Pharm - ET and PD Flashcards
First line agents to treat essential tremor
- Propranolol (and other BB)
- Primidone, an anticonvulsant
Second line agents to treat essential tremor
Anticonvulsants:
- Gabapentin
- Topiramate
- Benzodiazepines
Alcohol
What are the two benzodiazepines used to treat ET?
- Alprazolam (Xanax)
- Clonazepam (Klonopin)
When should intermittent therapy be used for ET?
Mild ET with situational exacerbations of tremor
Whens should continuous therapy be used for ET?
persistent functional or psychological disability (including embarrassment or anxiety)
What is the expected clinical effect of either propranolol or primidone?
- Reduced tremor magnitude by 50%
- Response rate of 50%
ADRs of propranolol
- Bradycardia
- Lightheadedness
- Fatigue
- Impotence
- these are more LT effects
Propranolol contraindications
- heart block
- asthma/bronchospasm
- DM (can mask hypoglycemia)
- unstable heart failure
ADRs of primidone
ADRs generally more severe at tx initiation (** Dr. Letassy mentioned out loud)
- Nausea
- Ataxia **
- Confusion **
- Sedation **
- Drowsiness
- Fatigue
- Depression
- Vomiting
- Malaise
- Dizziness
- Unsteadiness
- Vertigo
- Acute toxic reaction
Primidone contraindication
- no response after titration to 250 mg ea night
What is the onset of action of Propranolol
- Normal release is pretty quick, can use within one hour of situation where need therapeutic effect.
- Extended release lasts longer and is sometimes preferred dt its daily dosing
What is the onset of action of Primidone
slower onset of action than propranolol (sometimes limits its utility)
What is indication for use of both primidone and propranolol to treat ET?
- ET is resistant to mono therapy with either alone
- they have different MoAs…
Place in ET therapy for gabapentin
- Can be used as a 2nd line monotherapy to reduce limb tremor
- If failed both propranolol and primidone, unlikely gabapentin will work
- More often used if can’t tolerate propranolol or primidone
- Also used as adjunct to propranolol and/or primidone
Place in ET therapy for Topiramate
- 2nd line to reduce lib tremor
- very effective but bad ADR!
Place in ET therapy for Benzodiazepines
- 2nd line option
- Consider if tremor is aggravated by anxiety (bc these drugs lower anxiety)
- Caution for abuse, sedation, cognitive/behavioral changes
What ET patient would benefit most from botulinum toxin type A therapy
Inadequate response or poor toleration of first and second line oral drug therapies
botulinum toxin type A ADR when used to treat ET
- When used to treat voice tremor: breathiness, hoarseness, swallowing difficulty
- Also: injection site pain, stiffness, cramping, hematoma, paresthesias
What three PD drugs have the potential to cause orthostatic hypertension?
- Levodopa
- Dopamine agonists
- COMP inhibitors
Goals of therapy in PD treatment
- Improve motor and non-motor sx to maintain best quality of life
- Preserve ability to perform activities of daily living
- Improve mobility
- Minimize ADR, treat complications
- Improve non-motor features (cognitive impairment, depression, fatigue, sleep disorders)
What is the pharmacologic class for L-dopa (carbidopa/levodopa)
Levodopa
What is the pharmacologic class for Pramipexole
Dopamine agonist
What is the pharmacologic class for Ropinirole
Dopamine agonist
What is the pharmacologic class for Apomorphine
Dopamine agonist
What is the pharmacologic class for Bromocriptine
Dopamine agonist
What is the pharmacologic class for Rotigotine
Dopamine agonist
What is the pharmacologic class for Seligiline
MAOB Inhibitor
What is the pharmacologic class for Rasagiline
MAOB Inhibitor
What is the pharmacologic class for Trihexyphenol
Anticholinergic
What is the pharmacologic class for benzotropine
Anticholinergic
What is the pharmacologic class for Amantadine
Antiviral
What is the pharmacologic class for Entacapone
COMT inhibitor
What is the pharmacologic class for Tolcapone
COMT inhibitor
Levodopa MoA
- Immediate precursor of dopamine
- Crosses blood brain barrier (dopamine cannot)
- Is decarboxylated to dopamine in the substantia nigra par compacta (SNc)
- Converted dopamine is stored in presynaptic SNc neurons until released into the synaptic cleft
Levodopa ADR
MANY
- common early: Nausea*, somnolence, dizziness, HA
- serious: orthostatic hypotension, confusion, hallucinations, delusions, agitation, psychosis
Levodopa Place in therapy for PD
- most effective drug for symptomatic tx of PD
- Effective for management of bradykinetic symptoms (when intrusive, troublesome, uncontrolled by other anti-PD drugs)
- Also work for tremor and rigidity but less effective on postural instability
- Usually used first in patients who are ≥ 65
Dopamine agonist MoA
- Directly stimulate dopamine receptors
- Do not require metabolic conversion
- Longer duration than most forms of levodopa
Dopamine agonist ADRs
- ADR similar to levodopa (nausea, vomiting, orthostatic hypertension, confusion, vivid dreams, psychoiss) except:
- May impair impulse control
- Dopamine agonist withdrawal syndrome
Some differences between dopamine agonist and levodopa ADRs
dopamine agonist:
- Lower risk of dyskinesias, “wearing off”, and “on-off” fluctuations
- Higher risk of hallucinations, sleepiness (caution about driving), edema
Dopamine agonist withdrawal syndrome
- sx
- how to tx
- Resembles cocaine withdrawal: anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, drug craving
- Only way to treat is resume dopamine, refractory to other anti-PD meds
Dopamine agonist place in therapy for PD
- Monotherapy in early, mild-moderate PD, esp in pts <65 yo
- Adjunct therapy with levodopa to reduce motor fluctuation symptoms, reduce frequency of off periods, may allow reduction in levodopa dosage, and can help manage dyskinesias due to levodopa
- Not as effective as levodopa
True/false dopamine agonist is a good alternative for a patient unresponsive to levodopa
FALSE
dopamine agonists are ineffective in patients who show no response to levodopa
MOAB inhibitors MoA
Inhibits MAO-B, a mitochondrial enzyme that terminates the activity of intracellular dopamine, prolonging the action of dopamine
MOAB inhibitor ADRs
- Hallucinations or orthostasis
- Nausea, insomnia
- May worsen dyskinesias when used with levodopa or other dopaminergics
- Many drug interactions due to MAO inhibition
MOAB inhibitor place in therapy for PD
- Mild to moderate benefit for pts with early PD
- Selegiline and rasagiline can be used as first line therapy
- modest benefit as monotherapy
- Can be added to levodopa to reduce off time
- May have antidepressant effects
Anticholinergic MoA
- Inhibits acetylcholine
- ACh activity is increased in PD due to dopamine depletion, contributes to tremor symptoms
Anticholinergic ADRs
- Anti-SLUD
- Memory impairement, confusion, hallucinations, esp in elderly population*
- Caution in pts with prostatic hypertrochy or closed-angle glaucoma
Place in therapy for anticholinergics in PD
- Can be used as monotherapy or adjunct, esp if tremor is main symptom (no bradykinesia or gait disturbance) and patient is young
- Works best for tremor and dystonic symptoms
- Use is limited due to intolerable side effects
What sort of patient is the use of anticholinergic meds strongly discouraged?
- older/demented patients
- those without tremor
Amantadine MoA
- Antiviral agent
- MoA uncertain, known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and possibly exert anticholinergic effects
- Contains N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for therapeutic effect by interfering with excessive glutamate in basal ganglia
Amantadine ADRs
- Confusion, cognitive impairment, dry mouth, insomnia, hallucinations, nightmares
- More common when used in combo with other antiPD drugs in older patients
Place in therapy of Amantadine for PD
- Monotherapy to target tremor or adjunct to levodopa in later disease for dyskinesias
- Most useful in treating younger patients with early or mild PD
- provides symptomatic benefit for tremor, rigidity, bradykinesia
COMT Inhibitors MoA
- Inhibition of COMT reduces peripheral and central methylation of levodopa and dopamine
- Increases plasma half-life of levodopa
COMT inhibitors ADRs
- Symptoms of increased dopamine
- Dyskinesia, hallucinations, confusion, nausea, orthostatic hypertension
- Diarrhea that is poorly responsive to antidiarrheal meds
- Hepatotoxicity (tolcapone), monitor ALT/AST
- Entacapone can cause orange urine
Place in PD therapy for COMT inhibitors
- Always adjunct, never monotherapy
- Tx pts with motor fluctuations who are experiencing end-of-dose “off” periods
- No apparent advantage to use in patients without motor complications
When use Levodopa (vs. dopamine agonist)?
- Levodopa is the most effective drug for symptomatic tx of PD
- First drug of choice if symptoms (esp. related to bradykinesia) are intrusive or troublesome
- patient is ≥ 65
When use dopamine agonist (vs. Levodopa)
- monotherapy or in combo with other drugs (can think of as breakthrough adjunct)
- Ineffective in patients who show no response to levodopa
- Patient is <65
Pharmacokinetic differences between IR and CR carbidopa /levodopa
- Peak clinical effect of controlled release is less than the immediate release formulations – the controlled release formulations reach the brain more slowly over time. (Lower peaks reduce dyskinesias)
- Controlled release absorption is about 70% the amount of the immediate release formulation, requires 30% higher dose of controlled release to achieve similar response as immediate release
- both appear to maintain similar levels of symptom control
Which formulation of carbidopa /levodopa is best to use at first in PD treatment?
Begin therapy with immediate release, titrate dose to desired response; once response is stable, can switch to controlled release product if desired
What is the role of carbidopa when used in combo with levodopa to treat PD
- Peripheral decarboxylase inhibitor
- Blocks conversion to dopamine in systemic circulation and liver (prior to crossing BBB), allowing more to cross into the brain
- Also helps prevent nausea, vomiting, orthostatic hypotension
Measure to manage nausea with carbidopa/levodopa
- When taking for the first time, take with a meal or snack to avoid nausea
- Small starting doses combined with decarboxylase inhibitor TID are MORE likely to cause nausea due to inadequate amt of carbidopa → add supplemental dose of carbidopa or use antiemetics
What causes parkinsonism-hyperpyrexia syndrome?
- Stopping levodopa or dopamine agonist suddenly
- Life threatening neurologic emergency… do NOT run out of this medication!!!
- Can’t regulate basic homeostatic functions such as body temperature, blood pressure, etc.
List the motor complications of levodopa
- motor fluctuations, aka “end-of-dose wearing off effect”
- “Delayed on” or “no on” response (Delayed or absent)
- Start hesitation “freezing”
- Peak-dose dyskinesia
- “Off-period” dystonia
** Increase with younger age at PD onset and higher levodopa doses
What are motor fluctuations (“end-of-dose wearing off effect”)
Decreased length of time levodopa is effective in symptom control
What is start hesitation or “freezing”
- Sudden, episodic inhibition of LE motor function
- Interferes with walking, fall risk
- Difficulty taking step or making a turn
- Exacerbated by anxiety or anticipating obstacles
What is peak-dose dyskinesia
Involuntary choreiform movements usually in the neck, trunk, LE/UE
What is “off-period” dystonia
- Sustained muscle contractions, commonly in distal LE such as clenching toes or involuntary turning of foot
- Usually occurs in early morning hours before medication
What is best treatment/intervention for End-of-dose “wearing off” effect
- Increase frequency of levodopa/carbidopa
- Add either COMT inhibitor, MOA B inhibitor, or dopamine agonist
What is best treatment/intervention for “Delayed on” or “no on” response
- more common when taken with food
- Give levodopa/carbidopa on an empty stomach
- Use levodopa/carbidopa oral dissolving tablet
- Avoid levodopa/carbidopa controlled release, use apomorphine SC instead
What is best treatment/intervention for start hesitation “freezing”
- PT and sensory cues are more helpful than medication
- Increase levodopa/carbidopa dose
- Add dopamine agonst or MAO-B inhibitor
What is best treatment/intervention for peak dose dyskinesia
- Smaller doses of levodopa/carbidopa
- Add amantadine
What is best treatment/intervention for “Off period” dystonia
- Take medication (in am)
- Bedtime administration of long acting dopamine agonist
- SR levodopa/carbidopa
- Focal injections of botulinum toxin type A or B
What is the role of low-dose estrogen in the treatment of post-menopausal women with PD
- Adjunct therapy
- Postmenopausal women with motor fluctuations on antiPD meds
- In one study, improved “on” time and motor control
- No evidence that it works on dopamine receptors, benefit may be to overall well being
- Concerns about ADRs associated with long-term use may limit its use
