Pharmacotherapy of parkinson's agents 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.
