Download 5-Parkinson Disease

Introduction
• A neurodegenerative disorder caused by progressive
death of selected dopaminergic neurons in the CNS.
• The pathology of this disorder leads to deteriorating
motor,autonimic,cognitive and psychiatric function.
• First described by James Parkinson in his classic
1817 monograph, "An Essay on the Shaking Palsy,“
Epidemiology
• Affects between 100 and 200 per 100,000
people over 40
• Over 1 million people in North America alone
• Uncommon in people younger than 40
• Incidence of the disease increases rapidly over
60 years, with a mean age at diagnosis of
70years
Pathophysiology
Pathophysiology
A.
Dopaminergic cells originating in substantia nigra pars compacta and
terminating in the caudate & putamen (nigrostriatal pathway ) are lost
gradually during the course of the disease.
1.
2.
3.
B.
Factors contributing to autonomic dysfunction
1.
2.
C.
Degeneration of the intermediolateral columns of spinal cord
Degeneration of the sympathetic and parasympathetic ganglia
Loss of brainstem serotonergic & noradrenergic cells
–
D.
Pateints initially become symptomatic after 70%-80% cell loss in these area.
Accounts for development of rigidity & akinesia
May contribute to cognitive symptoms.
contribute to depressive symptoms
Formation of Lewy bodies
1.
2.
3.
Found in cortex, brainstem and basal forebrain in individuals with preclinical and advance
PD
Enclosed bodies containing eosinophils and cytosolic proteins
Nonspecific finding; may be unrelated to PD process
Motor features of Parkinson disease
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•
•
•
•
Cardinal manifestations
Craniofacial
Musculoskeletal
Gait
Visual
Cardinal manifestations
1.
Tremor
A. Coarse, slow “pill rolling” seen in upper extremities
B. More prominent at rest
C. Usually occurs in one arm at first, then spreads to the contralateral arm.
2. Bradykinesia
A.
B.
C.
D.
3.
Rigidity
A.
B.
C.
4.
Generalized slowness of motion
Difficulty initiating movement
Facial masking
Decreas swallowing
Cogwheeling
Muscle stiffness, fatigue and weakness
Resistance observed during passive motion a limb.
Postural instability
A.
B.
Alterations in balance and equilibrium
Contributes to falls & injuries
Craniofacial
Hypomimia
(masked facial
expression)
Decreased eye
blinking
Speech disturbances
(hypokinetic dysarthria,
hypophonia)
Dysphagia
Sialorrhea
Musculoskeletal
1.
2.
3.
4.
5.
6.
7.
Micrographia
Dystonia
Myoclonus
Stooped posture (camptocormia)
Kyphosis
Scoliosis
Difficulty turning in bed
NONMOTOR SYMPTOMS
• Cognitive dysfunction and dementia
• Psychosis and hallucinations
• Mood disorders including depression, anxiety,
and apathy/abulia
• Sleep disturbances
• Fatigue
• Autonomic dysfunction ????
• Olfactory dysfunction (Smell sensory)
• Pain and sensory disturbances
• Dermatologic findings (seborrhea)
STAGES
Hoehn and Yahr Scale
Stages
Symptoms
Stage I:
Unilateral involvement only, minimal or no fx impairment
Stage II:
Bilateral involvement, without impairment of balance
Stage III:
Evidance of postural imbalance, some reduction in activities
,capable of leading independent
Stage IV:
Severely disabled, unable to walk and stand unassisted , markedly
incapacitated
Stage V
Restricted to bed or wheelchair unless aided
Treatment
• The pharmacologic treatment of PD can be
further divided into
– Neuroprotective
– Symptomatic therapy.
SYMPTOMATIC THERAPY
• The decision to initiate symptomatic medical therapy
in patients with PD is determined by the degree to
which the patient is functionally impaired.
• The timing of this decision varies greatly among
patients but is influenced by a number of factors,
including :
1. The effect of disease on the dominant hand
2. The degree to which the disease interferes with work,
activities of daily living, or social and leisure function
3. The presence of significant bradykinesia or gait
disturbance
4. Personal philosophy regarding the use of drugs
SYMPTOMATIC THERAPY
• The major drugs available for symptomatic
therapy include
1.
2.
3.
4.
5.
6.
Levodopa
MAO B inhibitors
Dopamine agonists
COMT inhibitors
Anticholinergic agents
Amantadine
LEVODOPA
• Levodopa (L-dopa) is well established as the most
effective drug for the symptomatic treatment of
idiopathic or Lewy body PD.
• It is particularly effective for the management of
akinetic symptoms and should be introduced
when these become disabling and are
uncontrolled by other antiparkinsonian drugs.
• Tremor and rigidity can also respond to levodopa
therapy, but postural instability is less likely to do.
LEVODOPA
• Mechanism Levodopa is converted to
dopamine by dopa decarboxylase for use in
striatal neurons.
• Role in Therapy useful for motor symptom is
Stage II-V disease
LEVODOPA
Formulations
• Levodopa is combined with a peripheral decarboxylase inhibitor
carbidopa
• Advantage of combination;
1. Carbipoa to block its conversion to dopamine in the systemic
circulation and liver (before it crosses the blood-brain barrier)
in order to prevent nausea, vomiting, and orthostatic
hypotension.
2. Carbipoa increase F of levodopa to penetrate the CNS. Need
app. 75-200 mg\ day of carbidopa to effectively block the
peripheral conversion of levodopa.
• The combination drug carbidopa/levodopa (immediate-release
Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg
• Controlled release formulation has 70% bioavailability of immediate
release 25\100mg, 50\200 mg.
Dosing
• Initial:25/100 mg two to hree times daily with meals
avoid high fat meals ???.
– Interfere with abs. of levodopa in GI tract.
• Total daily dose of carbidopa/levodopa can be
titrated carefully upward over several weeks to a full
tablet of 25/100 mg three times daily as tolerated.
• If pt fail to respond to >1000 mg levodpa reconsider
PD diagnosis.
Adverse effects
• Nausea, somnolence, dizziness, and headache are among the
more common side effects that may accompany treatment
with levodopa, but they are not likely to be serious in most
patients.
• More serious adverse reactions to levodopa (mainly in older
patients) may include confusion, hallucinations, delusions,
agitation, and psychosis.
• Levodopa may also induce a mild to moderate elevation in
serum homocysteine levels which in turn may be associated
with an increased risk of hip fractures in elderly patients.
Adverse effects
Motor fluctuations
– Occur in at least 50 percent of patients after 5 to
10 years of treatment
– Called (the wearing-off phenomenon):
involuntary movements known as dyskinesia,
abnormal postures of the extremities and trunk
known as dystonia
MAO B INHIBITORS
selegiline
• Mechanism
– Selegiline irreversibly and selectively inhibits monoamine
oxidase (MAO) type B inhibitor the oxidative metabolism of
dopamine
• Role in Therapy
– is modestly effective as symptomatic treatment for PD and may
have neuroprotective properties (preclinical disease).
– Adjunctive treatment in Stage I-IV. May use lower doses of
levodopa and dopamine agonist.
Selegiline
Dosing
• 10 mg per day ; 5 mg qam and 5mg at lunch
– Metabolized by liver to …. (to avoid insomnia).
• However, lower doses are sufficient to induce MAO B
inhibition, and 5 mg once a day in the morning is
currently recommended.
• Doses higher than 10 mg daily are of no additional
benefit and may result in nonselective MAO inhibition,
thereby placing the patient at risk of hypertensive crisis
in the absence of dietary restrictions.
Selegiline
Adverse effects
• Nausea and headache
• amphetamine metabolites of selegiline can
cause insomnia
• Augment levodopa toxicities
• Potential food- drug interaction (tyramine)
• Potential drug-drug interaction (SSRI)
DOPAMINE AGONISTS
mechanisms
1.
2.
3.
4.
Bromocriptine
D1&D2 receptors Agonist
Pergolide
Ropinirole
D2 receptor Agonist
Pramipexole
DOPAMINE AGONISTS
• Pergolide has been voluntarily withdrawn from the United States
market and is best avoided because it is associated with a risk of
cardiac valve problems.
• Injectable apomorphine has been approved by the United States
FDA for treatment of motor fluctuations in PD section on Dopamine
agonists.
• Advantage
1.
Unlike levodopa-carbidopa ,these drugs are direct agonists that
•
•
•
2.
do not require metabolic conversion
do not compete with amino acids for transport across the gut or into the
brain
do not depend upon neuronal uptake and release.
longer duration of action .
DOPAMINE AGONISTS
Role of Therapy
• Monotherapy in early disease (younger pt) to
delay the time to start levodopa.
• Less effective monotherapy for sever stages
>stage 3
DOPAMINE AGONISTS
Dosing
•
Bromocriptine
–
is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals
by 2.5 mg a day.
– Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although
total daily doses as high as 90 mg can be used.
•
Pramipexole
– is usually started at 0.125 mg three times a day.
– The dose should be increased gradually by 0.125 mg per dose every five to seven days.
– Most patients can be managed on total daily doses of 1.5 to 4.5 mg.
•
Ropinirole
– Is usually started at 0.25 mg three times a day.
– The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a
total daily dose of 3 mg.
– After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a
maximum total daily dose of 24 mg.
– Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.
DOPAMINE AGONISTS
Adveres effect
• Poorly tolerated by about 30% due to
– Allergy
– Palpitation
– Sinus tachycardia
– Agitation
• Edema (hands, feet, face)
• Plural effusion
COMT INHIBITORS
• Mechanism
– Inhibits the enzyme catechol-O-methyl
transeferase that converts levodopa to 3-Omethyldopa and converts dopamine to 3methooxytyramine
• Drugs
– Tolcapone 100mg,200mg
– Entacapone 200mg
– Carbidopoa/levodopa/entacapone
COMT INHIBITORS
• Role in therapy:
– They are ineffective when given alone, but they
may prolong and potentiate the levodopa effect
when given with a dose of levodopa.
– These medications are mainly used to treat
patients with motor fluctuations who are
experiencing end-of-dose wearing "off" periods.
COMT INHIBITORS
Dosing
• The starting dose of tolcapone is 100 mg
three times daily; the clinical effect is evident
immediately, up to 600 mg/day
• The dose of entacapone is one 200 mg tablet
with each dose of levodopa, up to a maximum
of eight doses per day. ???mg/day
COMT INHIBITORS
Adverse effects
•
Tolcapone
1.
2.
3.
4.
The most common side effects of tolcapone are due to increased
dopaminergic stimulation and include dyskinesia, hallucinations,
confusion, nausea, and orthostatic hypotension. The adverse effects
are managed by lowering the dose of levodopa either before or after
the addition of tolcapone.
Diarrhea that is poorly responsive to antidiarrheal medications
appears in approximately 5 percent of patients.
An orange discoloration of the urine is a common but benign
adverse event.
Elevations in liver enzymes may rarely occur. Monitoring???
• Entacapone are similar to tolcapone ADR, although entacapone has
thus far not been associated with hepatotoxicity
ANTICHOLINERGICS
• Mechanism
– Antagoniza muscarinic cholinergic receptors in the
striatum
• Role of therapy
– Used to control tremor
• Drugs
– Trihexyphenidyl
– Benztropine
ANTICHOLINERGICS
Dosing
• Trihexyphenidyl The starting dose of
trihexyphenidyl is 0.5 to 1 mg twice daily, with a
gradual increase to 2 mg three times daily.
• Benztropine traditionally is more commonly used
by psychiatrists for the management of
antipsychotic drug-induced parkinsonism; the
usual dose is 0.5 to 2 mg twice daily.
.
ANTICHOLINERGIC
Adverse effects
• Peripheral antimuscarinic side effects include dry mouth, blurred
vision, constipation, nausea, urinary retention, impaired sweating,
and tachycardia.
• Caution is advised in patients with known prostatic hypertrophy or
closed-angle glaucoma.
•
Discontinuation of anticholinergic drugs should be performed
gradually to avoid withdrawal symptoms that may manifest as an
acute exacerbation of parkinsonism, even in those in whom the
clinical response has not seemed significant.
AMANTADINE
• Mechanism
– Blocks presynapatic dopamine reuptake; causes
release of dopamine from storage sites
– Synergistic effects with levodopa and dopamine
agonists
• Role of therapy
– Improves bradykinaseia, tremor, and rigidity, in
pateints with Stages I-IV disease
AMANTADINE
Dosing
•
The dose of amantadine in early PD is 200 to 300 mg daily; there is
no evidence that larger doses are of additional benefit. The main
advantage of this agent is a low incidence of side effects.
• It is excreted unchanged in the urine and should be used with
caution in the presence of renal failure.
• Adverse effects — Peripheral side effects include ankle edema,
which are rarely severe enough to limit treatment. Confusion,
hallucinations, and nightmares occur infrequently, but
unpredictably, even after long periods of use without side effects.
These effects are more likely when amantadine is used together
with other antiparkinsonian drugs in older patients.