PD Pharmacotherapy Flashcards
Parkinson’s Disease
Hallmark clinical features
A. Tremor – resting; begins unilaterally and slow in frequency (4-6 oscillations/sec)
B. Rigidity (cogwheeling) - limb muscles
C. Bradykinesia - slowing of movements
D. Postural instability - not caused by visual, vestibular, cerebellar, or proprioceptive dysfunction; often leads to gait disturbances
Parkinsons Disease
Motor complications
Altered axial posture Difficulty turning in bed Slow, shuffling gait Propulsion & festination Micrographia (small handwriting) Impaired fine movements Resting Tremor Masked Facies Soft, hesitant or dysarthric speech – impaired ocular accommodation Decreased eye blinking – blepharospasm Dysphagia Drooling
PD
Neuropsychiatric sx
Delirium Dementia Agitation Vivid dreams/sleep fragmentation Depression Anxiety/panic attacks
PD
Sensory & Autonomic sx
Paresthesias: sensory, thermal
Akathisia (sensation of restlessness)
Orthostatic hypotension
Impaired gastrointestinal motility
PD
pathophysiology
The pathogenesis of IPD is unknown
Motor deficits of IPD occur from loss of dopaminergic nerve terminals, therefore functionally there is a depletion of dopamine in the brain.
A positive correlation exists between the degree of dopaminergic loss and severity of clinical features.
In the normal healthy state, a balance exists between the effects of acetylcholine and dopamine.
With loss of the latter, the balance is disturbed and cholinergic activity predominates.
PD
Pharmacological goal
Goal is to restore dopaminergic/cholinergic balance via dopamine agonism and/or muscarinic cholinergic antagonism.
PD therapy
Anticholinergic agents
Place in therapy
Initial treatment for mild to moderate symptoms
Adjunctive treatment with dopaminergic agents in patients with moderate to severe disease.
Improvement in symptoms = 25%: Tremors > rigidity, no improvement in bradykinesis, posture, or gait.
No difference in efficacy between agents, however, individual patients response may vary with different anticholinergic drugs.
PD therapy
Anticholinergic agents
Pharmacologic action
Site of action = muscarinic receptors in striatum
Block over-stimulated muscarinic receptors
PD therapy
Anticholinergic agents
list
Benztropine** Trihexyphenidyl** Biperiden Cycrimine Ethopropazine Procyclidine Diphenhydramine** Orphenadrine **Most commonly used
PD therapy
Anticholinergic agents
contraindications
Benign Prostatic Hypertrophy
Narrow Angle Glaucoma
G.l. Obstruction
PD therapy
Anticholinergic agents
SE
Central:
Confusion
Hallucinations
Choreiform movements
Memory impairment
Peripheral:
Dry mouth Urinary retention Blurred vision Constipation Tachycardia Increased intraocular pressure
Amantadine
Place in therapy
Initial monotherapy for mild to moderate symptoms. (~50% response rate)
Adjunctive treatment with carbidopa/levodopa in advanced disease.
Improvement in tremor, rigidity, bradykinesia.
Amantadine
Pharmacologic mech
Increase central synthesis and release of dopamine.
Decrease central presynaptic dopamine reuptake.
Cholinergic antagonism? (mild)
? Neuroprotective effect (NMDA antagonist)
Amantadine
SE
Edema Livedo Reticularis CHF Seizures Hallucinations Gl (nausea/vomiting, diarrhea) Orthostatic hypotension Depression Confusion Insomnia
Carbidopa/levodopa
Role in therapy
Most efficacious symptomatic treatment for PD
Improves quality of life
Increases survival
Carbidopa/levodopa
Controversies with use
? long-term use may lead to degeneration of neurons
motor fluctuations with long-term use
increased dose may increase side effects with little improvement in mobility
Review the pharmacology of carbidopa/levodopa
Find
Review comparison of standard vs controlled release sinemet
Find
Sinemet SE
Peripheral - nausea/vomiting, orthostatic hypotension, tachycardia/cardiac arrhythmias, PUD
Central – dyskinesias, response fluctuations (motor complications), psychiatric complications (hallucinations)
Sinemet
Complications of long-term use
Dramatic improvement in symptoms generally occurs upon initiation of levodopa (“honeymoon period”) but this improvement is transient. After 5 years of levodopa, 50-90% of patients will experience motor complications, which can occupy as much as 50% of the day.
When assessing levodopa response fluctuations it is important to distinguish between effects attributable to the disease progression (e.g. response fluctuations) and those that are caused by the drugs used to treat the disease (e.g. levodopa-induced dyskinesias)
In many cases, elimination of one complication will come at the expense of worsening another. The impact of “off” time for each patient will be different and unique to that patient. Most patients prefer mobility or “on” with dyskinesias rather than being “off” or immobile.
Possible mechanisms of response fluctuations with sinemet
Often occur with prolonged levodopa use:
Central Causes:
Reduced buffering capacity to dampen rapid increases & decreases in levodopa delivery as PD progresses
Post-synaptic changes due to oscillations in dopamine concentrations
Possibly due to direct toxicity of dopamine (?)
Peripheral Causes: Gastric stasis
Sinemet
Response fluctuations
On-off effect
“On-Off’ effect: random and unpredictable fluctuations from mobility to parkinsonian state appearing suddenly as if a switch has been turned. Fluctuations may be brief lasting only a few minutes or they can go on for hours and increase over time in both frequency and intensity. Has no relationship to timing of dose. May be due to alteration in BBB levodopa delivery or post-synaptic alterations. May benefit from dopamine agonist, MAO-B inhibitors, COMT inhibitor, increasing the frequency of levodopa administration, or apomorphine. Initial management should include adding a dopamine agonist or apomorphine if not already part of the regimen. Switching to sustained-release levodopa has been tried in the past but recent evidence suggest this method does not reduce off-time any greater than immediate- release levodopa.
Sinemet
End of dose deterioration or “wearing off”
Loss of levodopa effect near the end of the dosing interval. Patient senses gradual waning of efficacy. Relates directly to levels of plasma levodopa. Effectiveness begins to diminish; ultimately, useful mobility may end within 1 hour of a single dose. Levodopa/carbidopa half-life of 1.5 hours contributes to fluctuating drug levels. More predictable than “on-off” effect. Improved by shortening dosing interval, a dopamine agonist, MAO-B inhibitor, COMT inhibitor or apomorphine. Primary options should include addition of dopamine agonists or increasing the frequency of levodopa administration.
sinemet
Delayed onset of response
Due to delayed gastric emptying, co-administration of levodopa with food or administration of too small a levodopa dose. Improved by taking levodopa on an empty stomach, reduction in dietary protein intake, if on CR product add an addition morning standard release carbidopa/levodopa dose, add dopamine agonist
Sinemet
Drug resistant “off” periods
Usually related to delayed GI emptying of increased absorption in upper GI tract. Improved by increasing dose and/or frequency, give on empty stomach, add dopamine agonists, or apomorphine.
Sinemet
Dopaminergic adverse effects
list
dyskinesias
Hallucinations
Hedonistic homeostatic dysregulation
Sinemet
Dopaminergic adverse effects
dyskinesias
Dyskinesias: develop in nearly all patients with PD as the duration of the disease progresses and levodopa therapy is used. Due to excessive dopamine and represents increasing difficulty to balance maximum response with adverse effects with long term therapy. Dyskinesias manifest as involuntary, choreiform-type movements. They may be present in large extremities, fine muscle groups such as orofacial twitching or grimacing. Careful reduction of levodopa dosage into smaller, more frequent doses is the primary strategy to treat dyskinesias. Substitution of part of the levodopa dose with a dopamine agonist may help. Initiating therapy early in the disease with a dopamine agonist has been found to have less risk for the development of dyskinesias due to its ability to provide a more continuous stimulation of dopamine receptors. The addition of amantadine or possibly a COMT inhibitor to the regimen may lessen dyskinesias.
sinemet
Dopaminergic adverse effects
hallucinations
Hallucinations: usually visual in nature and often revolve around animals, insects, or people. No treatment is necessary if the hallucinations are mild although it my eventually progress and become distressing to the patient. A stepwise dose reduction of dopaminergics can be attempted carefully but may aggravate immobility and cause more harm than managing the psychosis with drugs. Clozapine and quetiapine are the preferred atypical antipsychotic agents to use since the other agents have been shown to exacerbate parkinsonism.
Sinemet
Dopaminergic adverse effects
Hedonistic Homeostatic Dysregulation
Hedonistic Homeostatic Dysregulation: Several case series recently has raised public attention to pathological gambling induced by dopamine agonist therapy. Younger, male patients with early-onset PD characterize the core features of the syndrome. They take increasing quantities of their dopaminergic replacement therapy despite worsening dyskinesias. In the process they develop cyclical mood disorders with hypomania or manic psychosis. Other features include carrying out repetitive purposeless motor acts, hypersexuality, having the urge to walk great distances during “on” times with not purpose or destination, pathological gambling and shopping, alteration in appetite, drug hoarding, and social independence or isolation.
Sinemet
Drug/food interactions
drugs
Drugs that possess dopamine antagonist activity (phenothiazines, metoclopramide)
Ferrous sulfate: forms chelation complex with levodopa & carbidopa in Gl tract. Can decrease levodopa absorption by 25-50% and carbidopa 75%. Avoid concomitant administration.
Anticholinergics may alter GI absorption of levodopa by delaying gastric emptying. The drug solubilizes completely with the long gastric housing then dumps into the duodenum where very rapid absorption occurs. The result is delayed ON response with possible increase in dyskinesias once absorption occurs.
Sinemet
Drug/food interactions
food
Protein containing foods decrease absorption – advise patients to take Immediate release levodopa 30 minutes before or 60 minutes after meals due to competition for absorption – take controlled release levodopa with food to slow movement through GI system and improve bioavailability
Sinemet
contraindications
History of melanoma (dopamine is a melanin intermediate)
Concomitant non-specific MAOI (cheese effect – hypertension, vomiting, tachycardia, and headache due to build up of levodopa metabolites such as norepinephrine)
Direct DA agonists
advantages
Dopamine agonists do not depend on functioning presynaptic neurons for their pharmacological activity. Act directly on the dopamine receptors.
Used as initial treatment for patients age < 65; or as adjunctive therapy with carbidopa/levodopa in patients with response fluctuations (i.e., “on-off” phenomenon, “wearing off” effect). – Recent studies have found that with dopamine agonists are used as initial therapy in levodopa-naïve patients, symptoms can be successfully controlled and delay the need for levodopa therapy for as much as 4- 5 years in up to 80% of patients.
Does not generate oxidative metabolites like levodopa
Possible neuroprotective properties (free radical scavenger)
Less motor complications than seen with levodopa/carbidopa – Patients who are started initially on dopamine agonist therapy and eventually supplemented with levodopa therapy when needed were 2-3 times less likely to develop dyskinesias and motor fluctuations in the first 4-5 year of therapy than those patients receiving levodopa alone as initial therapy
Ergoline and Non-ergoline Dopamine Agonists
Direct DA agonists
disadvantages
Will eventually need levodopa as the disease progresses
Side effects
Does not completely prevent development of levodopa-related motor complications
Does not stop disease progression?
Ergot dopamine agonists
list
Bromocriptine
Pergolide – no longer on the market
Bromocriptine
MOA
Stimulates D2 and antagonizes D1 (partial & serotonin agonist)
Bromocriptine
SE
Common/rare
common: nausea/vomiting, dyskinesias, hallucinations, confusion, headache, orthostatic
hypotension (take first dose Iying down), fatigue
rare: Raynaud’s phenomenon, refractory edema in lower limbs, pleuropulmonary and retroperitoneal fibrosis (2-5% incidence after 5 years), paresthesias, skin inflammation
Bromocriptine
contraindications
Hx of psychosis
Severe angina
Recent MI
PUD
Bromocriptine
DDI
drugs that inhibit CYP3A4 (e.g., erythromycin) increase plasma bromocriptine levels several fold
Ropinorole
MOA
Stimulates D-2 & D-3 receptor sites
Ropinirole
Vs
bromocriptine
More effective than bromocriptine at reducing motor symptoms of IPD. Efficacious as monotherapy.
Reduces “Off” time associated with “Wearing-Off phenomenon”
May reduce levodopa requirements
Ropinirole
SE/DDI
Side effects: dyskinesias, nausea, dizziness, sedation, somnolence (sleep attacks), headache, confusion, hallucinations
Drug interactions: ciprofloxacin and estrogen therapy (inhibitors of CYP1A2) reduce clearance while smoking (inducer of CYP1A2) increases clearance.
Pramipexole
MOA
Stimulates D-2 & D-3 receptor sites
Pramipexole
Vs
bromocriptine
More effective than bromocriptine at reducing motor symptoms of IPD. Efficacious as monotherapy.
Reduces “Off” time associated with “Wearing-Off phenomenon”
May reduce levodopa requirements
Pramipexole
SE/DDI
Side Effects: dyskinesias, nausea, dizziness, sedation, somnolence (sleep attacks), headache, confusion, hallucinations, and peripheral edema which poorly responds diuretics
Drug interactions: cimetidine increases pramipexole levels by 50%.
Rotigotine
MOA
Non-ergot dopamine agonist formulated as a transdermal patch designed for once-daily applications which may provide more continuous stimulation of dopamine receptors.
Available in 3 strengths: 2mg/24 hrs (4.5 mg rotigotine content per system), 4 mg/24 hours (9 mg rotigotine content per system) and 6mg/23 hours (13.5 mg rotigotine content per system)
Rotigotine
SE
Adverse effects similar to other dopamine agonists (nausea, somnolence, dizziness) along with application site reactions (mild skin irritation, erythema, and rash)
Apomorphine
MOA
Stimulated D1 & D2 receptor sites
Apomorphine
Indicated for…
Can reliably trigger an “on” response within 4-8 minutes of injection with response lasting ~ 1 Hour
Indicated for acute, intermittent treatment of hypomobility “off” episode associated with “wearing off” and “on-off” episodes, or as an adjunct/supplemental therapy to standard levodopa therapy – typically in advanced disease
Apomorphine
SE/contraindications
Side Effects: dyskinesias, drowsiness, dizziness, postural hypotension, hallucinations, nausea/vomiting (may need antiemetic), skin nodules at injection site
Contains a metabisulfite preservative so contraindicated in sulfite allergies
COMT inhibitors
MOA
Inhibits peripheral and central catechol-O-methyltransferase (COMT)- Tolcapone
Entacapone inhibits peripheral catechol-O-methyltransferase (COMT) – no central inhibition because it does not cross BBB.
Increases levodopa bioavailability and plasma half-life.
Reduces “Off” time associated with “Wearing-Off phenomenon”
Reduces levodopa requirements, levodopa dose should be decreased ~30% upon initiating COMT inhibitor
COMT inhibitors
list
Tolcapone
Entacapone
Tolcapaone
SE
non-dopaminergic: diarrhea (delayed onset of several weeks to months); urine discoloration, liver transaminases (requires monitoring at baseline, q2 weeks x 1 year then every month x 6 months then every 8 weeks)
dopaminergic: dyskinesias, dystonia, nausea, cramps
Entacapone
SE
non-dopaminergic: diarrhea (delayed onset of several weeks to months); urine discoloration, currently no reports of liver transaminase abnormalities and thus does not require monitoring
dopaminergic: dyskinesias, dystonia, nausea, cramps
Entacapone
dosing
200mg with each levodopa dose (does not matter if CR or regular Sinemet). In some cases, may not need to give with every dose of Sinemet (max 8 tabs/day)
Stalevo
What is it?
Levodopa/Carbidopa/Entacapone
Stalevo
indications
1) To substitute (with equivalent strength of each of the three components) for immediate release carbidopa/levodopa and entacapone previously administered as individual products.
2) To replace immediate release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose “wearing-off” (only for patients taking a total daily dose of levodopa of 600mg or less and not experiencing dyskinesias)
MAO-B inhibitors
Disease modifying effect?
These drugs have been studied for a possible “disease modifying effect” however their effects in this regard has yet to be proven definitively
MAO-B inhibitors used in PD
Selegiline
Rasagiline
Selegiline
MOI/problem
Prevents degradation of dopamine in the brain through MAO-B inhibition. Selegiline metabolites (hepatic metabolism) L-amphetamine and L-methamphetamine are thought to inhibit presynaptic reuptake of dopamine.
Usefulness is confounded by low bioavailability, extensive 1st pass metabolism and production of amphetamine metabolites
Selegiline
Indication
Adjunctive therapy with carbidopa/levodopa, effective in the treatment of “wearing off’ effect.
Less effective in “on-off’ phenomenon; monotherapy for early PD (neuroprotective?).
When initiating selegiline, reduce levodopa dose by 10-30%.
Selegiline
DDI
SSRI (particularly fluoxetine), tricyclic antidepressants, lithium, and high dose dextromethorphan should be used with caution due to possibility of serotonin syndrome (confusion, agitation, restlessness, rigidity, hyperreflexia, shivering, fever, myoclonus, diaphoresis, nausea, diarrhea, autonomic instability, flushing, coma and occasionally death). Overall risk is low and occurrence is rare.
Meperidine use is contraindicated due to possibility of serotonin syndrome. Again the risk is low.
Selegiline
SE
insomnia, dizziness, nausea/vomiting, orthostatic hypotension, hallucinations
Selegiline ODT
chars
Formulate delivery system that allows tablets to dissolve within seconds
Quick dissolution and absorption via the oral mucosa allows significant bypassing of 1st pass metabolism and allows for enhancement of low-dose therapeutic effect and decreased risk of side effects
Decreases “off” time by 2 Hours
Concentration of amphetamine metabolites are 80-90% less than selegiline
Peak plasma concentrations are more than twice as high & less variable with this dosing formulation
Indicated as adjunctive therapy in patients who exhibit deterioration of response to levodopa/carbidopa therapy
Selegiline ODT
SE
nausea, dizziness, pain, headache, insomnia, rhinitis, dyskinesias
Rasagiline
MOA
Selective, irreversible MAO-B inhibitor
Rasagiline
Clinical use
Rasagiline can be used both on its own in early Parkinson’s disease, and as an adjunct to levodopa treatment in later stages of the disorder, where it is beneficial against end-of-dose fluctuations in motor function.
Rasagiline vs Selegiline
Rasagiline does not have the toxic amphetamine metabolic breakdown products of the structurally similar selegiline
Greater potency in MAO_B inhibition than selegiline
Rasagiline
SE
Weight loss, vomiting, anorexia, balance difficulties, orthostatic hypotension, depression, dizziness, hallucinations, sleep disorders, dyskinesias, peripheral edema
