IDT Exam 2 PD

•Huntington’s Disease Patho

–Error in Huntingtin, causes CAG repeat, neurotoxic protein accumulation, familial

–Whole brain affected but striatum is very vulnerable

–Symptoms include movement (chorea, dystonia), cognitive and behavioral changes

MS Patho

–Affects brain and spinal cord; immune mediated damage to myelin

Motor Neuron Disease (eg ALS) Patho

–Primarily changes voluntary muscle movement

•Parkinson’s Disease Patho

1.Degeneration of the nigrostriatal pathway. 

ØDopaminergic neurons of the susbstantia nigra pars compacta (SNc), which provide innervation to striatum (caudate and putamen) are lost

ØLater stages involve (cortex, hippocampus, brainstem and may explain non-motor features of the disease)

 2.  Appearance of intra-cytoplasmic inclusions known as Lewy bodies

ØRound structures with a halo of filaments that radiate from the center in the remaining dopaminergic neurons of SNc.

Ølinked to alpha-synuclein  gene mutation misfolding of alpha-synuclein, leaky vesicles,accumulation of cytoplasmic DA 

ØFamilial PD linked to mutations in Alpha-synuclein (SNCA)

3. Drug-induced

PD Epidemiology

>65

M>F

Heredity

Pesticide exposure

Dystonia

•involuntary muscle spasms leading to awkward, sustained postures (often painful)

Myoclonus

rapid jerking movements (a finger or whole body);

Chorea

•dyskinesia, dance-like flowing movements of arms, legs, whole body (involuntary) -

•Intracellular inclusions containing alpha-SYN occur in (3)

oMultiple System Atrophy (in the oligodendocytes)

o  Dementia with Lewy Bodies (in the neurons)

o  Parkinson's Disease (in the neurons)

Alphar-synuclein is highly expressed ?? and fx??
Misfolding leads to?

•Alpha-synuclein is highly expressed in the presynaptic terminal

•Maintenance of synaptic vesicles

the formation of oligomers and fibrils, which further aggregate into protein inclusions called Lewy bodies

Main PD Clinical Manifestations

Tremor at rest - shaking, pill-rolling

Characteristic rhythmic (oscillating) tremor when at rest (3 cycles/sec)

Rigidity - stiff muscles (Cogwheel or ratchet-like)

•Unique increase in muscle tone or rigidity

Akinesia /Bradykinesia— most responsive to RX

•Difficulty initiating movement (especially fine motor)

•Slowness of movement changing to lack of movement as disease progresses

•Characteristic shuffling gait, handwriting changes etc.

•Difficulty balancing and frequent falling (postural instability)

•Progression can be predicted by monitoring extent and severity of bradykinesia

•Increased bradykinesia is correlated with loss of DA terminals. DA terminals can also be assessed by measuring [¹⁸F]fluro-L-dopa (F-DOPA) uptake in PD patients by PET scan.

Postural instability

-UNILATERAL

Additional PD Clinical Manefestations

How are you going to feel ?

•Stiff, sore, weak muscles

•Increasingly hard to move or lift things

•Movement changes - slump forward, gait shortens

•Voluntary movement (e.g. feeding /lifting a glass) becomes difficult 

Changes include: 

D.Diminished sense of smell

E.Changes in handwriting – difficulties with fine motor movements

F.Changes in speech

G.Mask-like face, difficulty with unconscious movement, blinking, smiling

H.Increased salivation

Potential PD Clinical Complications

oDifficulty eating, chewing, swallowing

oDepression (should be treated as a distinct condition i.e. as in the non-PD patient)

oSleep disturbances and sleep disorders

oAnxiety, fear, emotional changes

oCognitive changes - Dementia* (in some advanced PD patients as disease advances *Dr. Aebi for complex patients)

oImpulse control

oBladder control

oConstipation

Non-Motor PD symptoms

•S - Sleep disturbances such as insomnia, REM sleep disorder

•O - Other symptoms: nausea, fatigue, speech changes, anosmia

•A - Autonomic symptoms (drooling, constipation, urinary problems, orthostatic hypotension, sexual dysfunction, dysphagia, muffled speech)

•P - Psychological symptoms (anxiety, depression, dementia, cognitive impairment, psychosis)

distinguish PD from parkinson-like symptoms

Asymmetry of symptoms & resting tremor, responsive to PD meds, Lewy bodies

-ESSENTIAL TREMOR stroke, infection, drug-induced toxicity (e.g. DA antagonists) these syndromes tend to:

  (i) show symmetry, less resting tremor, not improved L-DOPA

-Pharmacotoxicity (antiemetics, antipsychotics)

Environmental tox

Infections

Metabolic disorders

Parkinsonian syndrome

PD Imaging and biomarkers

DaTscan (visualize DA transporters)
MRI

Depigmentation of DA neurons

Lewy bodies

DA relationship to ACh

Balanced

when too little DA, more ACh

Causes of PD (3)

-Idiopathic

(2) Genetic basis

Two genes link sporadic PD and familial PD

•  Alpha-synuclein

•  LRRK2

Mutations in PARKIN and PINK1 associated with early onset PD  (< 45). Familial forms show varying degrees of Lewy body pathology

•-Environmental

2 Pathways from Basal Ganglia to Cortex

1. Direct pathway: Substantia nigra → Striatum → Substantia nigra → Thalamus → Cortex
   -involves 2 GABA neurons

2. Indirect Pathway: Substantia Nigra → Striatum → Globus Pallidus → Lateral thalamic nucleus (Subthalamic) → Substantia Nigra → Thalamus → Cortex

Present pharmacological strategies for PK

1. Replace DA

2.  Mimic DA action

-Work on other NT (ACh, MAOB inh)

3.Inhibit breakdown of DA

4.Other targets (e.g. anti-muscarinic agents)

-Control non-motor sx (Antidepressants, Quetiapine, Clozapine, Pimvanserin, Droxidopa)

General principles of PD RX treatment

•Dopamine agonists, MAO-B inhibitors

•monotherapy or adjunct for initial treatment of mild-moderate PD

•Levodopa/carbidopa

•Better tolerated than DA ags, esp for elderly patients + cognitive impairment

•moderate-severe PD to avoid motor complications

•Eventually all patients will need to be on L-Dopa/carbidopa as monotherapy or in comb

L-DOPA therapy over time

•Acute response to treatment is dramatic – patients can return to a normal lifestyle for a finite period of time

•Not clear if failure is due to progression of PD or drug-induced insensitivity + drug-induced side effects “patient becomes refractory ”

•Can expect 5-8 years (?) of positive beneficial treatment with L -DOPA therapy (majority of patients with classic PD will show improvement in all 3 classic motor symptoms during this time) 

ØBRADYKINESIA shows the greatest improvement

Øsome improvement in RIGIDITY and TREMOR

ØTremor typically responds less favorably

L-DOPA Motor complications - Risks, Tx, etc

•Risk factors: females, low weight, young age at onset of PD, long duration/higher dose of levodopa/carbidopa use

•Treatment

•Increase duration of action of levodopa/carbidopa

•Add another drug that can increase dopamine level

•Deep brain stimulation for severe dyskinesia

•Other recommendations:

•Track time and frequency of dyskinesia

•Increase physical activities, reduce stress, and improve sleep quality

L-DOPA Delayed or No-On response

•Delayed or absent of medication onset

•Result of delayed gastric emptying or decreased duodenum absorption

•Treatments:

•Chew/crush tablet

•Take medication on empty stomach

•Use ODT formulation

L-DOPA End-of-dose “wearing off”

•Periods of poor movements (return of slowness, tremor, rigidity)

Mechanisms:

•Levodopa’s short half life

•Increasing loss of neurons leading to loss of dopamine storage

•Medication non-adherence

Treatments

•^ dose incr

•Switch to ER

•Add COMT i or MAO-B i

•Add DA

•Use levodopa/carbidopa enteral suspension Duopa

L-DOPA Freezing

•Sudden akinesia (loss of movement): feeling “feet stuck to the floor”, difficulty initiating steps or turns

•Exacerbated by anxiety

•Increase risk of falls

•Treatments

•Optimization of pharmacotherapy

•Physical therapy

•Using walking devices

L-DOPA Peak dose dyskinesia

•Dyskinesia occurs secondary to peak striatal dopamine levels: too much movement due to extension of dopamine effect

•Treatment:

•Lowering dose of levodopa/carbidopa

•Monitor for subtherapeutic effect

•In case of subtherapeutic effect, treat by

•Adding dopamine agonists

•Administer levodopa/carbidopa more frequently

•In severe cases, surgery should be considered

L-DOPA Off period dystonia

•Dystonia is sustained muscle contractions

•Mostly affect lower extremities

•Examples: clenching of toes, involuntary foot turning

•Usually occurs in the morning due waning level of levodopa/carbidopa

•Treatments:

•Bedtime administration of long-acting formulations

L-DOPA ICD

•Impulse control disorder (ICDs)

•Behavioral disturbances such as pathological gambling, excessive spending, hypersexuality, overeating

•Mechanism: disturbances of reward system in brain regions which are controlled by dopamine

•Risk factors:

•Younger age

•History of alcoholism or gambling

•Treatment: slowly decrease levodopa-carbidopa dosing

•Tapering is necessary to prevent withdrawal symptoms: irritability, depression, suicidality

L-DOPA Psychiatric Disorders

•Depression, anxiety, psychosis, hallucinations, delusions

•Mechanism: hypersensitivity in limbic dopamine receptors

•Risk factors:

•High doses of levodopa

•History of psychotic disorder

•History of dementia

•Treatment:

•Slowly taper levodopa-carbidopa dosing

•Drug treatments: Clozapine, quetiapine, primavaserin

Tx for non-motor PD Symptoms

Depresion: SSRI, SNRI, TCA *Monitor for serotonin syndrome

Dementia : Rivastigmine

Psychosis: - Quetiapine is preferred due to low risk of movement disorders. Monitor for metabolic complications

- Clozapine low risk of worsening movement disorders. Monitor for seizures, agranulocytosis

- Pimavanserin (Nuplazid®) is FDA approved for psychosis in PD patients. Monitor for CYP3A4 drug interactions and QT prolongation

Ortho HoTN: Droxidopa * monitor BP

NMS/ PHS

Parkinsonism-hyperpyrexia syndrome (PHS)/Neuroleptic malignant syndrome (NMS)

•Withdrawal syndrome, potentially fatal condition

•Pyrexia, muscle rigidity, autonomic instability, altered mental status

•Onset: 18 hours to 7 days after sudden withdrawal/reduction of PD drugs

•Need to slowly titrate PD drugs to avoid withdrawal

•Risk factors:

•Concurrent antipsychotics

•Dehydration

•Altered PK of PD drugs

Medications to avoid/use with caution in PD

•Medications that block dopamine receptors

•Typical antipsychotics

-Chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine

•Atypical antipsychotics

-Dissociate from DA R more quickly than typical antipsychotics

-•Risperidone, olanzapine, ziprasidone, aripiprazole, lurasidone

•Antiemetics

- Chlorpromazine, droperidol, metoclopramide, prochlorperazine, promethazine

Non-Pharm PD Tx

•Refer to nutrition specialists: ^ fluid/fiber, v protein

•Refer to physical therapy specialists: ^strength, activity, sleep quality, and reduce fall risk

•Refer to occupation therapy specialists

•Provide training on daily living activities, maximize medication adherence

•Refer to speech therapy

•Improve articulation in speech, reduce dysphagia

DBS

Deep Brain Stimulation

Indications: severe motor complications despite optimized pharmacotherapy 

Procedure:

•Battery-powered neurostimulator implanted to provide electrical stimulation to targeted brain structures such as the thalamus

•Require routine electrical parameter adjustment (eg. voltage, frequency, and pulse width)

1.      Why do we need to slowly titrate levodopa/carbidopa and other PD medications if patient wants to be on drug holiday?

NMS
•Pyrexia, muscle rigidity, autonomic instability, altered mental status

1.      Which drug is FDA approved for orthostatic hypotension in PD patient? What monitor parameter associated with this drug?

Droxidopa

Monitor bp

1.      Which drug is FDA approved for psychosis in PD patient? What monitor parameters associated with this drug?

- Quetiapine is preferred due to low risk of movement disorders. Monitor for metabolic complications

- Clozapine low risk of worsening movement disorders. Monitor for seizures, agranulocytosis

- Pimavanserin (Nuplazid®) is FDA approved for psychosis in PD patients. Monitor for CYP3A4 drug interactions and QT prolongation

1.      What role does istradefylline play in PD treatment?

treat “off” time as an add-on to L-DOPA therapy

1.      What role does anticholinergics play in PD treatment?

•Mainly used to reduce tremors; Not very effective for bradykinesia, rigidity, or gait problems

1.      What role does amantadine play in PD treatment?

ØMost useful in treatment of L-DOPA induced dyskinesia (anti-dyskinesic agent) in advanced PD when other treatments start to fail

ØCan be used to treat mild symptoms delay L-Dopa therapy early PD

ØWarning: insomnia, dizziness, skin blotches, dry mouth

•Livedo reticularis: cutaneous reaction

ØLower dose if renal function is impaired

1.      Which drug in PD has the adverse effect of livedo reticularis?

Amantadine

1.      What is the food interaction associated with MAO-B inhibitors?

•Caution on consuming tyramine-rich food products due to risk of hypertensive crisis (tyramine pressor response)

•Cured meats (sausages, salamis), aged cheeses, alcohol, fava beans, sauerkraut, wine

1.      What are the contraindications of MAO-B inhibitors?

•Many drug-drug interactions

•Contraindication: concomitant use or within 14 days of other drugs that can increase risk of serotonin syndrome

•Linezolid

•Opioids: meperidine, methadone, tramadol

•Cyclobenzaprine

•St John’s Wort

•Caution with anti-depressants: SSRI, SNRI, TCA

Which PD rx require initial test dose under medical supervision?

Apomorphine

-SQ injection - initial test dose under supervision + titration

-•Antiemetic therapy  with trimethobenzamide (Tigan®) is recommended 3 days prior to initiation

1.      Which dopamine agonist is available as SQ injection? Which antiemetic therapy is recommended for this dopamine SQ injection?

Apomorphine

-•Antiemetic therapy  with trimethobenzamide (Tigan®) is recommended 3 days prior to initiation

1.      Which dopamine agonist is a transdermal patch? How often do you have to switch application sites?

Rotigotine

1.      What are adverse effects of dopamine agonists?

•Nausea and vomiting *** SEVERE IN APOMORPHINE

•Orthostatic hypotension

•Dyskinesia

•Psych disorders: hallucinations, confusion, mania, delirium, impulse control disorders

•Somnolence and sleep attacks

1.      Can COMT inhibitors be used alone?

•Needs to be used with levodopa

•Lengthen duration of action of levodopa/carbidopa 1-2 hours

1.      What are adverse effects of COMT inhibitors?

•Similar to carbidopa/levodopa

•Diarrhea

•Discoloration of body fluids

•Tolcapone: can cause liver failure and requires monitoring of LFTs

1.      What are some motor complications associated with long-term use of levodopa/carbidopa? General treatments for those motor complications?

Delayed On or No-On Response: •Chew/crush tablet •Take medication on empty stomach -Use ODT formulation

End-of-dose “wearing off”

•Increase frequency of dosing of levodopa/carbidopa

•Switch to ER formulations of levodopa/carbidopa

•Add COMT inhibitor or MAO-B inhibitor

•Add dopamine agonist

•Use levodopa/carbidopa enteral suspension Duopa

Freezing

•Optimization of pharmacotherapy

•Physical therapy

•Using walking devices

Peak-Dose Dyskinesia

•Lowering dose of levodopa/carbidopa

•Monitor for subtherapeutic effect

•In case of subtherapeutic effect, treat by

•Adding dopamine agonists

•Administer levodopa/carbidopa more frequently

•In severe cases, surgery should be considered

Off-Period Dystonia

•Bedtime administration of long-acting formulations

1.      What are the contraindications associated with levodopa/carbidopa?

•Narrow angle glaucoma

•Concurrent use of non-selective MAO-inhibitors; separate use by 14 days

1.      What are the adverse events associated with levodopa/carbidopa?

•Nausea, vomiting

•Impulse control disorder (eating, gambling, sex)

•Psychiatric effects: agitation, depression, delirium, hallucination, psychosis

•Orthostatic hypotension

•Dyskinesia

•Dark urine

1.      What can levodopa absorption be affected by? If a patient is on levodopa, how would you counsel patient to improve levodopa absorption?

•may be affected by high-protein meal

•Levodopa is absorbed in duodenum by amino acid transport system

•In advanced PD, protein restriction diet may improve levodopa responsiveness

1.      What are differences between Sinemet^Ò , Sinemet CR^Ò, Rytary^Ò, Duopa^Ò, Inbrija^Ò?

IR : Sinemet

CR: Sinemet CR

ER : Rytary

Enteral suspension: Duopa

Inbrija: Inhaler

1.      What is the mechanism of levodopa? Carbidopa?

1.      What are the drug classes used to treat PD?

•Dopamine precursors

•Dopamine agonists

•MAO-B inhibitors

•COMT inhibitors

•Amantadine

•Anticholinergic

•MAO-B inhibitors

•Anti-depressants

•Quetiapine

•Clozapine

•Pimvanserin

•Droxidopa

Hepatotoxic PD drugs

Safinamide

Tolcapone