Parkinson's+Disease

• Degenerative disorder of the basal ganglia that results in variable combinations of TREMOR, RIGIDITY, & BRADYKINESIA • Characterized by a progressive destruction of the nigrostriatal pathway à reduced concentration of dopamine (DA) • Onset usually after 50 yrs (most pts dx’d in 60s and 70s) • Clinical syndrome known as //Parkinsonism// • Cause unknown, several theories – Auto-oxidation of catecholamines during melanin synthesis – Genetics (w/ early-onset) • Clinical Features: – TREMOR • Most evident • “Pill-rolling” action • Initially unilateral, progresses to bilateral (usually) • Disappears w/ movement and sleep • Least disabling manifestation – RIGIDITY • Jerky, ratchet-like movements that require a lot of energy •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Flexion contractions may develop •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Initially unilateral, progresses to bilateral (usually) –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> BRADYKINESIA (slowness of movement) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> The most disabling symptom •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Small shuffling steps w/o swinging arms •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Loss of postural reflexes à falls (often backward) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Emotional and voluntary facial movements become limited à stiff, mask-like expression •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Stiffening of tongue, palate, and throat à difficulty swallowing à drooling •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Slow monotonous speech –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Falls –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Fluctuations in motor function –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Neuropsychiatric disorders –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Limitation of ANS function (present late in dz) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Excessive sweating, salivation, and sebaceous gland secretion •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Impaired lacrimation •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Dysphagia •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Orthostatic hypotension •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Impaired thermal regulation •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Constipation •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Impotence •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Urinary incontinence –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Sleep problems –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Dementia (20% of PD pts; r/t ACh degeneration) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Treatment –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Non-pharm •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Group support •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Education •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Daily exercise •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Adequate nutrition –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Pharmacological •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> __Goal__: increase the functional abilitiy of the underactive DAergic system __or__ to reduce the excessive influence of excitatory cholinergic neurons •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Increase DA levels •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Levodopa (discussed in greater detail later) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Carbidopa •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Augment the release of DA •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Amantadine (discussed in greater detail later) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Function as DA agonists or directly stimulate DA receptors •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Bromocriptine •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Pergolide •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Pramipexole •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Ropinirole •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Inhibits the metabolic breakdown of DA •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Selegiline •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Anticholinergics given to treat overactive cholinergic sites and restore balance between reduced DA and uninhibited cholinergic neurons •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Treats extrapyramidal effects (involuntary movements, muscle rigidity, & immobility w/o paralysis) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> More useful in alleviating tremor and rigidity than bradykinesia –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Surgical interventions •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Thalamotomy or Pallidectomy •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Destruction of part of the thalamus or globus pallidum in the basal ganglia via electrical stimulation or supercooled tip of a metal probe (cryothalamotomy) •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Restricted to those pts who do not respond well to drug tx •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Deep brain stimulation •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Implants electrodes into the areas of the brain responsible for tremors or motor dysfunction •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Reversible •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Limited ability to cause brain damage
 * Parkinson Disease**

•<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Action –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Increase the levels of dopamine in the substantia nigra –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Directly stimulate the dopamine receptors in that area –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Help to restore the balance between the inhibitory and stimulating neurons •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Indications –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Relief of the signs and symptoms of idiopathic Parkinson’s disease •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Contraindication –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Known allergy –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Angle closure glaucoma –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> GI obstruction •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Cautions –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> CV disease –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Bronchial asthma –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> H/O peptic ulcer –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Urinary tract obstruction –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Psychiatric disorders •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Adverse reactions –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Anxiety –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Nervousness –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Headache –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Blurred vision –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Arrhythmias •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Drug-to-drug interactions –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> MAOIs –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Vitamin B6
 * Dopaminergics**

•<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Mainstay of treatment for parkinsonism •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Precursor of DA that crosses the blood–brain barrier, where it is converted to DA •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Almost always given in combination form with carbidopa as a fixed-combination drug (//Sinemet)// –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Carbidopa decreases the amount of levodopa needed to reach a therapeutic level in the brain –<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> The dosage of levodopa can be decreased, reducing adverse side effects
 * Levodopa (P) dopaminergics**

•<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Dopaminergic •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> An antiviral drug that also increases the release of DA. •<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> Effective as long as there is a possibility of more DA release
 * Amantidine (Symmetrel)**