Parkinsons Dz

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pd

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slowly progressive degenerative neurological dz
shaky palsy

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pd characterized by

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tremor
rigidity
bradykinesia
postural instability
distinctive mortor disability

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bradykinesia

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sluggish neuromuscular responsiveness

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pd pathogenesis

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neurodegenerative dz assoc
depigmentation of substantia nigra and loss of dopaminergic input tp the basal gangia (extrapyrimidal sys)

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basal ganglia

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resp for initiating, sequencing and modulating motor activity

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dopamine

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produced by neurons that project from substantia nigra to neostriatum and globus pallidus

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neostriatum

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include caudate and putamen

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dopamine acts

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inhibitory neurotransmitter

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lewy bodies

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occur in basal ganglia, braun stem, spinal cord and sympathetic ganglia

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loss of dopamine-producing neurons in substantia nigra

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imbalance between dopamine and acetylcholine

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acetylcholine

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excitatiry neurotransmitter

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neurotransmitters involve in pathophysiology of pd

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norepi
serotonin
gaba

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primary (idiopathic) pd

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classic od or paralysis agitans

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hypotheses of neuronal loss in primary pd

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absorption of highly potent neurotoxins

exposure to the free radicals

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highly potent neurotoxins

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carbon monoxide
manganese
solvents
n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

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MPTP

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product of improper synthesis of a synthetic heroin-like compd

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MAO

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dopamine is catabolized by

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products of catabolism

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hydrogen peroxide
prodxn of free radicals

both toxic to cells

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protects cells from damage

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enzymes
free radical scavengers

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free radical scavengers

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vit e and c

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destruction of free radicals

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caused by either a dec in protective mechanisms or inc in prodxn of dopamine

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secondary parkinsonism

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caused by drugs incl dopamine antagonist

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dopamine antagonist

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phenothiazines (chlorpromazine , perphenazine)
butyrophenone (haldol)
reserpine

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poisoning by chemicals or toxins

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carbon monoxide poisoning
heavy metal poisoning -manganese and mercury
MPTP

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infectious causes

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encephalitis -viral
syphilis

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other causes

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arteriosclerosis
degenerative dz of cns -prog supranuclear palsy
metabolis disorder - wilsons dz

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pd s/s

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tremor
limb rigidity
akinesia or bradykinesia
gait and postural difficulties
changes in menta status
unified parkinsons dz rating scale (updrs)

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pill rolling tremor

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thumb and forefinger involve

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akinesia

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difficulty in initiating movements

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bradykinesia

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slowness in performing common voluntary movements

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precursor of dopamine

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carb/lev

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direct acting dopamine agonist

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bromocriptine
pergolide

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indirect acting dopamine agonist

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amantadine - dec uptake
selegiline - dec metabolism

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drug therapy for treating assc symptoms

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tricyclic antidepressants
b blkers
antihistamines

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tricyclic antidepressants

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depression

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b blocker

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propranolol - high lipophilicity
benzodiazepines
primidone - action tremor

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antihistamines

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diphenhydramine- mild tremor

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dyskinesia/ dystonia

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oral facial movmts, grimacing or jerky and writhing movmt of trunk and extremities

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3 types of dyskinesia

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peak dose
biphasic
off period

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peak dose dyskinesia trmt

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sustain release prep
dec l dopa dose
add comt inhibitor
add amantadine
perform surgery

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biphasic dyskinesia trmt

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sustain release prep
dec l dopa
inc dopaminergic dise
symptoms present- comt inhibitor
amantadine

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off perior dystonia trmt

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dec l dopa dose
inc dopaminergic dose

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drug holiday

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long term levodopa use results in downregulation of dopamine receptors

allows striatal nigra dopamine rec to be resensitized

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2ndary eff of pd incl

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cardiovascular eff
gi eff
genitourinary eff
cns eff

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cardiovascular eff

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orthostatic hypotension
arrhy

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gi eff

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constipation
hypersalivation

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genitourinary eff

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inc urinary frequency
impotence

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cns eff

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hallucinations
depression
psychosis

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pd late disabilities

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levodopa related disabilities
non-levodopa rel disabilities

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levodopa related disabilities

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motor fluctuation
dyskinesia
neuropsychiatric toxicity
reduced response

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non lec related disabilities

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cognitive impairement
instability - falls
gait disturbance, dysphagia speech disturbance

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management therapies

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motor fluctuation

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oxybutynin

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urinary urgency

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apomorphine

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urinary retention

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constipation

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fiber
peg

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tenesmus

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clonazepam
apomorphine

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hypersalivation

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antihistamine
anticholinergic

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dysphagia

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liquid levodopa

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sweating crises

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b blkers
anticholinergic agts

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daytime sleepiness

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selegiline

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nightmares

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amitriptyline
clonazepam

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panic attacks and depression

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liq levodopa
amitriptyline

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orthostatic hypotension

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domperidone
desmopressin

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dysphonia

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reduce levodopa dosage
speech therapy

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pain

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amitriptyline
fluvoxamine

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anticholinergic agents

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used for mild smptoms predominantly tremors

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anticholinergic moa

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blocks the excitatory neurotranmitter cholinergic influence in the basal ganglia

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anticholinergic interaxn

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antihistamines
antidepressants
phenothiazines
inc dig levels
haloperidol -schizo inc rxn

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levodopa/carbidopa

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most effective drug for managing pd

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levodopa

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converted to dopamine by enzyme dopa decarboxylase

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dopa decarboxylase

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elevates cns levels of dopamine

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levodopa sustain release

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designed to release the drug over 4-6 hrs thereby inhibiting variation in plasma conc and dec motor fluctutation "off" time or to omprove overall dose response in pt with adv dz

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lev/carb interaxn

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antacids
hydantoin
methionine
metoclopramide
false + in coombs test
inc uric acid test
mao inhib
furazolidine
tricyclic antid
food- protein restricted diet

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direct acting dopamine agonist - ergot deriv

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bromocriptine
pergolide

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direct acting dopamine agonist - non ergolines

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pramipexole
ropinirole

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direct acting dopamine agonist

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reduce motor fluctuations
not metabolized by oxidative pathway
do not produce free radical metabolites
direct antioxidative eff

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bromocriptine moa

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resp for directly stimulating postsynaptic dopamine rec
adjunct to lev therapy

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bromocriptine adv eff

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1st dose phenomenon
cardiac dysrhythmias

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bromocriptine interaxn

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antihypertensive drugs
doparmine antagonist

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pergolide moa

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semisynthetic ergosine deriv
directly stimulating postsynaptic dopamine rec in the nigrostriatal system

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pergolide 1000x more potent than

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bromocriptine

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pergolide inhibits

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secretion of prolactin

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pergolide use

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adjunctive trmt to lev/carb

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pergolide adv eff

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vent arrhy
card dysrhy
cns eff
gi eff
transient elevationsof aspartate aminotransferase
alanine aminotransferase
alkaline phosphate
pleural thickening

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pergolide interaxn

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caution with highly protein bound drug
antipsychotic agts (phenothiazines, haldol, metoclopramide)

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indirect acting dopamine agonists

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selegiline
amantadine

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lack of mao in intestinal tract

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causes absorption of tyramines => hypertensive crisis

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mao a

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predominantly found in intestinal tract

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mao b

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brain

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selegiline moa

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selective inhibitor of mao b

prevents breakdown of dopamine selectively in the brain

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selegiline use

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adjunct with lev/carb when pt experience wearing off phenomenon

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selegiline adv eff

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hypertensive crisis
tyramine containing foods

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tyramine containing foods

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aged cheese
beer
wine smoke meat

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selegeline interaxn

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meperidine
fluoxetine - 5 wks must elapse then dc fluoxetine and start selegiline otherwise death

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amantadine axn

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antiviral agent

inc dopamine levels at postsynaptic rec sites by dec presynaptic reuptake and enhancing dopamine synthesis and release

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amantadine adv eff

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dermatological eff - livedo reticularis- diffuse rose-color mottling of the skin

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amantadine interaxn

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anticholinergic drugs
hctz + triamterene

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non ergot dopamine agonist

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indicated for both early and advanced stages of pd

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pramipexole
ropinirole moa

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bind to dopamine rec and activate the d2 rec but have little or no affinity to d1 rec

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non ergot dopamine agonist
adv eff

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pleuropulmonary fibrosis
retoroperitoneal fibrosis
coronary vasocontriction
erythromelalgia
raynauds phenomenon

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ropinirole

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metabolized by the liver cyp1a2 and 1st pass eff

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COMT inhibitors

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tolcapone
entacapone

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tolcapone moa

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selective and reversible inhibitor of comt and used as adjunct to lev/carb therapy
inhibits both centrally and peripherally

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comt

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main enzyme resp fpr peripheral anc central metabolism of catecholamines incl levodopa

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addition of comt

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results in the doubling of the elimination t 1/2 of levodopa and inc oral bioavailability of lev

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rapid withrdrawal or abrupt reduction of comt dose

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hyperpyrexia
confusion symptoms

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comt adv eff

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liver toxicity
monitor AST AND ALT

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2 enzymes involve in the metabolism of catecholamines

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MAO
COMT

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Tolcapone + non selective MAO =

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inhibition of the pathway resp for normal catecholamine metabolism

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drugs metabolized by comt system

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methyldopa
dobutamine
apomorphine

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CYP2C9

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Tolcapone has an affinity with

similar to warfarin

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entacapone moa

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selective and reversible inhibitor of comt and permits additional lev to reach the brain

does not have any anti-parkinson eff of its own

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entacapone

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acts only peripherally by inhibiting comt

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entacapone

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improves the duration of "on" time and dec the duration of "off" time

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biliary excretion

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entacapone

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drugs known to interfere with biliary excretion

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probenecid
erythromycin
ampicillin

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entacapone side eff

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dyskinesia
brownish orange urine

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entacapone interaxn

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drugs that interact with cyp450

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globus pallidus internys pallidotomy

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a pallidotomy entails the surgical resection of parts of the globus pallidus

improves contralateral dyskinesia

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deep brain stimulation

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high frequency stimulation that induces functional inhibition of target regions of the brain by implnating an electrode into a target site and connecting the lead to a suncutaneously placed pacemaker

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adv of deep brain stimulation

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no desctructive lesion is formed

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fetal nigral transplantation

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implantation of embryonic dopaminergic cells into the denervated striatum to replace degenerated neuronal cells

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adv of fetal nigral transplantation

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implanted cells all survive and innervation of the striatum is accomplished in an organotypic manner
does not necessitate making a destructive lesion