Transcript Document

ANTIPARKINSONIAN
AGENTS
MA. LENY ALDA G. JUSAYAN, MD
DEPARTMENT OF PHARMACOLOGY
PARKINSONISM
• Tremors are present even at rest
• Rigidity & impairment of voluntary
movements
• Postural tremor, intention tremors
The UK Parkinson's Disease
Society Brain Bank Criteria For
Clinical Diagnosis:
• Bradykinesia plus one of rigidity,
tremor, or postural instability
• At least three of rest tremor,
progressive symptoms, unilateral
onset, early response to levodopa,
revodopa-induced dyskinesia
• No identifiable cause for the
parkinsonism.
Motor Symptoms:
 Tremor:
 70% of patients suffer resting tremor
 pill rolling quality
 can affect all of the limbs as well as the
face, neck, head and jaw.
 Rigidity:
 increased tone or stiffness in the
muscles
 mask-like face and clog-like release of
muscles.
 Bradykinesia
difficulty initiating and continuing
movement.
Postural Instability
Forward flexion of neck, hips, knees
and elbows leads to poor balance.
Gait disorders
 Shuffling, small steps described as
festination, reduced arm swing and
sudden freezing spells lead to problems
walking
Swallowing (dysphagia) and Speech
disorders (dysarthria)
Handwriting: Micrographia
Nonmotor Symptoms:
• Depression:
– 20-90% major depressive episode, reactive
or endogenous
• Dementia:
– 20% of patients will become demented
(have impairments of 3 of the following in
the presence of clear consciousness:
language, memory, visuospatial skills,
emotionality, personality and cognition
Sleep disturbances:
 Problems with sleep
fragmentation, sleep initiation, early
morning awakening, excessive
daytime somnolence and
parasomnias.
Sexual dysfunction
Ability to drive a car
Ability to gain employment
Constipation
CHOREA
• Irregular, unpredictable involuntary
jerks
• Impaired voluntary activity
• ballismus
ATHETOSIS
• Slow & writhing movements
• Abnormal postures (dystonia)
TICS
• Sudden coordinated abnormal
movements
• Repetitive sniffing
• shoulder shrugging
• face & head movement
PATHOGENESIS:
• Idiopathic
• Exposure to unrecognized
neurotoxins
• Oxidation reaction with generation of
free radicals
• Reduced level of dopamine in the
basal ganglia
•
Pyramidal System:
– begins in the primary motor cortex
– descends through the corticospinal
and corticobulbar tracts
– affects the lower motor neurones
in the brain stem and spinal cord.
•Extrapyramidal System:
•basal ganglia and their cortical
connection
•basal ganglia are made up of the:
Caudate Nucleus
 Putamen (Striatum)
 Globus Pallidus interna (Gpi)
 Globus Pallidus externa (Gpe)
 Subthalamic Nucleus
 Substantia Nigra
main outputs of this system are
the Substantia Nigra and the Gpi,
both of which feed to the
ventrolateral thalamus.
The main Pathological feature of
Parkinson’s disease is the loss of the
dopaminergic nigrostriatal pathway
80% of the Dopamine producing cells
must be lost before symptoms begin to
show
GOALS OF TREATMENT:
• Pharmacologic
attempt to restore
dopaminergic
activity with
levodopa and
dopamine agonists
• Restore normal
balance of
cholinergic &
dopaminergic
influences on the
basal ganglia
PATHOPHYSIOLOGIC BASIS
OF TREATMENT:
• Dopaminergic
neurons in the
substantia nigra
that normally
inhibit the output
of GABAergic
cells in the
corpus striatum
are lost
LEVODOPA
• (-) -3-(3-4 dihydroxyphenyl) L- alanine
• Immediate metabolic precursor of
dopamine
• Levorotatory stereoisomer of
dopamine
PHARMACOKINETICS:
• Rapidly absorbed from the SI
• Food delays absorption
• Amino acids in food competes
with drug
• Peak plasma concentration: 1-2
hrs
• Plasma t ½ : 1-3 hrs
• HVA, DOPAC
(dihydroxyphenylacetic acid) are
main metabolites
CLINICAL USE:
• Responsiveness may be lost secondary
to disappearance of dopaminergic
nigostriatal nerve terminals
• Early use lowers mortality rate
• Combined with Carbidopa & Benseraside
• Sinemet – dopa preparation containing
levodopa in fixed proportion (1:10 or 1:4)
• Sinemet 25/100 TID
• 30 -60 minutes before meals
ADVERSE EFFECTS:
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GIT effects
Cardiovascular
Dyskinesias
Behavioral effects
Fluctuations in response
Misc: mydriasis, blood dyscrasias,
hot flushes, gout, brownish
discoloration of the urine,
abnormal smell
DRUG INTERACTIONS:
• Vitamin B6 enhance extracerebral
metabolism of levodopa
• MAO – A inhibitors
CONTRAINDICATIONS:
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Psychoses
Angle closure glaucoma
Cardiac dysrhythmia
PUD
Melanoma or suspicious
undiagnosed skin lesions
DOPAMINE AGONISTS
• Do not require enzymatic
conversion for an active
metabolite
• No potential toxic metabolites
• Do not compete with other
substances for an active transport
• First line in parkinsonism
• End of dose akinesia to levodopa
• On & off phenomenon refractory
to levodopa
ERGOT ALKALOIDS:
• BROMOCRIPTINE
– D2 agonists
– Endocrinologic disorders
(hyperprolactinemia)
– Absorbed variably in GIT
– Peak plasma levels: 1-2 hrs
ERGOT ALKALOID:
• PERGOLIDE
– Stimulates both D1 and D2
– More effective than
bromocriptine
CLINICAL USE:
BROMOCRIPTINE:
– 7.5 mg & 30 mg
– 1. 25 mg BID after meals X 2-3
months and increase 2.5 mg q 2 wks
PERGOLIDE:
- 3 mg daily
- 0.05 mg starter dose
ADVERSE EFFECTS:
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GIT
Cardiovascular
Dyskinesias
Mental disturbances
Misc: erythromelalgia
NON-ERGOT DOPAMINE
AGONISTS:
PRAMIPEZOLE
Preferential affinity to D3
Monotherapy is effective
Neuroprotective (H scavenger)
Enhance neurotrophic activity
Rapidly absorbed
Peak plasma concentration: 2 hrs
0.125 mg TID then doubled after 1 wk
Increments of 0.75 mg at weekly
intervals
NON-ERGOT ALKALOIDS:
• ROPINIROLE
– Pure D2 receptor agonists
– 0.25 mg TID then total daily dose is
increased by 0.75 mg at weekly
intervals until the 4th wk & increased
by 1.5 mg thereafter
SIDE EFFECTS:
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Postural hypotension
Fatigue
Somnolence
Peripheral edema
Nausea
Constipation
Dyskinesias
Confusion
MONOAMINE OXIDASE
INHIBITORS
MAO – A: metabolizes NE &
serotonin
MAO – B: metabolizes dopamine
SELEGILINE (Deprenyl)
• Selective inhibitor of MAO-B
• Retards breakdown of dopamine
• Adjunct in fluctuating response to
levodopa
• 5 mg with breakfast & lunch
• Cause insomnia when taken
during the day
• Not to be taken with meperidine,
TCAs, SSRIs
• Increase adverse effects of
levodopa
RASAGILINE
• MAO-B inhibitor
• Potent than selegiline
• CI with levodopa – HPN crisis
CATHECOL-O-METHYLTRANSFERASE
INHIBITORS:
• TOLCAPONE- central & peripheral
metabolism
• ENTACAPONE
– peripheral metabolism
– Prolong the duration of levodopa by
decreasing its peripheral metabolism
– Helpful in patients receiving levodopa
who have fluctuations
– t ½ = 2 hrs
AMANTADINE
• Antiviral agent
• Potentiates dopaminergic function by
influencing the synthesis, release,
reuptake of dopamine
PHARMACOKINETICS:
peak plasma concentration: 1-4 hrs
after oral dose
Plasma t ½ = 2-4 hrs
CLINICAL USE:
• Less potent than levodopa and benefits
are short-lived
• 100 mg BID-TID
ADVERSE REACTIONS:
Restlessness, depression, irritability,
insomnia, agitation, excitement,
hallucinations & confusion
Livedo reticularis
CONTRAINDICATIONS:
• History of seizures
• Heart failure
ACETYLCHOLINE
BLOCKING AGENTS:
• Improve tremor & rigidity of
parkinsonism but have little effect
in bradykinesia
• Benztropine mesylate
• Biperiden
• Orphenadine
• Procyclidine
• Trihexyphenidyl
ADVERSE EFFECTS:
• CNS
• Mydriasis, urinary retention,
constipation, tachycardia,
tachypnea, increase IOP,
palpitations, cardiac arrythmias
• Acute suppurative parotitis
CONTRAINDICATIONS:
• Prostatic hyperplasia
• Obstructive GI diseases
• Angle closure glaucoma
The net result of all of these medications is
the balancing out of the
acetylcholine/dopamine balance and an
improvement in movement
SURGICAL PROCEDURES:
Thalamotomy –
conspicous
tremor
Posteroventral
pallidotomy