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Parkinsons final p pt

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Parkinson’s Disease

• 2nd commonest degenerative CNS disorder • Onset

– 6th & 7th decade – Young onset (<40 years)

• Loss of neurons – Dopaminergic Substantia Nigra (pars compacta)– Cholinergic nucleus basalis of Meynert – Norepinephrine Locus Ceruleus – Serotonin Raphe nucleus

2

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The direct and indirect basal ganglia loops.

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• Bradykinesia• At least one of the following criteria:1. Rigidity2. 4–6 Hz rest tremor3. Postural instability

Step 1

UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria

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• Exclude other causes of parkinsonism1. Head injury2. Encephalitis3. Neuroleptic drugs4. Strictly unilateral features after 3 yrs5. Cerebellar signs6. EarlyAutonomic symptoms and dementia7. Babinski sign8. Negative response to large dose levodopa9. Cerebral tumour ,MPTP exposure

Step 2

UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria

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• At least three of the following supportive (prospective) criteria:1. Unilateral onset2. Rest tremor3. Progressive disorder4. Persistent asymmetry primarily affecting side of onset5. Excellent response (70–100%) to levodopa6. Severe levodopa induced chorea (dyskinesia)7. Levodopa response for 5 years or more8. Clinical course of 10 years or more

Step 3

UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria

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Parkinsonian Syndromes

• Patient has bilateral onset of a gait disorder

• Patient has early falling• Patient does not respond

well to L-Dopa• Patient has prominent

dementia or autonomic nervous system dysfunction

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Modified Hoehn and Yahr staging

Stage 0 No signs of disease

Stage 1 Unilateral disease

Stage 1.5 Unilateral plus axial involvement

Stage 2 Bilateral disease, without impairment of balance

Stage 2.5 Mild bilateral disease, with recovery on pull test

Stage 3 Mild to moderate bilateral disease; some postural instability; physically independent

Stage 4 Severe disability; still able to walk or stand unassisted

Stage 5 Wheelchair bound or bedridden unless aided

Parkinson’s Disease – Stages of Symptoms

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IMAGING PROCEDURE

• MRI or CT Exclude differential diagnoses

vascular PD, Wilson’s disease, or atypical parkinsonian syndromes

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SPECT

• PET and SPECT - visualize the pre- and postsynaptic compartment of the nigrostriatal projections.– functionality of these pathways undestood

Help to differentiate –– iPD from atypical parkinsonian syndromes or from essential tremor

(ET).

• The dopaminergic deficit can be quantified by a DAT-SPECT (DaTSCAN®) using [123I]-FP-CIT and is a measure for the presynaptic dopamine transporter in the striatal dopaminergic synapse (Booij et al., 1997).

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TRANSCRANIAL USGThe first description of hyperechogenicity in the substantia nigra

in iPD patients (Becker et al., 1995)

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OLFACTORY AND GENETIC TESTING

• Most patients (90 %) with iPD show olfactory dysfunction early in the disease course (Katzenschlager and Lees, 2004). There are therefore reasons to suggest olfactory testing as an early clinical biomarker for iPD (Morley and Duda, 2010).

• 6 PD susceptibility loci have been identified .11 other genes are known to cause genetic Parkinson’s disease (reviewed in (Shulman et al., 2010).

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DOPAMINE RESPONSIVENESS TEST

• Dopamine replacement therapy initially results in transient, but marked amelioration of these symptoms, patients often experience as the “honeymoon-phase” due to the dramatic symptom reduction.

• Responsiveness to dopaminomimetic therapy is an important

supportive factor for the confirmation of the diagnosis of idiopathic Parkinson’s disease

• Lacking improvement of motor symptoms suggests the presence PSP, MSA or CBD.

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Differential Diagnosis of PD

• Drug induced parkinsonism• Normal Pressure Hydrocephalus• Toxin exposure

– Manganese– Carbon monoxide

• Vascular parkinsonism• Repeated head trauma

• Other Parkinsonisms– Progressive Supranuclear

Palsy– CBGD– Multiple Systems Atrophy– DLBD

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Treatment of Motor Function in Parkinson's Disease

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L-DOPA : L-DihydroOxyPhenylAlanine

• The gold standard and most powerful antiparkinsonian drugs.

• Marked symptomatic effect on all cardinal components.

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19

Periphery CNS - Striatum

L-Dopa

Dopamine

Carbidopa

Entacapone Tolcapone

3-O-Methyldopa

L-Dopa Dopamine

3 methoxyhydramine

Entacapone Tolcapone

COMT

COMT

DOPAC

MAO-B

SelegelineRasagiline

AADC

AADC

BBB

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Combination with Peripheral Decarboxylase Inhibitor

• Eg: Carbidopa/Benserizide

• Increases the bioavailability of the drug in CNS.

• Decreases side effects of dopamine

• Combination is available in 1:10;1:4 (Carbidopa:Ldopa)

• Usually started in combination 25/100 as half tab tid, 30 -60 mins before meal and gradually increased to a maximum of 25/250 combination tid

PDI decrease the daily requirement 75 % of levo dopa

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• Gastric emptying time delayed 1. Food 2. PD itself (Djaldetti 1996)3. Anticholinergic drugs.

• Dyskinesias or acute tolerability Take L-dopa with food.

• Majority it has to be taken before meals

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LIMITATIONS• L-dopa has no or little effect Non motor symptoms

(dementia, psychotic ,autonomic)

• It does not modify the underlying neurodegenerative process.

• Motor fluctuations and dyskinesias

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MOTOR FLUCTUATIONS• Early PD, effect of dose wanes days and up to weeks • As the disease progresses, the duration of effect gradually becomes

shorter.

• The time when this effect at the end of a dose effect first becomes noticeable is wearing off.

• Delayed on -- prolonged latency onset of a drug effect .

• Dose failure, a complete lack of effect of individual doses.

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DYSKINESIAS

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As the Disease Progresses, the Therapeutic Window Narrows*

Symptoms and side effects occur as the levodopa therapeutic window diminishes*

Smooth, extended response Diminished duration Shorter, unpredictable responseAbsent or infrequent dyskinesia Increased incidence “On” time with increased dyskinesia

of dyskinesia

Plasma Levodopa Concentrations

Adapted from: Stocchi F, et al. Eur Neurol, 1996.

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DOSES• In early PD daily doses 150m-400 mg

• Eventually, the total daily L-dopa dose may be in the order of 1000 to 2000 mg/day or higher.

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Side Effect 1. Nausea. • Addition of carbidopa • Immediately following a meal / with carbhydrate meal. 2. Orthostatic hypotension• Controlled by midodrine, fludrocortisone.3. Hallucinations, delusions• Treated with atypical neuroleptics. 4. Cognitive impairment, confusion • Later in disease with dementia • Confusion improve with levodopa dose alteration

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CONTROLLED RELEASE FORMULATION

• Fewer peaks and troughs in plasma concentration.

• Two double-blind, controlled 5-year trials failed to demonstrate such a reduction in risk (Dupont 1996, Block 1997, Koller 1999).

• Wearing off may benefit from the longer effect duration, the clinical use of these preparations is often hampered by their lower bioavailability.

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DUAL RELEASE FORMULATIUON

• Combines immediate and slow-release properties.

• The delay to a clinical effect was 43 minutes with dual-release and 81 minutes with slow-release L-dopa.

• On-time duration was significantly longer, and no increase in dyskinesias occurred on dual-release L-dopa (Descombes 2001).

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SOLUBLE L DOPA FORMULATION• Soluble L-dopa formulations dissolve and are absorbed quickly

• Clinical effect is within 20 to 30 minutes after ingestion (compared to 30 to 60 minutes with standard L-dopa).

• It is useful for delayed morning start-up time or as a rescue medication to provide quick relief.

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L DOPA INFUSION

• The development of a stable water-based gel suspension of L-dopa/carbidopa in methylcellulose has enabled continuous daytime infusion into the duodenum via a transabdominal delivery system.

• Enteral L-dopa infusion avoids gastric emptying as a factor of delayed or erratic L-dopa absorption.

• Stable plasma profiles and sustained reduction in motor fluctuations and dyskinesias (Kurlan 1986, 1988; Syed 1998; Sage 1988; Nyholm 2003).

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WHEN TO START LEVODOPA/CARBIDOPA

• For early symptomatic treatment and for rapid response, i.e. To aid patient to continue working – especially for rigidity & bradykinesia

• When other meds fail or become less effective

• As add-on treatment to dopamine agonists, etc.

• For de novo elderly patient. Dopamine agonists side effects?

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2. COMT inhibitors• Catechol-o-methyl transferase (COMT) • COMT a main enzyme responsible for metabolism of

levodopa. • COMT widely present in CNS.Action • COMT inhibitors block COMT in gut and periphery. • Decreases levodopa metabolism. • More levodopa available to act. • Striatal dopamine concentration increase.

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A. Entacapone

B. Tolcapone

A. Entacapone

• Reversible peripheral COMT inhibitor.

• Half life is ½ hr.

• Dose 200 mg with levodopa.

• Maximum 1600 – 2000 /day.

COMT inhibitors cont.

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Advantages • Prolong levodopa ½ life by 1.3 – 2.4 hr.• Increased levodopa bioavailability 35%• Decreased off time.• Improve motor functions. • Allow levodopa dose reduction. • Enhances clinical efficacy of CR preparation. • Celomen study improved UPDRS activity, on time

increased (1.7 hr), off time, decreased (1.5).

COMT inhibitors cont.

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Side Effect

• Most due to increased dopaminergic stimulation

• Dyskinesia.

• Nausea and hallucination.

• Diarrhoea 10%, 4 – 12 week of dosing.

• Organge coloured urine, saliva, sweat.

COMT inhibitors cont.

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B. Tolcapone (Aug 1998)• COMT inhibitor • Use is reserved for patient with motor fluctuations. • Rapidly absorbed, ½ life of 2 hr. • Dose 100 mg TID, increased upto 200 mg TID. Advantages • Improve motor function.• Levodopa dose reduction can be done. • Off time was reduced by 2 hr.

COMT inhibitors cont.

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Precautions • Drug should be stopped if no benefit in 3 weeks. • Levodopa induced dyskinesia may worsen. Side Effect • Dykinesia are common.• Nausea and hallucination. • Induce fatal hepatic failure. • Increase in SGOT, SGPT observed (3%) with 100 mg TID.

COMT inhibitors cont.

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• Women more prone. • Elevation seen within six weeks to six months of starting. Treatment and Precaution • Discontinuation will lead return of enzyme within 2-3

weeks. Monitoring • Baseline liver enzyme. • Every two weeks for 1 yrs of treatment. • Every 4 weeks for next 6 months.• Every 8 weeks further.

COMT inhibitors cont.

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3. Dopamine agonists. • Directly stimulate post synaptic dopamine receptors. • Used as monotherapy.• Following are drugs

– Bromocriptine – Pergolite – Ropirinole – Pramipexole – Cabergoline – Apomorphine

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Side Effect

• Nausea, vomiting, orthostatic hypotension.

• Nightmares, hallucination, daytime sleepiness.

• Cognitive side effect.

• Leg edema and constipation.

• Pathological gambling (Pramiperole 4.3 mg/d, pergolide

4.5 mg/d) 0.05%.

• Inappropriate sexual behaviour.

Dopamine agonists cont.

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1. Bromocriptine

• Ergot alkaloid dopamine receptor agonist.

• Strong D2 receptor agonist.

• Stimulates both pre and post synaptic receptors.

• ½ life is seven hr.

• Initiated at dose 2.5 mg/day increased every day 2.5 mg

upto 10 – 40 mg.

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Side Effect

• Nausea, vomiting, orthostatic hypotension.

• Confusion, hallucination.

• Erythromelalgia, retroperitoneal fibrosis.

2. Pergolide

• Semisynthetic compound.

• Ergot derivative dopamine agonist.

• Strong D2 receptor agonist.

• Peak plasma levels achieved in 1 -2 hr

Dopamine agonists cont.

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• ½ life 20 – 2 hrs.

• Starting dose 0.05 mg/day, initial target dose 0.25 mg TID over 4 – 6 weeks (4 –

5 mg/day).

Side Effect

• Cognitive dysfunction.

• Increased liver enzyme.

• Erythromelalgia.

• Peripheral edema.

• Valvular heart disease.

• Study show it permits mean levodopa dose reduction 24.%

Dopamine agonists cont.

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3. ROPINIROLE

• Highly selective D2 agonist.

• Non-ergoline dopamine agonist.

• ½ life of 6 hrs.

• Maximal plasma concentration reach in 1.5 hrs.

• Started as 0.25 mg TID, target dose 3 mg TID over 8

weeks (max 24 mg/day).

Dopamine agonists cont.

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Side Effect

• Somnolence, insomnia, dizziness

• Dyspepsia headache.

• Can be used as early monotherapy or adjunct therapy.

• Study show mean reduction of levodopa dose was 19.4%.

• Also demonstrated to reduce incidence of dyskinesia when used in

early PD.

• One study show 35% difference suggesting slower disease

progression with rapinirole v/s levodopa.

Dopamine agonists cont.

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4. Pramipexole

• Non ergot D2/D3 agonist.

• Synthetic amino-benzathiazole derivative.

• Initial dose 0.125 mg TID for 1 week, increased upto 0.5 mg TID

maximum 4.5 mg/day.

Side Effect

• Somnolence, constipation, hallucination.

Dopamine agonists cont.

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Advantages

• Used as early monotherapy or as adjunct.

• Improve motor function and activity of daily living.

• Levodopa dose reduced by 25%.

• Study demonstrate to reduce incidence of dyskinesia and

motor fluctuations when used in early PD.

• CALM-PD-CIT study showed slower disease progression.

Dopamine agonists cont.

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5. Cabergoline • Long acting ergot dopamine agonist. • High affinity for D2 receptors. • ½ life is 6 - hrs. • Initiaed as once a day dose 0.05 mg, maximum upto 5 mg/day. Side Effect• Dizziness, headache, nausea, arthostatic hypotension. • Fibrotic valvular heart disease. Advantages • It allows 18% reduction in levodopa

Dopamine agonists cont.

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6. Apomorphine

• Non-ergot dopamine agonist.

• Approved for subcutaneous injection to treat acute

intermittent hypomobility of OFF states.

• Strong activity at both D1 and D2 receptors.

• ½ life 40 min, onset on action by S/C injection 10 – 15 min.

• Effect last 90 – 120 min.

Dopamine agonists cont.

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Advantages

• Study show reduction of mean UPDRS motor score by 23.9 points

(62%) compared to 0.1 (1.1%) by placebo.

Precaution

• Antiemetic administered 3 day prior to its use, continued for at least 6

weeks.

• Test dose of 2 mg (0.2 ml) S/C.

• Monitoring of BP.

Dopamine agonists cont.

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SWITCH FROM ONE DOPAMINE AGONIST TO OTHER. • Can switch one to other drug by equivalent dosing OR • Gradual tapered off on drug before introducing other

drug. • The mg potency ratio of various agonist is 10 mg

bromocriptine = 1 mg pergolide = 1 mg pramipexol = 1 mg cabergoline = 3 mg, ropinirole.

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Advantages of dopamine agonists

• Long ½ lives than levodopa prevent fluctuating level and dyskinesia.

• In advanced disease good control of motor fluctuation.

New dopamine agonist

• Lisaride

– Oral preparation

– Stimulates D2 and 5 HT receptors.

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4. MAO-B INHIBITOR Selegiline • Irreversible monoamine oxidase type B inhibitors and

increase dopamine activity of levodopa. • Selegiline developed as antidepressant 1950s. Role • It delay need for levodopa in early PD. • Decrease off time in advanced disease. • Slow PD progression by

– Oxidation of MPTP and other environmental neurotoxin to develop PD as protected

– It prevent free radical production by oxidation.

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Indication • As adjunct to levodopa for patient experiencing

deterioration in quality of response. • It reduce off time and extends short duration response. • Modest symptomatic benefit as monotherapy in early PD,

delay need for other drug. Dose• 5 mg with BF or lunch. • Clinical effect lasts for months.

MAO-B INHIBITOR cont.

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Side Effect• Insomnia• Nausea• Peak dose dyskinesia, hallucination. Avoid following medications• serotominetic agents like tricyclic antidepressants, meperidine,

opiates. Zydis selegiline • Dissolves in mouth immediate. • Bypasses hepatic first pass metabolism. • Maintains high plasma concentration.

MAO-B INHIBITOR cont.

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ROSAGILINE• Second generation MAO-B inhibitor.• Given once a day.• 5 – 10 times potent than selegiline. • Used as monotherapy in early PD and adjunct to levodopa in

advanced disease. • Study (TEMPO) showed significant improvement in motor

function and may slow disease progression.

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ANTICHOLINERGIC MEDICATIONS• Mainstay of anti-parkinsonian treatment in latter part of century. • Block striatal cholinergic function. Advantage • Most effective in reducing tremor. • Minimal effective to bradykinesia and rigidity. S/E• Less tolerated by older patient.• Confusion ,Hallucinations,Dry mouth,Dry eyes,Urinary

retention ,Abnormal sweating, Tachycardia 1. Trihexyphenidyl2. Benztropine mesylate

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AMANTADINE• Antiviral medication. • In 1960s improved symptoms of PD while used to treat

influenza.Action • Augment dopamine release. • Inhibit dopamine reuptake. • Stimulate dopamine receptors.

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• Long half life of 24 hr. • Dose 100 mg BID or TID.Advantages• Reduce levodopa induced peak dose dyskinesia.S/E• Hallucination, confusion, nightmares. • Ankle edema, dry mouth. • Erythematous rash on lower limb. • Hyponatremia.

AMANTADINE cont.

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Management Wearing off effect

• Optimizing L-dopa treatment.

• Adjusting individual dosages and shortening the intervals between doses.

• Increasing the daily doses of L-dopa to more than 3 times a day

soon becomes a necessity, and some patients with very short duration of effect of each L-dopa dose may need L-dopa dosing every 2 to 3 hours during the waking day, with additional doses at night

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OTHER STRATEGIES• Improve L-dopa Absorption and Transport

– Avoid competition for intestinal absorption: avoid L-dopa intake with meals; dietary protein restrictions.In selected cases:

• Enhance gastric motility (domperidone).• Soluble L-dopa: as rescue medication when regimen otherwise optimized, e.g., early

morning offs.• In selected refractory cases: duodenal L-dopa infusions.

• Stabilize L-dopa Plasma Levels– Adjust L-dopa dose.– Adjust intervals between intakes.– Add COMT inhibitors.– Use sustained release formulations (for nocturnal akinesia and, in selected cases,

during daytime).

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• Enhance Striatal Dopamine Concentrations– Add MAO-B inhibitor.

• Add Dopamine Agonists– Oral dopamine agonist– Transdermal dopamine agonist.– Intermittent subcutaneous apomorphine injections; as rescue

medication when regimen otherwise optimized– Continuous apomorphine treatment: when fluctuations and

dyskinesias are refractory to oral adjustments. In selected cases, for refractory OFFs only.

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DYSKINESIA MANAGEMENT

• Peak-Dose Dyskinesias– Adjust L-dopa dose/schedule.– Adjust dosage of other dopaminergic drugs (MAO-B and

COMT inhibitors and dopamine agonists).– Add amantadine.– Use continuous drug delivery (subcutaneous apomorphine,

duodenal L-dopa).– Consider atypical neuroleptic (e.g., clozapine).

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• Diphasic Dyskinesias– Smooth out response oscillations: see options for wearing off.– Avoid sustained-release L-dopa.– Add/increase dopamine agonist.– Use subcutaneous apomorphine bolus injections at selected

times.– Use continuous drug delivery.

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• Early Morning/off-Period Dystonia– Bedtime L-dopa (sustained-release preparations).– Bedtime dopamine agonists.– Add L-dopa dose 1 to 2 hours before getting up from

bed.– Consider baclofen, lithium, diazepam.– Inject botulinum toxin type A into dystonic muscles.

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TREMORS• The dosage of dopaminergic agents, including L-dopa,

dopamine agonists, COMT inhibitors, or amantadine, should be increased according to tolerability and requirement.

• Anticholinergics

• Clozapine

• Primidone and clonazepam

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Key Points: Early but No Impairment

• Early patients- no functional impairment– Easiest treatment category– ADAGIO, TEMPO (rasagiline) and ELLDOPA trial

indicate earlier treatment may be better • Consider rasagiline (Azilect), selegiline

(Eldepryl,Zelapar)– Refer for potential neuroprotective trials

• Coenzyme Q10, selegiline, rasagiline, creatine

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Key Points: Early with Impairment

• Early patient-functional impairment– Bothersome tremor, stiffness, slowness, decrease in

dexterity interfering with ADLs or job• AAN guidelines 2002

– MAO B inhibitors provide some benefit– Dopamine agonists– Levodopa

• If the patient is chronologically or physiologically young (<70) try a dopamine agonist as the first robust treatment

• If older, or cognitively impaired, use levodopa first

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Key Points: Middle Stage Patients

• Starting to have wearing off of drug benefit prior to next dose • Goal is to enhance dopamine system in the brain, since these

medications have different mechanisms of action=Polypharmacy is expected!

• Layer on medications and adjust to best benefit

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Key Points: Later Mid-Stage Patient

• Experiencing fluctuation in motor control to include significant wearing off with poor mobility and dyskinesias– Have patients keep diaries of motor control– Add additional medications – Consider smaller, more frequent doses of medications to

minimize “off” time and dyskinesia• Onset or worsening of many non-levodopa responsive

symptoms, such as falling, worsening cognition, dysphagia, autonomic dysfunction

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Key Points: Advanced Parkinson’s Disease

• Treatment is made difficult by the worsening of motor complications, cognitive, psychiatric and autonomic disturbances

• Medications may need to be streamlined (reduced or eliminated) because of confusion or psychosis

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Treatment of Non Motor Complication of parkinson

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Parkinson’s Disease Non-Dopaminergic Drugs – Non Motor

Behavioural Dementia Donepezil Rivastigmine Galantamine

Depression SSRI Tricyclics ECT

Psychosis Clozapine Quetiapine Olanzapine

Anxiety Benzodiazepines

Fatigue Modafinil

Sleep related

Day-time sleep Modafinil

Insomnia Zolpidem Benzodiazepine

REM Sleep abn Clonazepam

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Parkinson’s Disease Non-Dopaminergic Drugs – Non Motor

Autonomic Orthostatic Hypotension

Fludrocortisone Midodrine

Urinary urgency Oxybutyrin Tolterodine

Impotence Sildenefil

GIT Nasuea Domperidone

Sialorrhea Propantheline & co BTX

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Surgical Treatment for PD• Patient selection is KEY• Patients who are very sensitive to levodopa are the best

candidates• Patients should have motor fluctuations including dyskinesias• Patients must be free of significant cognitive disease• Usually, consideration after 10 years of disease, but trend

toward earlier use in several trials

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Deep Brain Surgery

• Most commonly done is deep brain stimulation of the STN, bilateral

• Best patient is fluctuating, still responsive to levodopa, good cognitive skills

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DISEASE MODIFYING AGENTS16 > (ACNR > VOLUME 14 NUMBER 4 ) SEPTEMBER/OCTOBER 2014

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SOME NEUROPROTECTIVE AGENTS – MANY ONGOING STUDIES

• SERMS – PROTECT AGAINST DOPA-ERGIC NEURONAL DEGENERATION

• VITAMIN E (TS) – ENRICHES SUBST NIGRA MITOCHONDRIA, DECREASED OXIDATIVE STRESS

• COENZYME Q10 – ATTENUATES MPTP EFFECTS ON DOPAMINE NEURONS

• MINOCYCLINE – INTERFERES WITH ACTIVATION OF APOPTOTIC PATHWAYS

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82

Parkinson’s Disease

Non-pharmacologic intervention Pharmacologic intervention

Neuroprotection - MAOI

Functional Disability

Yes No

Dopamine agonists Levodopa

Combination Therapy Levodopa + Dopa agonist / MAO inhibitor / COMT inhibitor

Surgery

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REFERENCES