Mod 3 Antiparkinsonian Drugs Flashcards
Parkinson’s Disease (PD)
Chronic, progressive, degenerative disorder Affects dopamine-producing neurons in the brain Slide 2 Caused by an imbalance of two neurotransmitters 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
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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
Dyskinesia
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
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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
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
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
cont’d
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
Selective MAOI Therapy: Selegiline
(cont’d
Improves functional ability
Decreases severity of signs/symptoms
Only 50% to 60% of patients show a positive
Slide 19
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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
Presynaptic Dopamine Release
Enhancer
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
COMT Inhibitors
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
Direct-Acting Dopamine Receptor
Agonists
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
Direct-Acting Dopamine Receptor
Agonists (cont’d)
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
Dopamine Replacement Drugs
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
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
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)
Anticholinergic Therapy:
Indications
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 skin Decreased salivation, dry mouth
