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Pharmacologic Management of Parkinsonism & Other Movement Disorders…
Pharmacologic Management of Parkinsonism & Other Movement Disorders
DRUG-INDUCED PARKINSONISM
individuals attempted to synth & use a narcotic drug related to meperidine but actually synth MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)--> substantia nigra cell death--> striatal dopamine depletion
; --> spontaneously occurring Parkinson’s disease may result from exposure to an environmental toxin similarly selective in its target
antipsychotic drugs like chlorpromazine and trifluoperazine (bc of this a beperiden given)
OTHER MOVEMENT DISORDERS
Tremor
Physiologic
tremor:
normal
,
enhanced by anxiety, fatigue
, thyrotoxicosis, and IV
epinephrine
or isoproterenol (
b agonist
)
Essential
tremor: postural; dysfunction of
β1 Rs
implicated in some instances (may respond dramatically to standard doses of
metoprolol
as well as to
propranolol
): exactly opposite of jozve!;
propranolol (many CIs, ex cardiovasc)-->Primidone-->Clozapine-->gabapentin-->BDZ
Intention
tremor: present during movement but not at rest; sometimes as a
toxic manifestation of alcohol or drugs
;
Withdrawal
or reduction in dosage-->
dramatic relief
Rest
tremor: u due to
parkinsonism
Huntington’s Disease: dementia, severe motor dysfunction; seems as if cholinergic system weakened
Other Forms of Chorea
Ballismus
Athetosis & Dystonia
Tics
Chronic multiple tics (Gilles de la Tourette syndrome): Haloperidol (DA R antagonist)
Drug-Induced Dyskinesias
Restless Legs Syndrome
Wilson’s Disease
ATYPICAL PARKINSONISM SYNDROMES
■ PARKINSONISM
LEVODOPA
Clinical Use
sinemet
: levodopa w/
carbidopa
(a
peripheral dopa decarboxylase inhibitor
):
reduces peripheral conversion to DA--> 10% of dose reaches brain
instead of 1-3%--> can
give lower doses, reduce adverse affects
also
medopar: l-dopa + benserazid
Adverse Effects
A. Gastrointestinal Effects: most common (acute) side effect
levodopa w/o peripheral decarboxylase inhibitor, anorexia and
nausea and vomiting in 80%
minimized
by taking drug in divided doses, with or immediately after
meals
, and by incr total daily dose very slowly,
Antacids
B. Cardiovascular Effects
incr catecholamine formation peripherally--> cardiac arrhythmias (tachycardia, V extrasystoles, and rarely, AF)
C.
Behavioral
Effects: depression, anxiety, agitation, insomnia, somnolence, sleep attacks, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality
D. Dyskinesias (most common chronic effect) and Response Fluctuations
Dyskinesias: face & distal extremities most common;
Certain fluctuations in clinical response to levodopa occur w/ incr frequency as treatment continues--> should not use L-DOPA as first choice:/
E. Miscellaneous: Mydriasis; brownish discoloration of saliva, urine, or vaginal secretions;
pharmacokinetics:
Dopamine does not cross BBB--> immediate metabolic precursor of dopamine does, and is
decarboxylated to DA in brain: Levodopa
given
orally
Contraindications
psychotic
pxs
angle-closure glaucoma
active peptic ulcer
hx of melanoma or w/ suspicious undiagnosed skin lesions
Drug Interactions
pyridoxine (vitamin B6)
enhance
extracerebral metabolism
of levodopa
Levodopa should not be given to pxs taking
MOA inhibitors
-->can lead to
hypertensive crises
A drug holiday: (discontinuance of the drug for 3–21 days) may temporarily improve responsiveness to levodopa; hospitalized
DOPAMINE RECEPTOR AGONISTS
Non-Ergots
Pramipexole, Ropinirole
D3 agonist, used alone and adj to L-DOPA
adverse effects: GI, behavioral, CVS, dyskinesia
oral, quick action, short half-life
Ergots
Bromocriptine
a
D2 agonist
used to
terminate lactation
(DA inhibits prolactine)
used as
alternative/combination therapy
if L-DOPA doesn't work
short half life
excreted in bile and stool
Adverse effects like L-DOPA
CIs: psychotic, peptic ulcer, recent L V MI, peripheral vascular diseases like
Raynauds
Pergolide
Rotigotine
MONOAMINE OXIDASE INHIBITORS
Selegiline
: inhibitor of
monoamine oxidase B
; gradually
incr dose; neuroprotective like pramipexole: has same adverse effects
CATECHOL-O-METHYLTRANSFERASE INHIBITORS:
another pathway of levodopa metabolism: incr plasma of 3-O-methyldopa (3-OMD)--> competes w/ L-DOPA to enter brain
Selective COMT inhibitors:
tolcapone and entacapone
:
helpful in
response fluctuations—leading to a smoother response, more prolonged on-time; entacapone generally preferred
bc not been a. w/ hepatotoxicity.
APOMORPHINE
AMANTADINE
adverse effects like l-dopa +
skin
effects (
livedo reticularis
)
if
used alone--> only 2-3ws affective
; ; all excreted by
urine
used esp
in beginning
when we don't want to give L-DOPA;
ACETYLCHOLINE-BLOCKING DRUGS
sometimes first choice; Chlorphenoxamine, Biperiden, Procyclidine pass BBB;
adverse effects: mydriasis, flushing, behavioral changes (more than others)
CIs: severe psychosis, BPH, obstructive GI diseases
SURGICAL PROCEDURES
patho:
DA neurons degenerated, progressive;
Studies in twins--> genetics important; Epidemiologic studies--> Environmental or endogenous toxins; viral encephalitis; free radicals
pharmacologic attempts:
restore
dopaminergic
activity
restore the normal balance of
cholinergic
and dopaminergic influences on the basal ganglia w/ antimuscarinic drugs