restless leg synd joint24 kipit1hnid Flashcards

Creepy-crawly
• Itchy bones
• Electric shock
• Nagging
• Aching
• Painful

• Urge to move the legs, usually accompanied or caused by unpleasant leg
sensations
• Sx begin/↑ during periods of rest or inactivity
• Sx ↓ by movement, such as walking or stretching, for at least as long as the
activity continues
• Sx ↑ in the evening/night or present only at evening/night
• Not caused by other condition (e.g. leg cramps, arthritis)

-Dopamine dysfunction (eg PD)
• ↓ CNS iron stores (check ferritin)
• Diabetes
• Neurologic conditions (eg MS)
• Chronic kidney disease (related to anemia??)
• Vascular insufficiency – including varicose veins
• Pregnancy
• Medications
- EtOH, nicotine, caffeine, dopamine antagonists & depleters

Intermittent RLS
• Occur < 2 x per week but sufficiently bothersome to require tx
• Daily Tx NOT required

• Moderate to severe discomfort
• Sx occur at least 2 x per week
• Requires daily tx

engage in alertness activities

avoid caffeine, alcohol, nicotine,

try massage, hot baths, exercise

manage drug causes

-iron replacement therapy if ferritin levels <75mcg/l

-consider intermittent use of levodopa or benzos or low potency opioids

-iron replacement therapy if ferritin levels <75mcg/l

-consider daily use of Nonergoline dopamine agonists e.g pramipexole, ropinole, or transdermal rotigotine(consider pt factors) or GABA derivative (pregabalin, gabapentin)

-

-treat as refractory RLS

recheck serum ferritin -restart iron replacement therapy if ferritin levels <75mcg/l-if poor absorption consider IV iron

-consider and correct other possible exacerbating factors i.e changes in medications, lifestyle or other causes of sleep disturbance

-consider combination therapy with agents from different classes:- ie dopamine agonists, GABA derivatives, benzos, low or high potency opioids

- consider monotherapy with high potency opioids (oxycodone, hydrocodone or methadone)

Progressive
• Neurodegenerative
• Effect on the extrapyramdial motor system

Clinical diagnosis
– No definitive diagnostic test
– History
– Clinical signs and symptoms

-bradykinesia(masked face, reduced arm swing)

-rest tremor-early -asymmetrical pill rolling, increased

-gait disturbance -shuffling gait, stooped posture

-rigidity -cogwheel or lead-pipe rigidity on clinical exam

-constipation

-soft speech

-panic attacks

-loss of smell

-hypontension

-impulse control disorder and delusional disorder

-sleep disturbances

-bladder disfunction

-anxiety

-hallucinations

-sweating

-dementia

-erectile difficulties

-Multi-System Atrophy
• Progressive Supranuclear Palsy
• Corticbasalar degeneration
• Lewy Body Dementia
• Wilson’s Disease
• Drug-related Parkinsonism

Antipsychotics
• Conventional agents - higher potency agents have greater risk (e.g. haloperidol) but
also seen with moderate to low potency agents related to dose
• Atypicals
• Those with higher potency (e.g. risperidone)
• Can also be observed with other agents at higher doses

Antiemetics
• Metoclopramide versus domperidone (crosses BBB vs not expected to cross BBB)

SSRIs – low risk

crosses BBB

• Tends to be symmetrical versus asymmetrical
• Less likely associated with tremor
• Amiodarone, lithium, levetiracetam & valproate generally cause tremor without other
symptoms
• Tends to remain static and does not progress
• Poor response to levodopa compared to idiopathic PD
• Improvement in symptoms with withdrawal of offending agent

A. Cure disease
• No cure at present
B. Slow disease progression
• No evidence for Vitamin E, Coenzyme Q , dopamine agonists or MAOIs for neuroprotection
• Early use of CR Sinemet does not ↓ motor complications
C. Reduce severity/frequency of symptoms
• Present treatments

CR Sinemet

• Physical therapy
• Speech therapy
• Occupational therapy
• Counseling/education
• Fall precautions

• When functional impairment is present
• Not necessarily at time of diagnosis
• Ability to carry out activities of daily living in home, social and/or
occupational setting is impaired

Initial treatment depends on:
• Severity of sx
• Functional decline
• Cost
• Patient specific factors – including preference
• Treatment evolves as disease progresses
• Managing side effects

use a dopamine agonist stimulate the parts of the brain influenced by dopamine-less likely to cause dyskenesia

dopamine agonists

consider age and risk of impulse disorders

-pramipixole(mirapex)

-ropinirole

-apomorphine

-rotigotine-neupro

Dyskinesias

• Excessive daytime sleepiness or sudden sleep attacks
• Confusion or visual hallucinations
• Low blood pressure or lightheadedness
• Leg swelling and discoloration
• Dyskinesia
• Compulsive behaviors (such as uncontrolled shopping, gambling, eating, and sexual urges)

-use levodopa-there are some levodopa associated complications.

use levodopa-

consider MAO-I-B

-rasagiline

-selegiline

safinamide

no

-amantadine

-anticholinergics

Gold standard treatment
• Monotherapy or combination therapy
• Early or late disease
• Precursor drug converted to dopamine in CNS & periphery
• Therapeutic effect & adverse effects
• Dopa Decarboxylase Inhibitors coadministered

Carbidopa
Benserazide

Dopa Decarboxylase Inhibitors

↑ DDC dose if motor sx’s controlled but N/V

Depends on severity of symptoms
• Delay levodopa= delay motor complications
• Improving motor disability vs. limiting motor complications
• Previously thought young patients (< 60-70 yrs) may delay levodopa with
other medications until symptoms interfere with daily activities
BUT
This is now changing

• Amino acids from protein can compete for absorption in gut and at BBB
• Should not reduce daily protein intake
• May be able to overcome with increase in levodopa dose

• May delay or vary absorption
• If patient complains of delayed onset or variable effectiveness → administer 1 hr before or after meal

• Iron supplements can ↓ absorption
• Consider supplements, multivitamins
• Separate administration

DCC inhibits

• Supplement with Vitamin B12

1.Antihypertensives
• Contribute to orthostatic hypotension – consider modification of
antihypertensive therapy if symptomatic
2• Non-selective MAOIs
• Hypertensive crisis
3• Dopamine antagonists or depleters
4• Iron

Initial dose - depends on experience of prescriber and patient specific
factors
• 100/25 mg 1-3 x daily
• ↑ by 100/25 mg every 3-4 days
• Maximum daily dose is pt dependent
• Usually does not exceed 2000 mg/day

Usually does not exceed 2000 mg/day

Because CR formulation has unpredictable absorption generally
reserved for night-time doses
• IR formulation 30 minute onset
• CR formulation 1-3 hour onset

Dyskinesia
• Wearing off
• On-off phenomenon
• Unpredictable fluctuations in mobility
• Unrelated to timing of doses
• ↑ over time - 3-5 years
• Ability to regulate dopamine levels declines

• Progressive loss of dopaminergic neurons=loss of ability to regulate and store striatal dopamine
• Response becomes dependent on plasma levels
• Dopamine’s short t1/2 (1.5-2 hours)
• Dopamine receptors are exposed to high and low concentration of dopamine
• With disease progression striatal dopamine levels depend on peripheral
concentrations

• Return of symptoms before next dose
• ↑shortened duration of benefit from dopamine dose
• Related to timing of doses
• Loss of neuronal storage capacity for dopamine

• Common problem - 30 to 80% of patients
• involuntary movements involving the face, neck, trunk and upper
extremities
• Peak dose
• Associated with peak dopamine concentrations
• Diphasic
• Dyskinesias before and after therapeutic concentrations of dopamine are
achieved

Best evidence with entacapone & MAOI-B agents(Rasagiline or selgiline)
• Consider availability of MAOI-B agents

-add amantadine or decrease levodopa

-discontinue anticholinergic

-discontinue MAO-B inhibitor

-add amantadine

or increase frequency but smaller doses of levodopa

or -decrease levodopa and add dopamine agonist

if the above cause side effects or is inneffective-then consider surgical or intrajejunal levodopa/carbidopa infusion

-increase freq of levo

or add antacapone

or add dopamine agonist

or add nasagiline or safinamide(consider availaibility)

or change to slow release levodopa

-add amantadine

or increase frequency but smaller doses of levodopa

or -decrease levodopa and add dopamine agonist

• Nabilone has limited data in refractory dyskinesia
• 7 patients
• 0.03 mg/kg (no upper dosing limit mentioned)
• Short-term data only
• No long-term adverse event data
• Off-label indication

• Adverse effects
• CNS effects
• Dysphoria
• Somnolence
• Hallucinations/para
noia
• Exacerbate autonomic
instability
• Orthostatic hypotension

Indicated for severe, refractory motor complications – including dyskinesia
• Direct administration via PEG-J tube
• Requires specialized team
• Extensive patient education

1:1 ratio from oral tablet formulation
• Morning bolus dose (usually 100-200 mg levodopa)
• Maximum bolus is 300 mg
• Continuous maintenance dose (usually 40-120 mg/hr x maximum 16 hr)
• Adjust by 2 mg/hr

300 mg

• Simulate dopamine at postsynaptic dopamine receptors
• Do not require conversion to active form
• Longer t1/2- provide more continuous stimulation of dopamine
receptors
• Less likely to cause motor fluctuations

• Bromocriptine
• Ergot based – generally not used
• Pramipexole
• Renal dosing
• Ropinirole
• CYP450 metabolism- CYP 1A2 (e.g. ciprofloxacin)
• Rotigotine
• Patch
• Apomorphine
• Discontinued by manufacture

Orthostatic hypotension
• α antagonism
• Consider pharmacodynamic drug
interactions
• Avoid apomorpine with 5HT3
antagonists (e.g. ondansetron)
• Severe hypotension
• Edema
• Constipation
• Hallucinations
• Confusion
• Somnolence – sleep attacks
• Implications for driving
• Compulsive disinhibitory
behavior
• Gambling, shopping,
hypersexuality

↓ peripheral metabolism of levododa → ↑ CNS concentrations

- Only beneficial in combination with levodopa

Potentiate side effects of levopdopa
• dyskinesia, nausea-vomiting, orthostatic hypotension
• Consider ↓ levodopa dose 10-20% if start entacapone
• Entacapone
• Urine discoloration – orange-brown colour

entacapone

• Dosing
• 200 mg tablets - 200mg TID-QID, max 1.6 g/day
• Available in combination with levodopa (Stalevo®) - dose of levodopa varies

• Take/administer at the SAME TIME as levodopa
• Take with EACH levodopa dose
• Do not break/crush tablets

Selectively & irreversibly inhibit MAO-B metabolism of dopamine
• Selegiline, rasagiline
• Rasagiline not covered by NS Pharmacare

• Safinamide
• Not covered by NS Pharmacare
• Indicated only in late disease

Early disease as monotherapy – manage mild symptoms
• Selegiline & rasagiline only
• Combination with levodopa in late disease
-Selegiline, rasagiline and safinamide

•First generation
• Amphetamine metabolites-insomnia, agitation
-Zelaplar- transbuccal tablet available in U.S. with less amphetamine metabolites
• Side effects- nausea, dizziness, orthostatic hypotension, rash, dyskinesia
• Initial dose- 2.5 (with levodopa) -5 (as monotherapy) mg daily
- ↑ gradually to 5 mg twice daily – maximum dose
• Available as 5 mg tablets

• Second generation
• Side effects- headache, arthralgias, dyspepsia, depression, orthostatic
hypotension, chest pain, dyskinesia (when used with levodopa)
• Initial dose- 0.5 (with levodopa) to 1 mg (monotherapy) daily
• Available as 0.5 and 1 mg tablets
• CYP 1A2 inhibitors (e.g. ciprofloxacin)
• Not covered in NS

• Metabolism primarily non-CYP P450
• Pharmacodynamic interactions similar to other MAOI-Bs
• Side effects similar to other MAOI-Bs
• Indicated in late disease only
• “off” periods
• Start at 50 mg daily & increase to 100 mg at 2 weeks if partial response & tolerated
• Not covered in NS

1.Serotonin syndrome – use with caution if combined with:
• SSRIs, SNRIs, TCAs, MAOIs
• Meperidine – avoid
• Other opioids can be used
• Tramadol
• Cyclobenzaprine
• Dextromethorphan – cough and cold preparations
• St. John’s Wort
• Chlorpheniramine & brompheniramine
2• Severe hypertension – hypertensive crisis
• Alpha-agonists - cough and cold preparations

• Meperidine – avoid
• Other opioids can be used
• Tramadol
• Cyclobenzaprine
• Dextromethorphan – cough and cold preparations
• St. John’s Wort
• Chlorpheniramine & brompheniramine

• Toxicity caused by excessive
serotonin levels that result
from a drug overdose or a
drug interaction

Group A

Non-selective & irreversible
MAOi A & B
• Isocarboxazide
• Isoniazid
• Phenylzine
• Trancyclopromine

Group B

Antidepressants
• SSRIs
• SNRIs
• TCAs – imipramine &
cloimpramine

Non-selective & reversible
MAOi A&B
• Linezolid

Opioids-Group B
• Tramadol
• Meperidine
• Methadone
• Fentanyl

If 2nd Group B drug
added to Group B drug, start low,
go slow & monitor symptoms x
24-48 hours after every change

Group B

Antidepressants
• SSRIs
• SNRIs
• TCAs – imipramine &
cloimpramine

Opioids
• Tramadol
• Meperidine
• Methadone
• Fentanyl

Cough, Cold & Allergy
• Dextromethorphan
• Chlorphenriamine
• Brompheniramine

NHPs
• St. John’s Wort
• L-tryptophan

Meta-analysis
• 8 studies overall
• Retrospective cohort – 1504 patients – no serotonin syndrome
• Parkinson’s study group – 4568 patients – 11 cases of probable serotonin
syndrome with selegiline and antidepressants (including SSRIs)
• Conclusion
• Concomitant use of SSRIs and MAO-Bs is generally well tolerated
• Selegiline and rasagiline doses within therapeutic range
• Lower end of therapeutic doses of SSRI
• Consider use of multiple agents with serotoninergic activity
• Monitoring parameters for serotonin syndrome

Selegiline and rasagiline

sx start within hours to 1 day of increasing the dose or adding another drug

-assess the drugs(all)-most cases involve 2 drugs that increase serotonin in different ways:rx drugs, OTC and natural drugs, illicit drugs

-rule out other things-serotonin can look like other things: diagnosis requires accurate drug history.

nervousness

insomnia

nausea/diarrhea

tremor

big ppils

-age

-duration of therapy

-frequency and dose

-sx

-type interaction -absolute of relative??

• Monotherapy in early disease for mild sxs (~1-2 yrs) – not drug of first choice
• Combination with levodopa in late disease for dyskinesia

• 100 mg capsules or 100mg/10 ml syrup
• 100 mg daily (if other PD drugs) or twice daily
• Maximum dose – 400 mg daily
• Adjust dose for renal impairment

not the drug of choice -dosing??- adjust dose for renal impairment

-used in early disease or in combo with levodopa for dyskinesia

CNS (dizziness, insomnia, confusion, nightmares) especially in older
patients
•
• Dry mouth, nausea
• Leg edema, orthostatic hypotension
• Ataxia – falls
• Livido reticularis (molting of skin)

Benztropine

procyclidine

trihexyphenyidyl

Younger patients with severe, prominent tremor????
• Effectiveness?? – not recommended as first line therapy
• Avoid in older persons

Adverse effects limit use
• Blurred vision
• Exacerbate narrow angle glaucoma
• Dry mouth
• Urinary retention
• Constipation
• Confusion

Adverse effects limit use
• Blurred vision
• Exacerbate narrow angle glaucoma
• Dry mouth
• Urinary retention
• Constipation
• Confusion

Best results
• Adequate response to dopaminergic therapy
• Presence of on–off fluctuations
• Age < 70 yr
• Dyskinesia impairing quality of life
• Medication-resistant tremor
• Reasonable cognitive function

• Neuropsychiatric
- Dementia
- Psychosis – hallucinations
• Autonomic
- Constipation
- Orthostatic hypotension

↑ risk of dementia compared to general population
• develops at least 1 year after motor symptoms present
• Risk ↑ with ↑disease duration, severity, and age
• Slow progressive cognitive decline
• Discontinue cognitive unfriendly drugs
• Anticholinergic agents (consider total anticholinergic burden) – including TCAs & urinary agents
• Sedative-hypnotics
• Consider cholinesterase inhibitors
• Rivastigmine or donepezil

• Frequency ↑ as PD progresses
• Common reason for nursing home placement
• May be due to underlying dementia or medication induced
• Medications induced – visual hallucinations
• Dementia related psychosis – delusions (especially paranoid delusions)
• Treat distressing symptoms – not those that are not distressing to
patient

Treat precipitating
illnesses (e.g. infection,
heart failure)

Lower doses or
discontinue precipitating
medications

Add antipsychotic agent
for unresponsive,
distressing sx’s

Non-essential contributing medications

ALWAYS taper down to discontinuation/ dont stop abruptly
-Anticholinergics &/or nabilone
-Amantadine
-Dopamine agonists
-MAOI-B
-Levodopa

does not cause
confusion but can contribute to effect
of levodopa

• Risks to the patient
• neuroleptic malignant-like syndrome
• Aspiration → pneumonia
• deep vein thrombosis/pulmonary embolism
• Painful

• Tri-Cyclic Antidepressants
• Drugs to treat urinary incontinence
• Tolterodine, oxybutynin, darifenacin, solefenacin, trospium
• 1st generation anti-histamines
• Includes dimenhydrinate, diphenhydramine, doxylamine, chlorpheniramine

Treat if hallucinations/delusions are distressing to the patient or may cause
harm to themselves or others
• Typical antipsychotics should not be used due to extrapyramidal symptoms
(EPS)

Atypical antipsychotics may be considered
• Best evidence with clozapine – not practical – required blood work
• Quetiapine is a reasonable alternative
• Pimavanserin shows promise but not yet available in Canada

• Common – occurs up to 80% of patients
• Consider discontinuing any medications that may contribute to
constipation (e.g. agents with anticholinergic properties)
• Treatment includes:
• High fiber diets +/- bulking agents (usually insufficient as monotherapy)
• Ensure adequate hydration
• ↑ physical activity
• Laxatives
• Senna, isosomotic agents (PEG), lactulose
• Domperidone – prokinetic agent that does not cross BBB

Fall in systolic BP of 20-30/10 mmHg or more between lying and
standing

Treatment
• ↓ non-PD contributing medications, including antihypertensives
• ↑ salt & water intake (avoid dehydration)
• Compression stockings
• Elevating the head of the bed by 10-30 degrees
• Leg exercises prior to standing
• Avoid large meals (post-prandial effect), alcohol, excessively warm
environments

• ↓ dose or d/c contributing medications whenever possible – including
antihypertensives
• Consider risk/benefit of strict antihypertensive control
-Options
- Fludrocortisone – mineralcorticoid → Na + H2O retention
- Midodrine – alpha-agonist
Both can cause supine hypertension
- Pyridostigmine – cholinesterase inhibitor- Useful in presence of supine hypertension
- Some case reports suggesting domperidone helpful

• Fludrocortisone (Florinef®)
- Mineralocorticoid
- ↑ sodium retention (think about precautions/contraindications)
- Reduces serum potassium – potassium supplements usually necessary
- Start at 0.1mg/day and gradually increase – generally max 1 mg per day
• Midodrine
- α1 agonist
- ↑BP by ↑ peripheral vascular resistance
- Cardiac precautions
- Starting dose 2.5mg/day and gradually increase (max 10mg TID)
- Don’t take after 6 pm, especially if supine hypertension

• ↑BP by ↑ peripheral vascular resistance
• Cardiac precautions
• Starting dose 2.5mg/day and gradually increase (max 10mg TID)
• Don’t take after 6 pm, especially if supine hypertension

used to treat ortho-hypotension

• ↑ sodium retention (think about precautions/contraindications)
• Reduces serum potassium – potassium supplements usually necessary
• Start at 0.1mg/day and gradually increase – generally max 1 mg per day

• Useful as monotherapy in mild orthostatis
• 30 mg BID to TID - may increase to 60 mg
• Sometimes combined with low dose midodrine

• Work to your full scope of practice
• Observe patients presenting with Parkinsonian sx’s
• Tremor, rigidity, bradykinesia +/- postural hypotension
• Refer to primary care provider for assessment
• Review medications for drug-induced parkinsonism
• Provide education (written & verbal) to patients & caregivers – tailor individually
• Develop therapeutic goals in collaboration with pt & team
• Assist pt & team with appropriate dosing, administration & timing of PD medications
• Actively assess PD medications for effectiveness, adverse effects & affordability
• Assess adherence
• Assist pts & team with dosing adjustments