Download Movement Medications

Pharmacology: Pharmacotherapies for Movement Disorders (Bannon)
PARKINSON’S DISEASE:
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General:
Movement disorder
Age is a prominent risk factor (5-10% of people over the age of 85)
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Clinical Features:
Bradykinesia (slowness of movement and difficulty initiating movement)
Muscular (cogwheel) rigidity
Resting tremor (pill-rolling)
Impairment of postural stability
o Festination (falling forward)
o Retropulsion (falling backward)
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Clinical Presentation:
Early: presentation may be subtle
o Unilateral weakness or fatigue
o Weak voice
o Micrographia (really small writing)
o Olfactory losses
Comorbidities: depression and dementia are common
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Clinical Course:
Mean Duration (Diagnosis to Death): 15 years
o Postural Instability: contributes to falls, immobility, constipation, dependency and depression
o Death: due to general wasting and complications of immobility (pneumonia)
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Pathophysiology:
Basics: primarily a loss of midbrain DA-producing neurons (particularly nigrostriatal DA neurons)
o Presence of Lewy bodies (inclusions with radiating fibrils)
o Many other cell types in other brain regions are impacted in PD (but to a lesser extent)
o PNS affected as well
DA Pathways:
o Nigrostriatal DA: modulates learning and execution of complex purposeful motor patterns and learned
habits; 80% of total DA and particular affected by PD
o Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward
o Mesocortical DA: modulates cognition
o Hypothalamic DA: hormone regulation
o Area Postrema: DA receptors outside the BBB that mediate emesis
Effects of Loss of DA:
o DA modulates EXCITATORY information from the cortex and basal ganglia sends information back to
the cortex via excitation from the thalamus
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Direct pathway ENABLES movement
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Indirect pathway INHIBITS movement
o Loss of 70-80% if nigrostriatal DA results in PD
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Inhibition of the direct pathway (loss of D1 stimulation)
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Activation of the indirect pathway (release of D2 inhibition)
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Overall result of the above two effects is INHIBITION OF MOVEMENT
o Net Result= decreased excitation of the cortex and decreased drive to move
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Causes:
Majority of Cases: idiopathic (we do not know the cause)
Other Causes:
o Environmental Toxins:
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MPTP (destroys DA terminals)
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Epidemiology (ie. people who drink well water have an increased risk of PD)
o Infection: post-encephalitic
o Oxidative Stress: ongoing generation of ROS may make DA cells more susceptible to damage
o Mitochondrial Defects/Damage: have been implicated
o Genetic Forms: rare but some do exist
PHARMACOTHERAPIES FOR PARKINSON’S DISEASE:
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Levodopa (L-dopa):
MOA: dopa is the precursor of DA (replenish DA)
Pharmacokinetics:
o Absorption: via aromatic amino acid uptake systems (affected by food)
o Metabolism: largely decarboxylated in the periphery; less than 1% reaches the brain
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Solution to this problem: almost exclusively given with carbidopa, an amino acid
decarboxylase inhibitor, to all more to reach the brain
Efficacy:
o Early On: very effective, although more so for bradykinesia than for tremor
o Over Time: reduced efficacy (wearing off effect after 2-5 years)
Adverse Effects:
o Major Issues:
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On-off phenomenon (follows reduced efficacy)
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Dyskinesias (in up to 80% of patients after 5-8 years of treatment)
 Related to dopa-PD (drug-disease) interaction
o Other Effects:
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Early: anorexia, nausea, hypotesion
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Chronic: hallucinations, delusions, agitations, insomnia, pathologic gambling and
hypersexuality
Formulations:
o Sinemet/Atamet: levodopa + carbidopa combination (needs to be dosed 3-6 times per day)
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Sinemet CR (sustained release formulation) now available, but shows erratic absorption
o Parcopa: immediate-release levodopa/carbidopa that can be taken w/o water (manage acute events)
o Lodosyn: carbidopa alone that can be added to regimen if needed (not often)
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Direct Acting DA Receptor Agonists:
Ergots: first used DA receptor agonists
o Bromocriptine: not typically used for PD anymore (SE profile)
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Current Use: rescue from neuroleptic malignant syndrome (due to APDs)
o Pergolide: not FDA approved for PD anymore due to incidence of cardiac valve regurgitation
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Current Use: low doses for hyperprolactinemia
Non-Ergot:
o Currently Used Agents:
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Pramipexole: D3>D2
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Ropinirole: D2
o Efficacy: probably less effective than dopa, but less side effects make them first line monotherapy
o Current Use:
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PD: first used as an adjunct, now first line monotherapy
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Other: Restless Legs Syndrome
o Side Effects:
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Nausea
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Edema
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Hypotension
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Pathologic gambling and other compulsions
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Somnolence (drowsiness)
o Treatment of Side Effects:
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Daytime Sleepiness (Sleep Attacks): modafinil (CNS stimulation)
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Peripheral DA Effects: trimethobenzamide (anti-emetic) or domperidone (antidopaminergic)
Apomorphine:
o Administration: injectable (subQ)
o MOA: dopamine agonist with some preference for D2 receptors
o Use: FDA-approved for “off” episodes
o Side Effects: similar to above, plus yawning and hypersexuality
o Treatment of Side Effects:
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Emesis/Nausea: trimethobenzamide (anti-emetic)
 Ondansetron: contraindicated because combination with apomorphine results in
severe hypotension
Rotigone: once daily transdermal patch (similar efficacy and adverse effects, but more convenient)
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Monoamine Oxidase-B Inhibitors:
Selegiline:
o MOA: irreversible inhibitor of MAO-B, resulting in inhibition of DA metabolism
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Less peripheral MAO inhibition
 Can be used in combination with dopa
 Less interaction with tyramine-rich foods than MAO-A inhibitors
o Efficacy: modest benefits as initial monotherapy OR dopa co-therapy
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Possible Mechanisms of Benefit:
 Increased DA
 Metabolism to amphetamine (chemically similar to methamphetamine)
 Antidepressant effects
 Previously believed it may have neuroprotective qualities (untrue)
Rasagiline: newer
o MOA: same as above
o Efficacy: clearly effective for the treatment of early PD or as an adjunct in advanced PD
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May have neuroprotective qualities (still an open question)
o Adverse Effects:
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Nausea
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Orthostatic hypotension
Catechol-O-Methyltransferase (COMT) Inhbitors:
Entacapone:
o MOA: given with L-dopa to increase its levels by blunting metabolism in periphery and the brain
o Use: used as an ADJUNCT to Sinemet (levodopa + carbidopa) to reduce fluctuations and “off” time
o Side Effects:
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May increase risk of dyskinesia (due to the fact that it increases the action of L-dopa)
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Does NOT cause hepatotoxicity like earlier COMT inhibitors (Tolcapone)
Antivirals:
Amantadine:
o MOA: relevant MOA to the treatment of PD may be its action as an NMDA antagonist
o Efficacy: modest transient benefits (may only last a few weeks); better for tremor
o Side Effects:
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Livedo reticularis (skin condition causing lace-like purple discoloration of the lower
extremeties)
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Psychosis (rare, at high doses)
Antimuscarinics:
Currently Used:
o Benztropine
o Trihexyphenidyl
o Procyclidine
o Biperiden
MOA: offsets neurochemical imbalance in striatum created by loss of DA (ie. decreases action of ACh)
Use: LOW DOSES useful for the following conditions (it is NOT useful for bradykinesia)
o Early onset tremor
o Rigidity
o Drooling
Side Effects: prominent side effects may contraindicate its use in many patients
o CNS Effects: impaired memory, drowsiness, confusion, delusions
o PNS Effects: dry mouth, blurred vision, urinary retention, tachycardia
Treatment of Comorbidities:
Depression: SSRIs preferred
Psychosis: clozapine or other atypical antipsychotics (less risk for inducing parkinsonism)
Demetia: cholinesterase inhibitors that are used in AD/dementia
Other Therapies:
o Physical therapy and physical/mental exercise recommended
Surgical Interventions:
DA Cell Replacement: DA from adrenals, carotid bodies, fetal cells from human, transgenic pigs or stem cells
Ablations: not done anymore (irreversible and non-adjustable; replaced by deep brain stimulation)
o Helped with tremor, bradykinesia and medication response
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Deep Brain Stimulation: safer, reversible and adjustable
o Efficacy: more effective than ablations and with fewer complications (can be used bilaterally)
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Subthalamic nucleus (improves most Sx) > Globus pallidus > Thalamus
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>70% of patients improve (more “on” time per day, decreased meds)
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However, little/no improvement in instability AND may actually cause a slight decrease in
cognition
o Use:
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Patients refractory to medication treatment
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Patients with significant dyskinesia
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Patients with significant clinical fluctuation on dopa
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NEED TO HAVE INTACT COGNITION
o Adverse Effects: less of these effects at 6 months post-surgery than 3 months (decrease with time)
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May cause a decrease in cognition
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Serious effects in ~40% of patients (hemorrhage, surgical site infection)
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Increased depression and suicide (possibly unmasked due to decreased dose of DA drugs)
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Increased impulsivity (may underlie increase in compulsive gambling and falling)
Neurorestoration:
o Infusion of Trophic Factor GDNF into Putamen: had early promise but no efficacy overall
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Unexpected adverse effects:
 Surgical complications
 Ataxia
 GDNF Abs
o Local Injections of AAV-GAD: initial findings promising but double-blind results less stellar
o Local Injections of Transgenes: specificity conferred through receptor-mediated uptake (currently in
trials)
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Current Management of PD Patients:
All current treatments are for SYMPTOMATIC relief only
Long-term goal is neuroprotection, or at least, neurorestoration
Basics:
o Delay treatment until necessary (try lifestyle adaptations first)
o Consider a trial of antimuscarinic agent/MAO-B inhibitor/Amantadine ALONE to start
o When it becomes necessary, initiate DA therapy with newer direct acting DA agonist (NOT L-dopa)
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Pramipexole or Ropinirole
o If necessary, add low-dose Sinemet (levodopa-carbidopa) to the direct acting DA agonist
o Adjust Sinemet dosing as necessary
Other Additions:
o For long-term complications of L-dopa, add a COMT inhibitor (thought to prolong/stabilize L-dopa
effects, therefore reducing “on/off” phenomena)
o SubQ apomorphine for rescue during “off” periods
o Addition of anticholinergics to treat tremor or drooling
o Consider DBS in patients with treatment failure and intact cognition
ESSENTIAL TREMOR:
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Basics: most common neurological disorder among adults (0.4-4% prevalence)
Impact is on quality of life NOT life span, and therefore is mistaken as a benign disorder
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Clinical Features:
Hallmark Feature: action/kinetic tremor in both upper limbs; less commonly in head, tongue and lower limbs
o Often a crescendo tremor (resembling cerebellar intention tremor)
o Aggravated by emotions, hunger, fatigue and temperature extremes
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Pathophysiology: uncertain
Possibility: abnormal oscillations within thalamocortical and olivocerebellar loops
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Causes:
Autosomal dominant pattern of inheritance: gene defects unknown but chromosomal loci identified
o Variable penetrance (~50% of cases), but 5-10x increased risk if you have an affected 1st degree relative
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Treatments: over 50% respond to drug therapy
Beta Blockers: propanolol or others
Anti-Seizure Drugs: low doses of primadone or topiramate
Refractory Patients: ventralis intermedius thalamotomy or DBS (completely effective in >80% of tx resistant
patients; DBS preferred)