonton • Tolcapone • Opicapone • Decarboxylase inhibitor • Carbidopa • Mono amino oxidase-B inhibitors • Selegiline • Rasagiline • Salfinamide 4. Unknown : Amantadine cogent Block Cholinergic activity: 5- Anticholinergic medications: benztropine, trihexphenidyl) Block movement 6- Adenosine receptor antagonist: Istradefylline BBB theyp in selectivetothebrain COMT = catechol-o-methyltransferase T M Labonittakew protein Lp stomach Eptalreadytake onempty nextsteprestfreequenayoraddcom Pt toworkonPI I NOSSBBB notcross should Ét Carbidopa/Levodopa • Levodopa : dopamine precursor • Carbidopa reduces metabolism of levodopa in the periphery. ( Peripherally acting L-amino acid decarboxylase) • Increasing L-dopa crossing BBB • Most effective medication for symptomatic treatment of PD. Levodopa Carbidopa/Levodopa Who/What/Why /How Information Who? Brand in the market Sinemet® Parcopa® (disintegrating) Rytary (Extended release) Crexont (Extended release) Intestinal suspension (Duopa ®) – infusion via PEG-J tube Inhaled levodopa (Inbrija®) for “off” episodes What does it treat? All motor symptoms (tremor>rigidity>bradykinesia. Not postural instability) Why it works? Direct replacement of dopamine. How to administer? (Dose) Starting dose Max dose Fyi Conversion to SR f d c 10/100 or 25/100 (Carb/L-dopa) TID higherthedosemore sideeffect 75- 100 mg carbidopa usual maintenance ( 200 mg/day carbidopa). No max allowable total daily dose of L-dopa ( usually around 1500 mg/ day tolerate) Approximately 10% more levodopa Dosing interval of 4-8 hours during waking day Carbidopa/Levodopa : Special considerations, complications Problem Explanation Pharmacokinetic (Intra and intersubject variability PK) • • Possible Solution Etf Gastric emptying difference Competition on transporter with neutral amino acids( leucine, phenylalanine) • • Protein restriction Taking on empty stomach or ( low protein snack if nausea exist) Short elimination half-life • • • + Carbidopa t1/2= 1.5 hrs + COMT I t1/2 = 2-2.5 hrs CR formulation ( bioavailability 70-75% compared to IR) • • • Increase frequency of L-Dopa Add COMT inhibitor, MAO-B inhibitor, or DA agonist Istradefylline (next slide) Delayed “on” response • • • Give L-Dopa on empty stomach Use ODT formulation (avoid CR formulation) Use apomorphine SQ injection “Freezing” • • Increase L-Dopa dose Add DA agonist or MAO-B inhibitor • Provide smaller doses or more frequent doses of L-Dopa Add Amantadine Reduce dose of adjunctive dopamine agonist 2• levo COMTtcarb Costalibo End-of-dose 3 “wearing off” enough u Not Eopomin Effin pomin notenoughdo Peak-dose dyskinesia • • Involuntary choreiform movements (involves neck, trunk, lower/upper extremities). Shakiness from too much dopamine • • Carbidopa/Levodopa : Side effects , Interactions System Side effect Cardiovascular Hypotension, orthostatic effects including orthostatic hypotension. Gastrointestinal Nausea, vomiting , diarrhea, dyspepsia, dark saliva, duodenal ulcer. Nervous system Psychotic episodes, NMS, dyskinesia, bradykinetic episodes, confusion, agitation, dizziness, somnolence, dream abnormalities Pathologic gambling. Skin Rash, increased sweating Interaction Adjustment MAOIs Nonselective MAOIs are contraindication with Carbidopa/L-dopa Selective MAO-Bi can be administered Antihypertensive Symptomatic postural hypotension may occur. Dose adjustment of anti-hypertensive may be needed. D2 receptor antagonists Will reduce therapeutic effects of L-dopa. 6Surandabove Sweaturine looksbrown Carbidopa/Levodopa: motor complications newred t thedose if ptsmokesocialdays m yo • Istradefylline (Nourianz®) : Adenosine receptor antagonist onitsown • Approved as an adjunctive treatment to L-dopa for patients with “off” episodes. • Dose : 20 mg daily up to 40 mg daily ( in smokers + 20 cigarettes daily) • Adverse effects : insomnia, hallucination, nausea, and constipation. yo contraindication • Metabolism : CYP 450 (CYP 1A1, CYP 3A4) ( avoid use with strong CYP3A4 inducer) • T1/2 = 80 hours Pharmacological Agents ( Motor symptoms) Dopamine : Dopamine precursor: • Levodopa (L-Dopa) 2. Reduce dopamine degradation: • COMT inhibitors • Entacapone • Tolcapone • Opicapone • Decarboxylase inhibitor • Carbidopa • Mono amino oxidase-B inhibitors • Selegiline • Rasagiline • Salfinamide 3. Dopamine receptor agonist: • Pramipexole • Ropinirole • Apomorphine 4. Unknown : Amantadine Block Cholinergic activity: 5- Anticholinergic medications: benztropine, trihexphenidyl) Block movement 6- Adenosine receptor antagonist: Istradefylline 1. hastwork Dopa wi L COMT = catechol-o-methyltransferase Wecanuseit alone so Inhibition of degradation enzymes : MOA-B inhibitors • Selective inhibition of MAO-B in the brain interferes with degradation of DA and results in prolonged DA activity. • Three MAO-BIs : • Irreversible inhibitors: Rasagiline, selegiline. • Reversible inhibitor: Safinamide • Common concern is potential for interactions with drugs that possess serotonergic activity • Theory of neuroprotective effect ( L-dopa degradation through COMT instead). MAO-B Inhibitors Medication Dose Safety/side effects/ monitoring Selegiline (Zelapar®) Capsules, tablets, ODT 5 mg po bid + food • • FYI: patch (Emsam®, only for depression) ODT 1.25-2.5 mg daily ( not recommended with CrCl<30 ml/min) • • • • Rasagiline (Azilect®) 0.5-1mg daily asthe properties Better ofMIB rest Safinamide (Xadago®) 50 mg once daily for 2 weeks then 100 mg daily ( taper down if d/c) • • • • • • Modest effect as monotherapy (early PD) Adjunctive effect + L-dopa (advanced PD) for extra “ON” time or “ wearing off”. SE: agitation, insomnia ( end product Lamphetamine), hallucinations, can worsen dyskinesias or psychiatric symptoms. ODT ( no 1st pass, less amphetamine metabolites) Monitor: BP, signs of serotonin syndrome. ALL MOA-Bi contraindications: + with MOA inhibitors (linezolid, TCAs, opioids, SNRIs), avoid high tyramine food , aged , fermented food. Monotherapy or adjunctive (early vs advanced stage PD) No Amphetamine like properties, well tolerated, minimal GI or neuropsychiatric effects. Add-on therapy for “off” episodes. Well tolerated , minimal GI or neuropsychiatric effects. Monitor : BP, visual changes. Contraindication: Severe hepatic impairment. Pharmacological Agents ( Motor symptoms) Dopamine : Dopamine precursor: • Levodopa (L-Dopa) 2. Reduce dopamine degradation: • COMT inhibitors • Entacapone • Tolcapone • Opicapone • Decarboxylase inhibitor • Carbidopa • Mono amino oxidase-B inhibitors • Selegiline • Rasagiline • Salfinamide 3. Dopamine receptor agonist: • Pramipexole • Ropinirole • Apomorphine 4. Unknown : Amantadine Block Cholinergic activity: 5- Anticholinergic medications: benztropine, trihexphenidyl) Block movement 6- Adenosine receptor antagonist: Istradefylline 1. COMT = catechol-o-methyltransferase Inhibition of degradation enzymes : COMT inhibitors • Catechol-O-Methyltransferase ( COMT) inhibitors have been developed to extend the effect of L-dopa. Notenough see Dopenin • Indicated for managing “wearing off” • Reduce CNS and peripheral conversion of L-dopa to DA, increasing central Ldopa bioavailability. • Have no effect on PD symptoms in absence of L-dopa. • COMT inhibitors > effective than CR carbidopa/L-dopa in providing extension of L-dopa effect. COMT inhibitors Medication Dose Safety/side effects/ monitoring Entacapone (Comtan®) + carbidopa/L-dopa (Stalevo®) 200 mg po with each dose of carbidopa /L-dopa ( max = 1600 mg/day) • • • Stalevo: carbidopa/levodopa ratio 1:4 with 200 mg of entacapone • (12.5/50/200mg) discation bryn SE: similar to L-dopa When adding COMT inhibitor : dose of Ldopa by 10-30% Dyskinesias can occur earlier with COMT inhibitors. Brownish-orange urine discoloration , diarrhea may occur ( weeks up to months after initiation) ODT 1.25-2.5 mg daily ( not recommended with CrCl<30 ml/min) Opicapone (Ongentys®) 50 mg qhs dose in liver disease (25 mg daily) • • • • • • • • Tolcapone (Tasmar®) Rarely used due to hepatotoxicity risk 3rd generation COMT inhibitor. Longer duration of action compared to Entacapone thus once daily dosing Contraindications: MAO concomitant use. Hx of pheochromocytoma, catecholamine secreting neoplasms. Precautions: Hypotension, syncope, falling asleep during ADL. Compulsive disorder, psychosis not arable Pharmacological Agents ( Motor symptoms) Dopamine : Dopamine precursor: • Levodopa (L-Dopa) 2. Reduce dopamine degradation: • COMT inhibitors • Entacapone • Tolcapone • Opicapone • Decarboxylase inhibitor • Carbidopa • Mono amino oxidase-B inhibitors • Selegiline • Rasagiline • Salfinamide 3. Dopamine receptor agonist: • Pramipexole • Ropinirole • Apomorphine 4. Unknown : Amantadine Block Cholinergic activity: 5- Anticholinergic medications: benztropine, trihexphenidyl) Block movement 6- Adenosine receptor antagonist: Istradefylline 1. COMT = catechol-o-methyltransferase vegas N'Thimitas Dopamine Receptor Agonists: • Two pharmacologic subtypes: • Ergot derived agonist (Bromocriptine) Don'tstartonolder adult • Non-ergot agonist (Pramipexole, Ropinirole, Rotigotine, Apomorphine) • Non-ergot have better safety profile and are more commonly used than ergot-derived agonists. • Stimulate dopamine receptors (eg, D1, D2, D3) • Useful as monotherapy in mild to moderate PD • Also, as Adjuncts to carbidopa/L-dopa to reduce “off” time in patients with motor fluctuations. • Beneficial in younger patients ( L-dopa likely to develop motor complications) • Older patients may experience more intolerable adverse effects ( cognitive problems, confusion, orthostatic hypotension). • Common AE's: nausea, confusion, hallucinations, light-headedness, lower-extremity edema, postural hypotension, sedation and vivid dreaming. • Less common but serious AE's: impulsive behaviors, psychosis and sleep attacks Dopamine Agonist O Medication Dose Safety/side effects/ monitoring Pramipexole Mirapex® Mirapex ER® IR 0.125 mg po TID, titrate weekly to max 1.5 mg TID • • Impulse control disorder ( up to 10%) Gambling, shopping, hypersexuality IR ( also used for restless leg syndrome) ER: 0.375 mg po daily titrate weekly to max 4.5 mg daily dose if CrCl < 50 ml/min ( 90% renal excretion) Ropinirole Requip® Requip XL ® IR: 0.25 mg po TID ( weekly titration) max 8 mg TID XL 2 mg daily to max = 24 mg/day • • • Liver excretion Cipro (CYP1A2 inhibitor ) affect metabolism Cigarette smoking (inducer) Rotigotine Neupro® Patch Start at 2mg /24 hrs (early PD) Max dose = 8mg/24hrs • Apply once daily same time ( hip, stomach, shoulder, upper arm) Not affected by renal or hepatic impairment. • Apomorphine 2-6 mg S.C (last 90 minutes) Apokyn®SQ injection *test dose in medical office Kynmobi® SL film Film : 10-30 mg prn (max 5 doses/day) • • • FQ : fluoroquinolone, 5HT-3: 5 hydroxy-tryptamine (serotonergic) Contraindication : don’t use with 5HT-3 antagonists (ondansetron) cause severe hypotension, loss of consciousness SE : N/V, hypotension, yawning, QT prolongation. Emesis prevention : Trimethobenzamide (Tigan) 300 mg TID , 3 days prior. Pharmacological Agents ( Motor symptoms) Dopamine : Dopamine precursor: • Levodopa (L-Dopa) 2. Reduce dopamine degradation: • COMT inhibitors • Entacapone • Tolcapone • Opicapone • Decarboxylase inhibitor • Carbidopa • Mono amino oxidase-B inhibitors • Selegiline • Rasagiline • Salfinamide 3. Dopamine receptor agonist: • Pramipexole • Ropinirole • Apomorphine 4. Unknown : Amantadine Block Cholinergic activity: 5- Anticholinergic medications: benztropine, trihexphenidyl) Block movement 6- Adenosine receptor antagonist: Istradefylline 1. COMT = catechol-o-methyltransferase Amantadine • Provides modest symptomatic benefit to tremor, as well as rigidity and bradykinesia • Precise MOA is unknown; enhancement of DA release from presynaptic terminals and inhibition of NMDA receptors are implicated • Typically, 300 mg/d in divided doses • Useful for suppressing L-dopa-induced dyskinesia • Common side effects - confusion, dizziness, dry mouth and hallucinations • Dose adjustment is needed for renal dysfunction Anti-Cholinergic drugs: • DA provides negative feedback to ACh neurons in the striatum • Degeneration of nigrostriatal DA neurons also results in relative increase of striatal cholinergic interneuron activity • This increase cholinergic activity is believed to contribute to the tremor of PD Drug Dose Monitoring/Side effects Benztropine Cogentin® 0.5- 2mg TID (start at bedtime) SE: Anti-cholinergic effects including dry mouth, constipation, urinary retention, blurred vision, mydriasis, confusion. Trihexyphenidyl 1-5 mg TID (start 1 mg at bedtime) Avoid use in elderly patients (beneficial in younger patients + tremor) • Which of the following is TRUE regarding the selection of initial therapy for PD? A) Dopamine agonists are preferred in older patients. B) Controlled-release levodopa delays the onset of motor complications. f C) Levodopa is the most effective option for improving motor disability. D) Motor complications are minimized by keeping the levodopa dose greater than 600 mg/day. General Treatment Guideline • Two main guidelines published regarding management of PD : • American Academy of Neurology (AAN) • International Parkinson and Movement Disorder Society (MDS) • Since PD is a progressive disease , the choice of treatment depends on several factors ( age, main symptoms, comorbidities, etc.…) • The optimal time to initiate therapy depends on the degree to which symptoms functionally impair the patient along with patient preference. • When the decision to initiate therapy is made, use lowest effective dose and titrate/taper slow. • Medications must be taken with consistent schedule and should not be abruptly discontinued. • Levodopa is the most effective drug for the symptomatic treatment of PD. • Either levodopa or a DA can be used initially. However, it is current practice to start therapy with a DA in younger patients (age <60 years) and levodopa in older patients -related motor complications in young onset PD and the DAs are associated with fewer motor fluctuations than levodopa. General guide summary • Anticholinergic = younger , tremor • Amantadine = younger, mild PD • Dopamine Agonists = younger, moderate symptoms • MAO-B inhibitors = early Mild PD symptoms • Carbidopa/Levodopa = severe symptoms, older (most effective) Psychosis in PD patient • Affects 1 in 5 PD patients ( visual hallucinations > auditory) • Reasons may include : • Disease progression ( loss of DA neurons in substantia nigra, unclear mechanism) • PD Medications increase Dopamine level, excess Dopamine cause hallucinations. • General approach : • Evaluate any contributing cause ( hyponatremia, hypoxemia, urinary tract infection, sepsis, etc). • Evaluate and simplify drug regimen: 1. D/c or reduce dose of medications with the highest risk to benefit ratio 2. D/c Anti-cholinergic, including non-Parkinson medications ( anti-histamines, TCA antidepressants,etc) 3. If on Amantadine, taper and d/c. 4. D/c MAO-B inhibitors 5. Taper and d/c dopamine agonists 6. Consider reduction in L-dopa ( bedtime dosing especially, d/c COMT inhibitors) Summary of the step-by-step approach to the management of psychosis in Parkinson's disease. CBC = Complete blood count COMT = Catechol-O-methyl transferase; DA = Dopamine; ECT = Electroconvulsive therapy; MAO-B = Monoamine oxidase inhibitor-B; PD = Parkinson's disease; PD-P = Parkinson's diseaseassociated psychosis rTMS = Repetitive transcranial magnetic stimulation. Lenka A, Gomathinayagam V, Bahroo LB. Approach to the management of psychosis in Parkinson’s disease. Ann Mov Disord 2019;2:83-90. Treatment Options: • Consider atypical antipsychotic medication if disruptive hallucinosis or psychosis persists • Quetiapine and clozapine (second generation antipsychotics) have lower binding affinity for D2 receptors • Quetiapine 12.5–25 mg at bedtime; gradually increase by 25 mg each week if necessary, until hallucinosis or psychosis improved or • Clozapine 12.5–50 mg at bedtime; gradually increase by 25 mg each week if necessary, until hallucinosis or psychosis improved (requires frequent monitoring for leukopenia) • New option approved by FDA in April 2016: Pimavanserin (Nuplazid®) • Indicated for hallucinations and delusions associated with PD psychosis • Mechanism: Inverse agonist & antagonist at 5HT2A • Dosage :34 mg (two 17 mg tablets once daily) • Adverse effects :Peripheral edema, confusional state, nausea • Warning : QT prolongation ( avoid use + drugs increasing QT prolongation risk) • CYP3A4 substrate : interact with strong inhibitors ( as ketoconazole) , dose reduction is needed. All of the following are TRUE regarding psychosis in PD, EXCEPT: 1. Antipsychotic agents can exacerbate motor symptoms. 2. Psychosis in PD develops in as many as 60% of patients. 3. Dopaminergic agents can exacerbate psychotic symptoms. 4. First-generation antipsychotics (e.g., haloperidol) are standard treatment. Abbreviations • COMT: catechol-O-methyltransferase • IR : immediate release • CR: controlled release • L- dopa : levodopa • CYP450 : cytochrome P450 • D1 : dopamine receptor subtype 1 • D2 : dopamine receptor subtype 2 • DBS : deep brain stimulation • MAO : monoamine oxidase • NMDA : Nmethyl D aspartate • ODT : orally disintegrating tablet • ER : extended release • PD : Parkinson disease • GABA : amino butyric acid • SNc substantia nigra pars compacta • GI : gastrointestinal • SQ : Subcutaneous • IR immediate release