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Flashcards in Mod 3 Antiparkinsonian Drugs Deck (20):

Parkinson’s Disease (PD)

Chronic, progressive, degenerative disorder
 Affects dopamine-producing neurons in the
Slide 2
 Caused by an imbalance of two
 dopamine
 acetylcholine (Ach)


Parkinson’s Disease (cont’d)

Signs and symptoms occur when about 80%
of the dopamine stored in the substantia nigra
of the basal ganglia is depleted
Slide 5
g g p
 Signs and symptoms can be partially
controlled as long as there are functioning
nerve terminals that can take up dopamine


Parkinson’s Disease (cont’d)

Signs and symptoms include:
 akinesia
 bradykinesia
Slide 6
 rigidity
 tremor
 postural
A progressive condition
 Rapid swings in response to levodopa occur
(“on off phenomenon”)
Slide 8
( on-phenomenon )
 PD worsens when too little dopamine is present
 Dyskinesia occurs when too much is present



Difficulty in performing voluntary movements
 Two common types of dyskinesias
h i l di i l t
Slide 9
 chorea: irregular, spasmodic, involuntary
movements of the limbs or facial muscles
 dystonia: abnormal muscle tone leading to
impaired or abnormal movements


Levodopa Therapy

Levodopa is a precursor of dopamine
 Blood-brain barrier does not allow
Slide 10
exogenously supplied dopamine to enter, but
does allow levodopa


Levodopa Therapy (cont’d)

Levodopa is taken up by the dopaminergic
terminal, converted into dopamine, then
released as needed
Slide 11
 As a result, neurotransmitter imbalance is
controlled in patients with early PD who still
have functioning nerve terminals
As PD progresses, it becomes more difficult
to control it with levodopa
 Ultimately, levodopa no longer controls the
Slide 12
y, p g
PD, and patient is seriously debilitated
 This generally occurs between 5 and
10 years after the start of levodopa therapy


Drug Therapy for PD

Aimed at increasing levels of dopamine as
long as there are functioning nerve terminals
Slide 13
 Antagonize or block the effects of Ach
 Slow the progression of the disease
Indirect-acting dopamine-receptor agonists
 MAO-B inhibitors: selegiline, rasagiline
COMT i hibi l
Slide 14
 inhibitors: entacapone, tolcapone
 Presynaptic dopamine release enhancer:


Drug Therapy for PD (cont’d)

Anticholinergic drugs
 benztropine, trihexyphenidyl
 Antihistamines
 diphenhydramine
Slide 15
 Nondopamine-receptor agonists
 Ergot: bromocriptine
 Nonergot: pramipexole, ropinirole, apomorphine
 Dopamine replacement drugs
 carbidopa, carbidopa-levodopa


Selective MAOI Therapy: Selegiline

MAO breaks down catecholamines in the
CNS, primarily in the brain
Slide 16
 Selegiline is a selective MAOB inhibitor
 Causes an increase in levels of dopaminergic
stimulation in the CNS


Selective MAOI Therapy: Selegiline

Selegiline is a newer, potent, irreversible
MAOI that selectively inhibits MAOB
Slide 17
 Does not elicit the “cheese effect” of the
nonselective MAOIs used to treat depression
(if 10 mg or less is used)
Used in combination with levodopa or
U d dj t h ti t’
Slide 18
 Used as an adjunct when a patient’s
response to levodopa is fluctuating
 Allows the dose of levodopa to be decreased
 Delays development of unresponsiveness to
levodopa therapy


Selective MAOI Therapy: Selegiline

Improves functional ability
 Decreases severity of signs/symptoms
 Only 50% to 60% of patients show a positive
Slide 19
y p p
response to therapy
 Prophylactic selegiline may delay the
development of serious debilitating PD for
9 to 18 years
 Rasagiline approved in 2008 with similar action
to selegiline
Adverse effects usually mild
 Nausea, lightheadedness, dizziness, abdominal
Slide 20
pain, insomnia, confusion, dry mouth
 Doses higher than 10 mg/day may cause more
severe adverse effects, such as hypertensive


Presynaptic Dopamine Release

Amantadine (Symmetrel)
 Indirect-acting
 Causes release of dopamine from storage sites at
Slide 21
the end of nerve cells that are still intact
 Blocks reuptake of dopamine into the nerve
endings, allowing more to accumulate both
centrally and peripherally
 Does not stimulate dopamine receptors directly
Amantadine (Symmetrel)
 Used early in the course of the disease
Slide 22
 Usually effective for only 6 to 12 months
 Also used as an antiviral for influenza virus


COMT Inhibitors

 Tolcapone (Tasmar) and entacapone
Slide 23
 Inhibit COMT, the enzyme responsible for the
breakdown of levodopa, the dopamine
 Prolong the duration of action of levodopa;
reduce wearing off phenomenon
Tolcapone (Tasmar)
 Has caused severe liver failure
Slide 24
 Requires monitoring of liver enzymes
 Not used unless other drugs do not work


Direct-Acting Dopamine Receptor

Nondopamine dopamine receptor agonists
 Ergot derivatives (bromocriptine and pergolide)
 Nonergot drugs (pramipexole ropinirole
Slide 25
pramipexole, ropinirole,
 Dopamine replacement drugs
 Levodopa, carbidopa, carbidopa-levodopa
Nondopamine dopamine receptor agonists
 Ropinirole (Requip)
• Newer, nonergot
Slide 26
• Used for PD and restless leg syndrome
 Apomorphine (Apokyn)
• Newer, nonergot dopamine agonist
• Subcutaneous injection


Direct-Acting Dopamine Receptor
Agonists (cont’d)

 Bromocriptine (Parlodel)
Di tl ti l t d i t
Slide 27
 Directly stimulate dopamine receptors
 Activate dopamine receptors and stimulate
production of more dopamine
 Pergolide (Permax) is another direct-acting


Dopamine Replacement Drugs

Replacement drugs (presynaptic)
 Work presynaptically to increase brain levels of
Slide 28
 Levodopa is able to cross the blood-brain barrier,
and then it is converted to dopamine
 However, large doses of levodopa needed to get
dopamine to the brain also cause adverse effects
Replacement drugs
 Carbidopa is given with levodopa
 Carbidopa does not cross the blood-brain barrier
Slide 29
blood and prevents levodopa breakdown in the
 As a result, more levodopa crosses the
blood-brain barrier, where it can be converted
to dopamine


Anticholinergic Therapy

Anticholinergics block the effects of ACh
 Used to treat muscle tremors and muscle
rigidity associated with PD
Slide 30
 These two symptoms are caused by excessive
cholinergic activity
 Does not relieve bradykinesia (extremely
slow movements)


Anticholinergic Therapy (cont’d)

Ach dominates because of the imbalance of
 As a result, overstimulation of the cholinergic
Slide 31
excitatory pathways occurs
 Muscle tremors and muscle rigidity
 Cogwheel rigidity
 Pill-rolling movement of fingers and head bobbing
while at rest
benztropine mesylate (Cogentin)
 Also used to treat extrapyramidal symptoms
caused by use of antipsychotic drugs
Slide 32
 Trihexyphenidyl (generic only)
 Antihistamines also have anticholinergic
 diphenhydramine (Benadryl)


Anticholinergic Therapy:

Used in the treatment of PD to cause smooth
muscle to relax, resulting in reduced muscle
rigidity and akinesia
Slide 33
 Also used to treat drug-induced
extrapyramidal reactions to certain
antipsychotic drugs


Anticholinergic Therapy:
Adverse Effects

Drowsiness, confusion, disorientation
 Constipation, nausea, vomiting
Slide 34
 Urinary retention, pain on urination
 Blurred vision, mydriasis, photophobia, dry
 Decreased salivation, dry mouth