Etiology of parkinsons disease
Degeneration of dopaminergic neurons in the substantia nigra, presence of Lewy bodies and non-dopaminergic neuron degeneration
Parkinsons disease course
Starts with non-motor symptoms (hypotension, anxiety, depression, urinary dysfunction)
Progresses to having motor symptoms (tremor, bradykinesia, rigidity, postural instability)
Parkinsons Disease- general treatment approach
All treatments are symptomatic. There are currently no proven neuroprotective therapies.
Levodopa with carbidopa is the gold standard for symptomatic treatment
Need to treat motor and non motor symptoms
Nonpharm treatments for PD
Lifestyle modifications- nutrition, exercise, speech
Surgery:
Pallidotomy- helps tremors and drug induced dyskinesia
Thalamotomy- helps tremors
Deep brain stimulation- less traumatic surgery
Medication classes used for PD
Carbidopa/Levodopa Dopamine agonists COMT inhibitors MAO-B inhibitors Adenosine receptor antagonist NMDA antagonist/DA release Anticholinergics
What are the PK differences in the forms of levodopa/carbidopa
IR- Great bioavailability, but short T1/2. Needs to be dosed frequently.
CR- Lasts longer, but poor F
Rytary- Better F, preferred formulation
Absorption of carbidopa/levodopa
Active transport into the BBB
Diets high in proteins (large neutral AA) may decrease abs and reduce clinical response.
When is Rytary preferred?
Ideal for pts who have predictable motor fluctuations, end of dose wearing off, and/or dyskinesia
Levodopa/ Carbidopa and the BBB
Levodopa is absorbed in the small intestine and transported into the BBB via active transport. Carbidopa does not cross the BBB.
Why use Levodopa/Carbidopa in PD?
It is the most efficacious
Increases QOL
Increases survival
Complications of levodopa
N/V- decreased by carbidopa Neurogenic Orthostatic hypotension (nOH) Constipation Motor complications/fluctuations- wearing off, unpredictable "on-off" Dyskinesias Mental status changes
What happens to the efficacy of levodopa as PD progresses?
The therapeutic window narrow.
Wearing- off of levodopa
Regular and predictable decline in response 2-4 hours after LD dose.
The benefits from each dose get shorter over time, symptoms return between doses.
Strategies to address levodopa wearing off
Increase LD dose or frequency of doses
Add (not change to) Rytary formulation
Add DA or COMT inhibitor
Carbidopa/Levodopa withdrawal
Rapid cessation of Simemet can result in a syndrome like neuroleptic malignant syndrome.
-Rigidity, altered consciousness, fever, tremors
Duodopa
Carbidopa/Levodopa enteral suspension
Inbrija
Levodopa inhalation powder
Fastest onset of action
Dopamine agonists
Bromocriptine, pramipexole, ropinirole, rotigotine, apomorphine
When are DA used?
Primarily used in early tx of PD before initiating levodopa and in patients with motor fluctuations in order to prolong response to levodopa
Which DA is renally excreted?
Pramipexole
DA adverse effects
Sedating effects Unintended sleep episodes Hypotension Hallucinations May cause dyskinesias ( less likely than LD) N/V Leg edema
Which DA requires pre-med with an anti-emetic before administering?
Apomorphine
DA and impulse control disorders
There is an association between DA and ICD. Pts most at risk are those with a previous history of impulsive activity.
Typically ICS’s are reversible with DA dose reduction or d/c
Rotigotine
DA transdermal patch
Overnight switch to rotigotine is effective if pt is having sleep issues.
How do COMT inhibitors work?
Increase levodopa bioavailability in the brain
Reduce levodopa burden
Increase “on” time
COMT inhibitors agents
Tolcapone, Entacapone, Opicapone
Stalevo- combo entacapone/ LD/ carbidopa
Monitoring for COMT inhibitors
LFT monitoring for tolcapone
AE for COMT inhibitors
Brownish orange fluid discoloration
Orthostasis
Tolcapone BBW
COMT inhibitor
BBW- hepatotoxicity. Informed consent available
Which COMT inhibitor has no evidence of hepatotoxicity?
Entacapone
Which COMT inhibitor is QD?
Opicapone
Opicapone absorption
Food decreases the abs
MAO-B inhibitor agents
Selegiline, Rasagiline, Safinamide
Which MAO-B inhibitor is reversible?
Safinamide
When do you use MAO-B inhibitors?
In mild symptomatic PD pts who choose to delay dopaminergic meds.
Combining with LD in early tx may delay motor symptoms.
Use to improve wearing off in advanced disease
Selegiline BBW
BBW- suicidal thoughts and behaviors (patch)
It is an amphetamine metabolite, so it is neurotoxic
MAO-B inhibitor
Selegiline and food
Bioavailability increases 3-4 fold when taken with food
Safinamide metabolism
Metabolized by oxidation
MAO-B inhibitor interactions
Theoretical risk of serotonin syndrome Tyramine reaction (hypertensive crisis) Avoid Cipro with rasagiline
Istradefylline
Adenosine receptor antagonist that is indicated as adjunct tx to LD in pts experiencing “off”episodes
When do you need to dose adjust with Istradefylline?
Cigarette smoke
CYP3A4 inducers- avoid
CYP3A4 inhibitors- adjust dose
Istradefylline AE
Dyskinesia, insomnia, dizziness, hallucinations, N, constipation
Amantadine
Monotherapy option for newly diagnosed patients with mild PD symptoms. Provides mild to moderate benefit for tremor, rigidity, and bradykinesia
Amantadine AE
Neuropsychiatric AE limit use in older patients or those with dementia
-confusion, hallucinations, nightmares, insomnia
Other AE- anticholinergic, livedo reticularis
When to use anticholinergics in PD
Option for younger patients (<60) whose predominant symptom is resting tremor.
No effect on bradykinesia
Available anticholinergic agents for PD
Trihexyphenidyl
Benztropine
Diphenhydramine
AE of anticholinergics
Memory impairment, confusion, hallucinations, sedation, dysphoria, antimuscarinic effects, dry mouth, blurred vision
Preferred anti-emetics for parkinsons
Domperidone and Trimethobenzamide
Ondansetron, dolasetron, granisetron
Which anti-emetics should you avoid in PD
Metoclopramide, promethazine, prochlorperazine
Have dopamine antagonist properties and can worsen PD
Psychosis with PD
Common
Hallucinations, delusions, sensory disturbances like illusions
Risk factors- age, illness severity, cognitive impairment, depression, insomnia
Management of psychosis in PD
Assess for triggers- infection, electrolyte imbalance, sleep disorfer
Minimize polypharmacy
Reduce PD med doses
Add atypical antipsychotics - quetiapine or clozapine
Add cholinesterase inhibitor
Atypical antipsychotics in PD
Quetiapine
Clozapine
Pimavanserin
Droxidopa
NE prodrug
Approved for nOH
BBW for supine HTN
Clozapine AE
Need blood count monitoring due to risk of fatal agranulocytosis
Management of orthostatic hypotension in PD
Fludrocortisone
Midodrine
Droxidopa
Management of hypersomnia in PD
Sleep hygiene
Modafinil
Armodafinil
Methylphenidate
Management of dyskinesia in PD
Does not always need to be treated
Lower dose of LD if practical
Amantadine
DBS
Benztropine brand and dose
Cogentin
0.5-3mg BID
Pramipexole brand and dose
Mirapex
0.125-1.5mg TID
Ropinirole brand and dose
Requip 1-4mg TID
Requip XL 1-6 QD
Levodopa/ Carbidopa brand and dose
Sinemet- 10/100-25/100 Q8H
Sinemet CR- 50/250 Q12H
Parkinsons disease- should you ever substitute meds or stop levodopa abruptly?
No, doing so may cause neuroleptic malignant syndrome (NMS)
Which pain medicines to avoid if patient is taking MAO-B inhibitor?
Meperidine
Which anesthetics to avoid if patient is taking MAO-B inhibitor?
Meperidine, tramadol, droperidol, propoxyphene, cyclobenzaprine, halothane
Which antidepressant are safe in PD
Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine
PD S/S
Tremor
Rigidity
Akinesia/Bradykinesia
Postural instability
A 40 yo pt with no pmh presented to the neurologist with mild
left hand tremor x 6 months & no other symptoms. He is
diagnosed with Parkinson’s Disease. Which of the following
regimens is most appropriate for initial treatment?
Amantadine 100mg QD
What is MS?
Most common disabling neurological disease of young adults.
Characterized by areas of inflammation, demyelination, axonal loss and gliosis in CNS
Unknown cause
Potential triggers of MS
Infectious agent, genetic predisposition, environmental factors
Symptoms of MS
Spasticity, bladder symptoms, visual symptoms, bowel symptoms, cognitive symptoms, depression and mood symptoms, sexual dysfunction, pain, incontinence, optic neuritis, diplopia, constipation
Clinical course of MS
Relapsing Remitting MS- most common
Primary progressive MS
Secondary Progressive MS- common after 10 years
Progressive relapsing MS
Why should you treat MS?
Disease modifying therapies (DMT) have been shown to reduce long term disability and rate of relapse. Treating early may delay progression to clinically relevant MS.
Treatment goals for MS
No evidence of disease activity (NEDA)
Rio score
MS treatment of acute relapses
IV methylprednisolone
PO prednisone
Choosing initial DMARD for MS
No consensus on initial therapy, but alemtuzumab should not be used
Immunomodulators used in MS
Interferons, Teriflunomide, Glatiromer, Dimethyl fumarate, Diroximel fumarate
Common AE of interferons
Injection site reactions, flulike symptoms
Monitoring for interferons
CBC, LFT, Thyroid
Teriflunomide contraindications
Contraindicated in patients with severe hepatic impairment and in pregnancy
Glatiramer AE
Injection site reactions, lipoatrophy, rash, vasodilation, skin necrosis
Which is better tolerated, dimethyl fumarate or diroximel fumarate?
Diroximel fumarate
Cell traffickers for MS
Fingolimod Siponimod Ozanimod Ponesimod Natalizumab
AE of fingolimod, siponimod, ozanimod, and ponesimod
Bradycardia first dose, mild BP increase, elevated liver enzyme, HA
Shingles, fungal infections, macular edema, PML
Risk of rebound inflammation
Natalizumab AE
PML
Must check for JCV-Ab
Cell depleting therapies in MS
Ocrelizumab
Ofatumumab
Alemtuzumab
Cladripine
Cladripine BBW
Tumor development
Cell depleting therapies AE
Infusion site reactions, UTI, URI, neutropenia, hypogammaglobulinemia, reactivation of Heb or TB
DMT transition considerations
There is no standard protocol and reason for switching must be considered.
After DMT is effective, switch after one or more relapses, two or more lesions, or increased disability.
Which MS drug is safest in pregnancy?
Copaxone
Teriflunomide and vaccines
No live vaccines until 6 months after stopping teriflunomide
S1Ps and vaccines
Immunize for Varicella if not immune, no live vaccines during therapy or until 2 months post therapy
Ocrelizumab and vaccines
Complete live vaccines at least 4 weeks prior to initiation of drug
Complete non-live vaccines at least 2 weeks prior to initiation of drug
Alemtuzumab and vaccines
No live vaccines 6 weeks prior to therapy and during therapy
Wait 6 months after infusion to re-initiate vaccine
Which of the following are oral modifying therapies for MS?
A.) Interferons, copaxone, alemtuzumab
B.) Copaxone, fingolimod, mitoxantrone
C.) Fingolimod, teriflunomide, dimethyl fumarate
D.) Alemtuzumab, natalizumab, copaxone
C- Fingolimod, teriflunomide, dimethyl fumarate
Which of the following medications are most similar to dimethyl fumarate (Tecfidera)?
a. Avonex & Betaseron
b. Plegridy & copaxone
c. Vumerity & Bafiertam
d. Fingolimod & teriflunomide
C
Avonex class
Immunomodulator
Safest during pregnancy
Glatiramer (Copaxone)
Oral MS agents
Fingolimod Teriflunomide Dimethyl fumarate Ozanimod Ponesimod
Which MS agent has the highest incidence of GI effects?
Dimethyl fumarate
What class is Ocrelizumab?
Cell depleting therapy
What class is Betaseron
Immunomodulator
What class is natalizumab
Anti-cell trafficking agent
What med is indicated for primary progressive MS
Ocrelizumab
Glasgow Coma Scale
Motor component is most predictive of outcome.
Used to assess injury severity.
13-15= mild
3-8= severe
What can decrease outcomes in a TBI?
Hypotension and hypoxia
Monroe-Kellie Doctrine
Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This results from brain swelling or bleeding from a head injury, stroke, or brain tumor.
Elevated Intracranial Pressure (ICP)
Normal ICP is <15 in adults and lower in children
S/S- bradycardia, resp depression, HTN, irregular pupil response to light, HA, confusion, loss of consciousness, seizures, diplopia
Cerebral Edema therapy
High ICP Resuscitation- Oxygen BP control (AVOID hypotension) Fluid management (AVOID free water/ D5W) Can use fentanyl and/or propofol for pain and sedation
How does hypertonic saline and mannitol work cerebral edema?
Draws water across BBB, decreasing brain volume
Hypertonic saline bolus or “bullet” or high osmolar hypertonic saline
NaCl 23.4% IV doses prn Target serum Na 145-155 mEq/L Watch out for rebound cerebral edema Administer via central line
Hypertonic saline intermittent or infusion
NaCl 2 or 3%
Target sodium concentrations per protocol
2% can be given by peripheral line
3% may need central line in some patients
Mannitol
20% 500ml bags or 25% 50 ml vials
Must use filter due to crystallization
Serum osmolality <320 mmol/L, renal function, electrolytes
Monitor for AKI and dehydration
When do post-traumatic seizures (PTS) occur?
Immediate
Early (<7 days after injury)
Late (>7 days after injury)
Early seizure prophylaxis for TBI
Levetiracetam for 7 days preferred
Phenytoin and carbamazepine 2nd line
Post-traumatic agitation in TBI
Subtype of delirium
Characterized by aggression, inhibition, emotional lability, motor disturbances
Treatment of post traumatic agitation
Aggression- serotonin agents Memory- acetylcholine agents Arousal/attention- catecholamine agents Motor disturbances- dopamine agents Disinhibition- combo
TBI possibly harmful agents
Benzodiazepines Metoclopramide Neuromuscular blockade Amitriptyline Cimetidine Clonidine, prazosin Phenytoin, phenobarbital
TBI electrolytes
Hyponatremia- SIADH, CSW
Potassium
Magnesium
Glucose
TBI dysautonomias
Suggests poor prognosis
Increase in HR, respiratory rate, temp, BP, tone, posturing, sweating
General care for TBI
DVT prophylaxis
Enteral feeding
Early rehabilitation
Neurostimulants for TBI
SSRIs, valproic acid for depression
Behavior/cognitive- SSRI, valproic acid, amantadine, methylphenidate
Spasticity agents for TBI
Baclofen is most common
Also dantrolene, tizanidine, benzodiazepines
Pharmacologic management of elevated ICP includes
sedation and hyperosmolar therapies
What is a common adult dose of IVP 23.4% Nacl (aka “bullet” or HOT salt) for lowering intracranial pressure (ICP) ? a. 10 ml given over 60 mins b. 100 ml given over 2 mins c. 30 ml given over 15 mins d. 1000 ml given over 30 mins
c. 30 ml given over 15 mins
A patient with a severe TBI 7 days ago is ordered baclofen 30 mg pNG tube four times daily (120 mg/day) for spasticity. You call the prescriber to decrease the initial baclofen dose. Which of the following is true about baclofen ?
A. Baclofen is utilized for the therapy of spasticity after sTBI
B. Baclofen can cause significant sedation
C. Sudden cessation of baclofen can lead to
withdrawal symptoms & seizures
D. All of the above are true
All of the above