parkinson drugs Flashcards
Dopaminergic Agents
7
Amantadine
Ropinirole
Pramipexole
Bromocriptine
l-DOPA plus Carbidopa plus Entacapone = stalevo
l-DOPA plus Carbidopa = sinemet ~ parcopa
l-DOPA
MAO-B Inhibitors
2
Selegiline/Deprenyl
Rasagiline
COMT Inhibitor
Entacapone
Antimuscarinic Agents
2
Benztropine
Trihexyphenidyl
Antihistamine
Diphenhydramine
Parkinson’s Disease is also known as ……
Paralysis Agitans
Parkinson’s Disease Symptoms
Progressive, degenerative disease with onset usually after 50 years of age
Tremor
Muscular Rigidity
3. Bradykinesia, Akinesia
Postural & Gait Defects
Autonomic Disturbances (sweating, difficulty in swallowing, drooling, etc…)
Apathy, Social Withdrawal, Cognitive Impairment, Dementia
what are the 3 classifications of Parkinson’s disease?
Primary or Idiopathic
Seconday - post traumatic, post encephalitic, or atherosclerotic
Iatrogenic - drug induced, particularly by antipsychotic
Parkinsonian symptoms result from an alteration of the _______-________
balance in the striatum so that there is a relative deficiency of _________
activity in relation to that of _________
dopamine - acetylcholine
dopaminergic
acetylcholine
In Parkinson’s disease (_____ or
______ parkinsonism), this results from the death of dopaminergic neurons in
the nigrostriatial dopamine pathway.
primary or idiopathic
In _______ parkinsonism,
the imbalance usually results from the blockade of dopamine receptors in the
stiatum.
iatrogenic (drug induced)
In the striatum (a key nucleus of the extrapyramidal motor system), there is a
close anatomical relationship between what 2 types of neurons.
which neurons project from the substantia nigra to the
striatum
In this pathway what is inhibitory, whats excitatory
dopaminergic and cholinergic neurons.
dopamine
dopamine is mainly inhibitory, whereas acetylcholine
is excitatory
match theses situations (NORMAL, PARKINSONISM, and CHOREIFORM MOVEMENTS) with the following relationships
DA = ACh, GABA
DA > ACh, GABA
DA < ACh, GABA
NORMAL = DA = ACh, GABA
PARKINSONISM = DA > ACh, GABA
CHOREIFORM MOVEMENTS = DA < ACh, GABA
Fof family D-1. give the location of the receptor subtypes D1 and D5.
D1 = Striatum N. accumbens, Amygdala and Olfactory bulb
D5 Hippocampus and Hypothalamus
For the D-2 family what are the locations of the receptor subtypes D2, D3, and D4
D2 = Striatum. N. accumbens, Substantia nigra, Olfactory bulb
D3 = Striatum, Hypothalamus,
N. accumbens, and Olfactory bulb
D4= frontal cortex and midbrain
Whats the most studied chemicals associated with Parkinsons disease that was found in a batch of synthetic heroine?
what is it metabolized to?
how does it cause Parkinson’s?
MPTP
It is now known that
MPTP is metabolized to MPP+ by MAO-B. MPP+ accumulates in and eventually destroys the nigrostriatal dopamine neurons.
(note- MPTP rapidly undergoes oxidation to MPP+ . The actual toxin is
thought to be one of the intermediates in the conversion.)
Presently-available drugs are thought to alleviate symptoms of Parkinsonism by????
restoring the functional balance between dopaminergic and cholinergic systems
in the striatum
Name the Drugs that enhance dopaminergic activity (7)
l-DOPA Selegiline/Deprenyl Entacopone bromocryptine pramipexole ropinirole amantadine
how does l-DOPA enhance levels of dopamine?
dopamine precursor that
is converted to dopamine
how does Selegiline/Deprenyl enhance the levels of dopamine?
inhibit the metabolism of dopamine by MAO-B – Some evidence suggests that these agents may slow the progression of the disease, possibly by blocking the conversion of MPTP to MPP+ , but this is controversial.
how does Entacopone enhance the levels of dopamine?
inhibits the metabolism of dopamine by COMT
how does bromocryptine enhance the levels of dopamine?
stimulate post-synaptic dopamine receptors
how does pramipexole and ropinirole enhance the levels of dopamine?
newer non-ergot
dopaminergic agonists
how does ropinirole and pramipexole enhance the levels of dopamine?
newer non-ergot
dopaminergic agonists
how does amantadine enhance the levels of dopamine?
stimulate the release of dopamine
Drugs that reduce cholinergic activity (3)
theses are centrally acting antimuscarinics
- triheriphenidyl
- benztropine
- diphenhydramine
l-DOPA is the amino acid precursor of ____ that is transported to the ____ and converted to ______
amino-acid precursor of dopamine that is transported to the brain and converted to dopamine
l-DOPA and the GI tract
variable absorption from the GI tract
how does l-DOPA enter the brain?
enters the brain by active transport amino acid pump
I-DOPA is metabolized by ____ _______ to form _____ in the brain and the periphery ; a small portion may be converted to _______ and ______; the major final metabolites are _____ and _____.
metabolized by DOPA decarboxylase to dopamine in the brain and
the periphery ; a small portion may be converted to norepinephrine and
epinephrine; the major final metabolites are DOPAC and HVA.
Addition of a ______ ______- ______ ______ (Carbidopa), which itself does not enter the brain, significantly reduces the metabolism of DOPA to dopamine in the periphery. This allows a reduction in the dose of l-DOPA by about 75% and greatly decreases the severity of some peripheral side effects.
Addition of a peripheral DOPA-decarboxylase inhibitor (Carbidopa), which itself does not enter the brain, significantly reduces the metabolism of DOPA to dopamine in the periphery. This allows a reduction in the dose of l-DOPA by about 75% and greatly decreases the severity of some peripheral side effects.
because of the individual effects of I-DOPA you must _____ and monitor each patient
titrate
I-DOPA takes about ____ weeks to become effective
4
I-DOPA can stop the progression of Parkinsons (T/F)
F
Remember - Parkinson’s disease is a progressive, degenerative disorder; l-DOPA does not halt the progression of the disease! Moreover, the drug becomes less effective as the disease progresses.
Side effects of I-DOPA are Nausea and vomiting - occur in about 80% of patients receiving l-DOPA alone; tolerance usually develops how can you minimize this?
Incidence can be minimized by giving the drug in divided doses after meals, or by building up the total daily dose gradually
I-DOPA causes vomiting, whats this attributed to?
Vomiting is attributed to the stimulation of the chemoreceptor trigger zone (CRTZ) by dopamine
How can you reduce vomiting associated with I-DOPA?
Since the CRTZ is located outside of the blood-brain barrier, concurrent administration of carbidopa significantly reduces the incidence and severity of nausea.
Cardiovascular effects of l-DOPA include what? (3)
postural Hypotension
tachycardia
arrhythmias
(NOTE) Although the frequency and severity of the effects can be decreased significantly by the concurrent use of carbidopa, one must exercise extreme caution in using l-DOPA in patients with existing cardiovascular disease.
Does I-DOPA effect behavior ?
depression, psychotic reactions, hallucinations, exacerbation of psychoses, nightmares, euphoria, mood & personality changes.
SO…. YES!
the atypical antipsychotic ____ is the preferred drug for
managing psychiatric side effects of l-DOPA, but _____ is associated
with agranulocytosis, and thus requires close monitoring of patients.
clozapine
clozapine
choreiform movement is??
When taking I-DOPA when would you see these movements?
choreiform movement (countable and uncountable, plural choreiform movements) repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated;
particularly after long term therapy or when
used with carbidopa; chorea, ballismus, athetosis, dystonia, myoclonus,
tics and tremor may occur.
explain the “end of dose phenomenon” related to I-DOPA
A patient who may be showing a good therapeutic response may
suddenly exhibit parkinsonian symptoms. There are several variants of
this type of phenomenon. One is referred to as the “end of dose
phenomenon” and appears to be related to the decline in blood levels of
l-DOPA near the end of the dosage interval.
explain the “on-off” phenomenon related to I-DOPA
can occur at any time in the dosage interval
and appears to be related to the progression of the disease. These effects can be minimized by using a sustained release preparation or by adding a dopamine agonist and/or COMT inhibitor to the regimen.
what are the Endocrine Effects when taking I-DOPA
- decreased levels of prolactin due to inhibition of prolactin release
- A dopamine-containing neuronal pathway normally acts to inhibit prolactin secretion.
Miscellaneous Effects while taking I-DOPA (a-h)
note. I put theses here but doubt we will be tested on them
a. precipitation of glaucoma
b. precipitation of gout
c. hot flashes
d. taste and smell disturbances
e. elevation of liver enzymes
f. positive Coomb’s test
g. blood dyscrasias
h. exacerbation of malignant melanoma
When is the use of I-DOPA Contraindicated (a-e)
a. cardiac arrhythmias
b. psychosis
c. melanoma
d. glaucoma
e. active peptic ulcer disease
What are the Major Drug Interactions with I-DOPA (a-d)
a. pyridoxine-enhancement of extracerebral metabolism decreases
therapeutic effects
b. antipsychotics (DA antagonists) - inhibit effects
c. MAO inhibitors - hypertensive crisis (Note, this does not occur with the
selective MAO-B inhibitors when they are used at appropriate doses.
d. tricyclic antidepressants - hypertensive crises have been reported..
Carbidopa inhibits ______ ______ in the periphery but (??does/does not??) not enter the brain.
Carbidopa inhibits DOPA decarboxylase in the periphery but does not enter the brain
SIDE NOTE
permits a reduction in the dose of l-DOPA, thus reducing some of its side effects
Sinemet = _______ + _______
Sinemet = Carbidopa + l-DOPA
In addition, a sustained release of
preparation (Sinemet CR) is available. “Parcopa” is a newer combination product
with the same general combination of drugs.
Bromocryptine is an ergot derivative that act as relatively nonspecific DA receptor \_\_\_\_\_\_. It is (??more/less??) effective than l-DOPA in the treatment of Parkinson's disease .
Usedin patients who do not tolerate or respond to l-DOPA; also used as the therapeutic effects of l-DOPA diminish; may decrease severity of the ___________ phenomenon
agonists
less
use in patients who do not tolerate or respond to l-DOPA; also used as the therapeutic effects of l-DOPA diminish; may decrease severity of “on-off” phenomenon
Pharmacokinetics (2) and Side Effects (5) of Bromocryptine
Pharmacokinetics
a. oral administration
b. variable absorption
Side Effects
a. nausea and vomiting
b. postural hypotension
c. mental disturbances - confusion, agitation, hallucinations, seizures
d. choreiform movements
e. endocrine disturbances - due to inhibition of prolactin secretion
Bromocryptine used to be used in mothers of newborns but not anymore. why?
Because of its ability to inhibit prolactin secretion, bromocryptine has sometimes been used to
treat ammenorhea (is the absence of menstruation) and galactorrhea (is a milky nipple discharge unrelated to the normal milk production of breast-feeding) associated with hyperprolactinemia (is a condition of elevated serum prolactin). Although it has been used
to inhibit lactation in mothers who chose not to breast-feed their infants, it is no longer approved for
this use because of the risk of psychotic reactions and seizures in the mother. Carbergoline (Dostinex)
is a newer dopamine agonist that is approved for the treatment of hyperprolactinemia. In the
treatment of Parkinsonism, the best results with bromocryptine have been obtained when the drug
was given concurrently with l-DOPA; in some patients bromocryptine can ameliorate the “on-off”
effects that occur with l-DOPA. However, the toxicity of these two drugs, particularly their mental
effects, may also be additive. A major disadvantage of all of the agonists is that they are expensive.
Ropinirole, Pramipexole are Newer non-ergot dopaminergic agonists that may preferentially target what receptors?
what are some side effects associated with these? (8)
D2 and D3
The side effects are similar to, but less severe than with the older dopamine
agonists.
a. choreiform, dyskinetic movements
b. nausea
c. dizziness, confusion, sedation, behavioral changes, hallucinations etc.
Recent studies suggest that _______ may have antioxidant and neuroprotective effects which may be beneficial in slowing the progression of the disease
Pramipexole
Both ______ and ______ are used in the treatment of “restless leg
syndrome”
ropinrole and pramipexole
what does Amantadine do?
in Parkinsonism, it is less effective than l-DOPA but more effective than
__________ drugs
- may potentiate the actions of l-DOPA
- used as a supplement to l-DOPA
Amantadine stimulates release of dopamine from nerve endings; it may also inhibit reuptake
anticholinergic
Side effects and toxicities of Amantadine? (7)
Side effects and toxicities
a. mental disturbances, hyperexcitability, ataxia (The loss of full control of bodily movements), confusion, convulsions
b. choreiform movements
c. excreted by kidney - may require dosage adjustment in patients with impaired renal function.
1st where is MAO-B located?
2nd…. Selegiline/Deprenyl (Eldepryl) and *Rasalagine (Azilect) _____ MAO-B and prevents the breakdown of ______ in the CNS
MAO-B found mainly in CNS
inhibits MAO-B and prevents the breakdown
of dopamine in the CNS
compare Selegiline/Deprenyl (Eldepryl) and *Rasalagine (Azilect) at low doses vs high doses
At therapeutic doses, they do not interact with tyramine as do the non-selective MAO inhibitors; however, at higher doses it acts like other nonspecific MAO inhibitors
place the following in the blanks below. each can be used more than once. Pramipexole, , Selegiline, increase, decrease, l-DOPA, Rasalagine, Bromocryptine
______ is approved for use as a supplement to ______, particularly in the latter stages of parkinsonism; it may ______ the severity of the “on-off” phenomenon. ______ is a newer, more powerful drug approved for use in both the early and late stages of Parkinsons disease.
Selegiline is approved for use as a supplement to l-DOPA, particularly in the latter stages of parkinsonism; it may decrease the severity of the “on-off” phenomenon. Rasalagine is a newer, more powerful drug approved for use in both the early and late stages of Parkinsons disease.
selegiline may be of some benefit in the treatment of ______ disease as well as parkinsons
Some experts now advocate the use of selegiline early in the treatment of Parkinsons disease, why is this controversial.
There is also preliminary evidence that selegiline may be of some benefit in the treatment of Alzheimer’s disease. However, this is very controversial.
Several years ago, reports in the literature suggested that selegiline may slow the progression of Parkinsons disease, possibly by inhibiting the conversion of MPTP to neurotoxic metabolites. However, recent studies have not confirmed the earlier results. Nevertheless, some experts now advocate the use of selegiline early in the treatment of Parkinsons disease, although this is
controversial
Selegiline Side effects include:
Side effects include:
a. tremor, dyskinesias, choreiform movements
b. hallucinations, agitation, behavior and mood changes,
c. nausea, weight loss
d. “cheese toxicity” with tyramine is usually not seen at common doses, but
can occur at high doses.
what does Entacapone do?
can it be combined with another drug to treat parkinson’s?
newer drug that inhibit the metabolism of dopamine and l-DOPA by COMT. It provides a more sustained blood level of l-DOPA
yes approved for use in conjunction with l-DOPA and l-DOPA plus carbidopa for the treatment of parkinsons disease
main adverse effects of Entacapone are due to what?
name 3 side effects
main adverse effects are due to increased levels of dopamine and other catecholamines (hallucinations, nausea, hypertension, etc).
____+ _____ + ______ = Stalevo
Stalevo is a new combination product that contains l-DOPA plus carbidopa plus entacapone
- name 2 Anticholinergic Drugs
- Anticholinergic Drugs may be effective in treating (??initial stages/mild/moderate??) parkinson’s. usually more effective against tremor than rigidity.
Anticholinergic Drugs benztropine, trihexyphenidyl
may be effective in mild parkinsonism, usually more effective against tremor than rigidity
drugs of choice for treatment of iatrogenic Parkinsonism from DA antagonists
Anticholinergic Drugs benztropine, trihexyphenidyl
Anticholinergic Drugs side effects? (a-d)
Anticholinergic Drugs benztropine, trihexyphenidyl
side effects
a. automatic - dry mouth, dry, hot skin, hyperthermia, constipation, urine
retention, loss of visual accommodation, tachycardia
b. behavioral - sedation, confusion, memory impairment, especially in
elderly patients
c. drug interactions with CNS depressants (alcohol, sedatives, opioids,
muscle relaxants, etc..)
d. In addition to blocking muscarinic receptors, benztropine has some ability
to inhibit the synaptic reuptake of dopamine.
name 2 Anticholinergic Drugs
Anticholinergic Drugs benztropine, trihexyphenidyl
name the Antihistamine and explain why its effective in treating parkinson’s
*diphenhydramine (Benadryl)
effectiveness in parkinsonism is primarily due to anticholinergic activity
Parkinson’s Disease (Primary Parkinsonism, Idiopathic Parkinsonism)
mild-moderate symptoms – amantadine, ______ agonists, ______ inhibitors or __________ may be adequate, but are generally less effective than _____. The newer dopamine agonists _______ and ______ are becoming increasingly popular as first line drugs
Parkinson’s Disease (Primary Parkinsonism, Idiopathic Parkinsonism)
mild-moderate symptoms – amantadine, dopamine agonists, MAO-B inhibitors or anticholinergics may be adequate, but are generally less effective than l-DOPA. The newer dopamine agonists pramipexole and ropinirole are becoming increasingly popular as first line drugs
Note: While some experts recommend that l-DOPA and carbidopa therapy should be started early in the course of the disease, others recommend that dopamine agonists, particularly pramipexole, should be the drugs of choice for initial therapy.
Parkinson’s Disease (Primary Parkinsonism, Idiopathic Parkinsonism) moderate - severe symptoms
- _______ and _______ with or without _______ .
moderate - severe symptoms - l-DOPA and carbidopa with or without entacapone.
Note: While some experts recommend that l-DOPA and carbidopa therapy should be started early in the course of the disease, others recommend that dopamine agonists, particularly pramipexole, should be the drugs of choice for initial therapy.
Parkinson’s Disease (Primary Parkinsonism, Idiopathic Parkinsonism)
While some experts have advocated the early use of ______, the evidence is controversial and the drug is not officially approved for this use. ______ is a new drug that is approved for use in early and late stages.
While some experts have advocated the early use of seligeline, the evidence is
controversial and the drug is not officially approved for this use. Rasaligine is a
new drug that is approved for use in early and late stages.
how to stop or reverse Iatrogenic Parkinsonism caused by antipsychotic drugs, reserpine, or metoclopramide (Reglan)
(2)
i dont know if this is on the exam but it was in bold in the notes
- stop or decrease dose of drug
2. add anticholinergic drug for more rapid reversal
Huntingdons Disease Etiology (6)
Etiology
1. autosomal dominant
2. onset in middle-age
3. progressive deterioration
4. many of the extrapyridal motor symptoms are similar to those seen in tardive
dyskinesia
5. pharmacologically similar to tardive dyskinesia
6. Effects at treatment have focussed on decreasing dopaminergic activity
(antipsychotics) or enhancing the effects of GABA (benzodiazepines) or
acetylcholine (physostigmine, rivastigmine). Presently available treatments are
inadequate.
