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Antiparkinson AgentsAntiparkinson Agents
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A neurodegenerative disordercharacterized by progressive motordysfunction which includes:Tremor
Rigidity
Bradykinesia (slow movement)
disturbance of posture
Affects ~ 1% of over age 65
Parkinsons Disease
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Anti Parkinsonian Drugs
These are the specific drugs used to treat
the ExtraPyramidal Side effects of
antipsychotic agents.
EPS: includes
Parkinsonism
Akathisia
Acute Dystonia
Tardive Dyskinesia
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CLASSIFICATION
Anticholinergic Drugs:
- Benzotropine (0.5-0.6 mg/day)
- Trihexyphenidyl Hydrochloride (THP){2-12 mg/day}
- Procyclidine hydrochloride (5-20 mg/day)
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Contd
Antihistamines
- Diphenhydramine
Benadryl
75-100 mg/day
Capsule and syrup
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Contd..
Dopamine Drugs-Levadopa
Larodapa
2-3 gms/day Tablet
-Carbidopa & L.dopa
Sinemet
10-100mg/day
Tablet
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Contd
-Selegline
Deprenyl
5-10 mg/day
Tablet
-Amantidine Hydrochloride
Symmetrel 10-100mg/day
Tablet
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Drugs Used in the Treatment ofParkinsonism
Levodopa single most effective agent
immediate precursor of dopamine
crosses the blood brain barrier by means of
transporter for aromatic amino acids
Pharmacological properties
Levodopa itself is fairly inert
activity is due to conversion to dopamine in CNS,
thus increasing dopamine in the basal ganglia
(replacement therapy)
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Levodopa
Pharmacological properties No change in muscle tone or movement innormal individuals
Bradykinesia and rigidity are reversed
quickly Changes in mood associated with
parkinsonism are reversed patients more alert and interested in
environment dementia may not reverse
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LDopa
Pharmacological properties (cont.)Cardiovascular
Asymptomatic (usually) orthostatic hypotension Dopamine stimulates both alpha and beta
receptors Cardiac stimulation
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LDopa
Pharmacokinetics
Well absorbed orally via aromatic amino
acid transporter but can be altered by
Rate of gastric emptying
pH of gastric fluids (acidity interferes with
absorption)
Degradation by enzymes in intestinalmucosa
Dietary protein (amino acids compete for
transport)
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L-Dopa
Pharmacokinetics (cont.)
~ 95% of l-dopa is metabolized in the
periphery to dopamine; metabolism may be
increased with prolonged therapyPasses from gut lumen through liver
Only a small portion enters the brain
Metabolites are excreted in urine
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ORAL DISPOSITION OF LEVODOPA
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L-Dopa
Adverse effects (caused mostly by DA)Most patients treated with l-dopa develop side
effects.
Intensity and type vary at different stages oftherapy
Early side effects
Dose dependent; tolerance may develop GI nausea, vomiting (80%)
CVS orthostatic hypotension (30%), cardiac
arrhythmias
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L-Dopa
Adverse effects (cont.)Long term effects
severity correlates with the degree of clinical improvement,
duration of therapy and dose. No tolerance develops
Abnormal involuntary movements Levodopa-induced dyskinesia (80% after 1 year)
Most commonly jerky, dance-like movements of arms
and/or head
Reduction in dosage required
Psychiatric and behavioral disturbances (15%) Depression, anxiety,agitatio, insomnia, delusions
Hallucinations, euphoria ,nightmares
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L-dopa
Long term adverse effects
On-Off syndrome oscillations in
performance involving rapid changes from
akinesia to dyskinesia different from end of dose or wearing off effect
Mechanism of On-Off syndrome unclear
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L-Dopa
Drug interactionsPyridoxine (vitamin B6) increases peripheral
conversion of dopa to dopamine (co-factor for LAAD)
Antipsychotic drugs are dopaminergic antagonistsand thus counteract the effects of dopa
MAO inhibitors increase the effects of dopa, may leadto hypertensive crises
Anticholinergic drugs may slow gastric emptying
time and decrease absorption of l-dopaTricyclic antidepressants may aggravate
hypotensive symptoms
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Drugs Used in the Treatment ofParkinsonism
CarbidopaL-aromatic amino acid decarboxylase (LAAD) is
responsible for the conversion of dopa to dopamine
LAAD activity causes 95% of a dose of dopa to be
converted to dopamine before entering the CNS.
Carbidopa is an inhibitor of this peripheraldecarboxylase and allows greater amounts ofdopa to enter the CNS (carbidopa doesnt cross
BBB) Only available in combination with l-dopa (Sinemet)
Highly effective in first 2 5 years
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Carbidopa
Advantages
Allows reduction in dopa dose
Nausea and vomiting are decreased
Cardiac side effects decreased
Pyridoxine (vitamin B6) antagonism of
levodopa prevented
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Dopamine agonists used in theTreatment of Parkinsonism
Ergot derivativesBromocryptine (Parlodel) is the prototype but
now rarely used.
Pergolide (Permax) no longer available because of valularheart disease.
directly stimulate dopamine receptor (D2)
Not dependent on uptake into DA neurons
Rapidly absorbed, effective levels reached
quickly and persists 3-4 times longer than l-
dopa
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Non-ergot DA Agonists
ropinirole (Requip) and pramipexole(Mirapex) non-ergot DA agonists
Ropinirole relatively pure D2 agonist
Pramipexole prefers D3
They also alter cellular metabolism so that
progression of disease appears to be
slowed somewhatEffective as monotherapy in mild PD also
helpful in pts with advanced disease
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Dopamine agonists
Kinetics
Pramipexole -Largely eliminated unchanged
by kidneys
Ropinirol metabolized by CYP1A2 and
other drugs may slow its elimination
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Non-ergot Dopamine agonists
Adverse effects Anorexia, nausea, vomiting
Confusion, hallucinations, delusions and otherpsychiatric reactions are more common and severe
than with levodopa Orthostatic hypotension can occur early in
treatment. Occasional cardiac arrhythmias
Pramipexole and ropinirole may cause sudden
onset of sleep with no warning
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Dopamine agonists
ContraindicationsDA agonists are contraindicated in pts with ahistory of:
Psychotic illness
Recent myocardial infarct
Active peptic ulceration
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Dopamine agonists
Clinical use Useful doses usually established within week or two
Often used as initial PD treatment rather than otheradjuncts
Used as initial therapy (without l-dopa) that may delayneed for levodopa Rx
adjunctive therapy with l-dopa (lower the doserequirement of levodopa)
May be effective in restless leg syndrome
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Other drugs Used in theTreatment of Parkinsonism
Amantadine (Symmetrel)antiviral agent found to be effective against
parkinsonism
Apparently acts by increasing dopaminerelease from intact dopaminergic neurons
Also blocks NMDA glutamate receptors
Some anticholinergic effects
Block reuptake of DA into presynaptic terminal
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Amantadineeffective quickly but for short time (6-8 weeks)
Adjunct used early in treatment
Adverse effects are mild and reversible
and include:
Hallucinations, confusion, and nightmares
Insomnia, dizziness, lethargy, slurred speech
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Other drugs used in theTreatment of Parkinsonism
Some other drugs are used as adjunct tol-dopa therapy and generally less effectivethan dopaminergic drugs
Central acting agents block the unopposedcholinergic effects in the basal ganglia ofparkinsonism patients
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Other drugs for PD
trihexyphenidyl (Artane) and benztropine(Cogentin)
Decrease tremor
less effect on rigidity and bradykinesia
Generally have little peripheral effect, but mayreduce some autonomic symptoms
Useful adjunct early and advanced PD alsouseful to reduce parkinson symptoms causedby DA receptor antagonists such ashaloperidol
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Antimuscarinic drugs for PD
Adverse reactions
CNS confusion, delirium, somnolence,
hallucinations
Peripheral may produce cycloplegia,constipation, and urinary retention in certain
patients
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MAO inhibitors used in theTreatment of Parkinsonism
Selegiline (Eldepryl)selegiline selectively and irreversibly inhibits
MAOBto decrease catabolism of DA (mostly
MAOB in striatum) Prolongs and enhances the effects of levodopa
(allows dosage reduction)
Does not inhibit peripheral catabolism of
catecholamines
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Selegiline
Used in early or mild PD alone or as anadjunct in advanced disease
Reduces levodopa dose requirement and mayimprove motor function in pts who experiencewearing off or on-off difficulties with ldopa
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Selegiline
Adverse effects Some metabolites are methamphetamine and
amphetamine which produce some of the adverseeffects
Nausea (10%), dizziness (7%), hallucinations,confusion, depression
Insomnia if taken late in the day
Dose must be kept at 10 mg/day or less to
selectively inhibit MAOB, otherwise adversereactions associated with non-specific MAOs occur
Hypertension with tyramine
Potential serotonin syndrome (e.g. SSRIs, meperidine)
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Therapy for Parkinsonism
Goal
No cure of underlying pathology (although gene
therapy is being tested)
Drug + physiotherapy + exercise +psychological support provide maximal
symptomatic relief and permits a near normal
lifespan.
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Some Anesthetic implications
Abrupt withdrawal of levodopa can lead toskeletal muscle rigidity which can interfere
with adequate ventilation
Continue levodopa therapy duringperioperative period including usual morning
dose
Consider possibility of orthostatic
hypotension, cardiac dysrhythmias, and
maybe hypertension in pts Rx with
levodopa
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Bibliography
Stuart and Laria Principles and practice of Psychiatric Nursing 8th
edition Mosby Publishers Pp 604-606
Kapoor Bimla; Psychiatric Nursing; first edition; Kumar Publishing
Home, New Delhi; Pp 112-129
.Varcarolis Elizabeth M Foundation of Psychiatric Nursing; secondedition; W.B.Saunders Company. Philadelphia; Pp 451-453
Malik Santosh Textbook of Psychiatric Nursing; first edition; Lotus
Publishers, Jalandhar; Pp 285-293
Kaplans & Sadocks Synopsis Of Psychiatry; tenth edition;
lippincott William & Wilkins. Philadelphia; Pp 1115-1121INTERNET REFERANCES
http://jama.ama-assn.org/content/291/9/1065.3.sh
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