Mod 3 Antiparkinsonian Drugs

Question 1

Parkinson’s Disease (PD)

Answer 1

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

Question 2

Parkinson’s Disease (cont’d)

Answer 2

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

Question 3

Parkinson’s Disease (cont’d)

Answer 3

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

Question 4

Dyskinesia

Answer 4

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

Question 5

Levodopa Therapy

Answer 5

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

Question 6

Levodopa Therapy (cont’d)

Answer 6

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

Question 7

Drug Therapy for PD

Answer 7

Aimed at increasing levels of dopamine as
long as there are functioning nerve terminals
remaining
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:
amantadine

Question 8

Drug Therapy for PD (cont’d)

Answer 8

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

Question 9

Selective MAOI Therapy: Selegiline

Answer 9

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

Question 10

Selective MAOI Therapy: Selegiline

cont’d

Answer 10

Selegiline is a newer, potent, irreversible
MAOI that selectively inhibits MAOB
Slide 17
y
 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
levodopa-carbidopa
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

Question 11

Selective MAOI Therapy: Selegiline

(cont’d

Answer 11

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
crisis

Question 12

Presynaptic Dopamine Release

Enhancer

Answer 12

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
infection

Question 13

COMT Inhibitors

Answer 13

Indirect-acting
 Tolcapone (Tasmar) and entacapone
(Comtan)
Slide 23
 Inhibit COMT, the enzyme responsible for the
breakdown of levodopa, the dopamine
precursor
 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

Question 14

Direct-Acting Dopamine Receptor

Agonists

Answer 14

Nondopamine dopamine receptor agonists
 Ergot derivatives (bromocriptine and pergolide)
 Nonergot drugs (pramipexole ropinirole
Slide 25
pramipexole, ropinirole,
apomorphine)
 Dopamine replacement drugs
 Levodopa, carbidopa, carbidopa-levodopa
(Sinemet)
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

Question 15

Direct-Acting Dopamine Receptor

Agonists (cont’d)

Answer 15

Direct-acting
 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
drug

Question 16

Dopamine Replacement Drugs

Answer 16

Replacement drugs (presynaptic)
 Work presynaptically to increase brain levels of
dopamine
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
periphery
 As a result, more levodopa crosses the
blood-brain barrier, where it can be converted
to dopamine

Question 17

Anticholinergic Therapy

Answer 17

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)

Question 18

Anticholinergic Therapy (cont’d)

Answer 18

Ach dominates because of the imbalance of
dopamine
 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
properties
 diphenhydramine (Benadryl)

Question 19

Anticholinergic Therapy:

Indications

Answer 19

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

Question 20

Anticholinergic Therapy:

Adverse Effects

Answer 20

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