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#US Neuro 2 Depression COPY ahmed > Lecture 2: Pharmacology of Movement Disorders > Flashcards

Lecture 2: Pharmacology of Movement Disorders Flashcards

1
Q

Which 4 drugs are Dopamine receptor agonists?

A
  1. Apomorphine
  2. Bromocriptine
  3. Pramipexole
  4. Ropinirole
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2
Q

What 2 drugs are Monoamine oxidase inhibitors?

A
  1. Rasagiline
  2. Selegiline
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3
Q

What are the 2 Catechol-O-methyltransferase inhibitors?

A
  1. Entacapone
  2. Tolcapone
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4
Q

What are the 5 anticholinergic drugs used for movement disorders?

A
  1. Benztropine
  2. Biperiden
  3. Orphenadrine
  4. Procyclidine
  5. Trihexyphenidyl
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5
Q

Under normal conditions, dopaminergic neurons originating in the substantia nigra inhibit the GABAergic output from the _________

A

Striatum (caudate and putamen)

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6
Q

Cholinergic neurons exert an _________ effect on GABAergic neurons of the striatum

A

Excitatory

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7
Q

How does Levodopa enter the CNS?

A

L-amino acid transporter (LAT); dopamine does not cross the BBB

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8
Q

What is the MOA of Levodopa?

A

Agonist at dopamine (D) receptors

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9
Q

What is the absorption of Levadopa like?

How long to reach peak plasma concentration and what is the half life?

A

- Rapidly absorbed from the small intestine w/ a peak plasma concentration usually between 1-2 hours after an oral dose

  • Half-life usually between 1-3 hours
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10
Q

How is the problem of Levadopa being metabolized extracerebrally (in the periphery) solved?

What effects will this decrease and increase?

A
  • Coadministration with a DOPA decarboxylase inhibitor that does NOT cross the BBB (carbidopa)
  • This will significantly decrease the adverse peripheral effects of: nausea, vomiting, and postural hypotension!
  • But may enhance the adverse behavioral effects!
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11
Q

What is the result of co-administration of carbidopa with levodopa?

A
  • Reduced peripheral metabolism of levadopa
  • Increased half-life
  • Increased levodopa available for entry into the brain

*May reduce the daily requirments of levodopa by approximately 75%

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12
Q

What are the adverse GI effects of levadopa?

A
  • Given in absence of peripheral decarboxylase inhibitor causes: anorexia, nausea, and vomiting (activation of chemoreceptor trigger zone)
  • Less troublesome effects when combo of levodopa/carbidopa given
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13
Q

What are the cardiovascular effects of levodopa?

A
  • Postural hypotension (frequently asymptomatic), diminishes with continuing tx
  • HTN can occur when taking large doses of levodopa or in combo w/ non-selective monoamine oxidase inhibitors or sympathomimetics
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14
Q

What are some adverse effects on movement that can result from treatment w/ Levodopa?

How common?

A
  • Dyskinesias in 80% of patients!!!
  • Choreoathetosis (movement of intermediate speed) of FACE and distal extremities
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15
Q

What are some of the adverse behavioral effects caused by treatment with Levodopa?

A

Depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, or euphoria

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16
Q

What is the “on-off phenomenon” associated with Levodopa?

A

Off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia

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17
Q

Administration of which drug and via what route, may provide temporary benefit to those patients with severe off-periods while taking Levodopa?

A

Subcutaneous injections of apomorphine (DA receptor agonist)

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18
Q

Levodopa is contraindicated in patients taking which drug?

May cause what adverse effect?

A
  • Pts taking monoamine oxidase A inhibitors (or within 2 weeks of discontinuation)
  • May experience hypertensive crisis
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19
Q

Levodopa is contraindicated in which patients?

A
  • Psychotic patients
  • Patients w/ angle-closure glaucoma (can be used with well-controled open-angle glaucoma)
  • Hx of melanoma or w/ suspicious undiagnosed skin lesions (levadopa is precursor of skin melanin)
  • Use w/ caution in pt w/ active peptic ulcer due to possibility of GI bleeding
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20
Q

Which drug class has a lower incidence of the reponse fluctuations and dyskinesia that occur w/ long-term levodopa therapy?

A

Dopamine receptor agonists

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21
Q

Which dopamine receptor agonist is an ergot alkaloid derivative and acts on the D2 receptors?

A

Bromocriptine

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22
Q

Bromocriptine (dopamine receptor agonist) is also approved for the treatment of which disorders?

A

Endocrine (i.e., hyperprolactinemia, prolactin secreting adenomas, acromegaly)

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23
Q

Which CYP metabolizes Bromocriptine?

A

CYP3A4 (extensive first pass metabolism, bioavailabilty 28%)

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24
Q

Which Dopamine receptor agonist has preferential affinity for D3 receptors?

A

Pramipexole

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25
Q

Pramipexole (dopamine receptor agonist) is also approved for the treatment of what?

A

Moderate-to-severe Restless Leg Syndrome (RLS)

26
Q

Which dopamine receptor agonist has preferential affinity for D2 receptors and is also approved from the treatment of RLS?

A

Ropinirole

27
Q

Which CYP metabolizes Ropinirole?

A

CYP450 (primarily CYP1A2)

28
Q

What are the adverse GI effects caused by dopamine receptor agonists?

A
  • Anorexia, nausea, and vomiting (reduced if taken before meals)
  • Constipations, dyspepsia, and sx’s of reflux esophagitis
29
Q

What are the adverse cardiovascular effects caused by dopamine receptor agonists?

A
  • Postural hypotension (more common early in therapy)
  • Digital vasospasm (during long-term tx)
  • Peripheral edema and cardiac arrhythmias (may indicate need to discontinue therapy)
30
Q

What are the adverse effects on movement caused by dopamine receptor agonists?

A

Dyskinesias similar to those by levodopa (reversed by reducing dose)

31
Q

What are the adverse mental effects caused by dopamine receptor agonists?

A
  • Confusion, hallucinations, delusions
  • Other psychiatric rxns are more severe than with levodopa and clear during withdrawl of medication
32
Q

Dopamine receptor agonists should be used with caution in which patients?

Contraindicated in?

A
  • Patients w/ hx of psychotic illness, recent MI, or w/ active peptic ulceration
  • Contraindicated in pts w/ peripheral vascular disease (vasoconstricting effects)
33
Q

What are the 2 forms of monoamine oxidase and what does each preferentially metabolize?

Which 2 compounds are metabolized equally by each?

A

1) MAO-A metabolizes norepinephrine and serotonin
2) MAO-B metabolizes phenylethylamine and benzylamine

*Dopamine and tryptamine are metabolized equally by MAO-A and MAO-B

34
Q

What is the MOA of the Monoamine oxidase (MAO) inhibitor Selegiline (aka deprenyl)?

Used for the treatment of?

A
  • Selective irreversible MAO-B inhibitor (inhibits MAO-A at high doses)
  • Slows breakdown of dopamine and prolongs the antiparkinsonian effects of levadopa
  • May reduce mild on-off or wearing-off phenomena
35
Q

What is the bioavailability of Selegiline (aka deprenyl)?

A

10% bioavailability

36
Q

The monoamine oxidase (MAO) inhibitor, Selegiline (aka deprenyl), is contraindicated/should be used with caution in which patients?

A

Pts taking meperidine, tricyclic antidepressants, or SSRIs (risk of serotonin syndrome)

37
Q

What is the MOA of the Monoamine oxidase (MAO) inhibitor, Rasagiline?

Used for treatment of?

A
  • Irreversible inhibitor of MAO-B; more potent than selegiline
  • Used as a neuroprotective agent and for early symptomatic tx of PD
38
Q

The combined administration of levodopa and a _____________ must be avoided because it may lead to a hypertensive crisis (peripheral accumulation of NE)

A

Nonselective MAO inhibitor

39
Q

What is the action of Catechol-O-methyltransferase (COMT) on levodopa?

A

Metabolizes levadopa to 3-O-methyldopa, which competes with levodopa for transport across the intestinal mucosa and BBB

40
Q

COMT inhibitors (tolcapone and entacapone) are used in conjunction with levadopa for what?

May be helpful in which patients?

A
  • Prolongs the activity of levodopa by inhibiting its peripheral metabolism, which decreases clearance and increases bioavailability
  • Helpful in pts receiving levodopa who have developed response fluctuations
41
Q

How does Tolcapone differ from Entacapone in regards to site of action?

A
  • Tolcapone is central and peripheral acting
  • Entacapone is peripheral acting only
42
Q

What is a possible negative side effect of Tolcapone?

A
  • Increase in liver enzyme levels
  • HEPATOTOXICITY*** CIS Q
  • Has been associated, rarely, with death from acute hepatic failure
43
Q

Although most of the side effects of COMT inhibitors are due to use with levodopa, what are some additional side effects seen?

A
  • Orange discoloration of the urine
  • Diarrhea, abdominal pain, and sleep disturbances
44
Q

What is the MOA of Apomorphine?

A

Dopamine agonist at D2 receptors

45
Q

How is Apomorphine administered and for what?

A

Injected subcutaneously for quick, temporary relief of off-periods of akinesia in patients on dopaminergic therapy (clinical benefits within 10 mins.)

46
Q

To combat the adverse effect of nausea associated wth Apomorphine, what can be used as a pre-treatment?

A

Trimethobenzamide (antiemetic)

47
Q

What is the Amantadine and its MOA as a drug used in PD?

A
  • Antiviral agent whose MOA in parkinsonism is unknown
  • May potentiate dopaminergic function by influencing synthesis, release, or reuptake of dopamine
48
Q

Which drug used in PD may cause livedo reticularis, a vascular condition characterized by purplish mottled discoloration of the skin, usually on the legs?

A

Amantadine

49
Q

Amantadine should be used with caution in which patients?

A

Hx of seizures or heart failure

50
Q

What are the anticholinergic drugs (benztropine, biperiden, ophenadrine, procyclidine, trihexyphenidyl) used for in PD?

Which receptor do they target?

A
  • mAChR antagonists may IMPROVE tremor and rigidity
  • Not much effect on bradykinesia
51
Q

What is the standard of care for the use of anticholinergic drugs in PD?

A
  • Start w/ low dose, which is titarted upwards in amount until benefit occurs or adverse effects limit use
  • If one agent unsucessful, trial w/ different agent is warranted and may be sucessful
52
Q

Tremors due to β1-receptors respond well to which 2 Beta-blockers?

A
  • Metoprolol
  • Propranolol
53
Q

Symptomatic tremor can be controlled with smaller doses of which antiepileptic drug?

A

Primidone

54
Q

Which serotonin receptor agonist, benzodiazepine, and intramuscular injections of which drug have been show to be of benefit in the treatment of symptomatic tremors?

A
  • Topirimate (serotonin receptor agonist)
  • Alprazolam (benzodiazepine)
  • Intramuscular injections of botulinum toxin A
55
Q

Which 2 drugs impair dopaminergic neurotransmission and often alleviate the chorea associated with HD?

A
  • Reserpine
  • Tetrabenazine
56
Q

What drug/class is the most predictive and effective pharmacologic approach for treating Tics?

Adverse effects?

A
  • Neuroleptic antipsychotics: pimozide
  • Cause extrapyramidal syndromes, weight gain, sedation, irritability, and various phobias
57
Q

Which drugs are effective in the treatment of Tics and have less adverse effects?

A
  • α-adrenergic agents: clonidine and guanfacine
  • Injection of botulinum toxin A at tic site is beneficial in some cases
58
Q

Symptoms are Restless Leg Syndrome may resolve with correction of which co-existing deficiency?

A

Iron-deficiency anemia

59
Q

Which drug is the only drug to have any impact on survival in ALS and may prolong survival by a few months?

A

Riluzole

60
Q

What is the MOA of Riluzole used in the treatment of ALS?

Major adverse effects?

A
  • Inhibits glutamate release and blocks postsynaptic NMDA- and kainite-type glutamate receptors
  • Inhibits voltage-dependent Na+ channels
  • Adverse effects: nausea and weakness
61
Q

Which drugs may be used in the treatment of Wilson disease?

How does each drug work?

A
  • Penicillamine: chelating agent, forms stable complex w/ copper and is readily excreted by kidney
  • Potassium disulfide: reduces intestinal absorption of copper
  • Trientine (chelating agent); zinc acetate and zinc sulfate (increase fecal excretion of copper by decreasing GI absorption)
62
Q

What are the adverse effects of Penicillamine used in the treatment of Wilson disease?

A
  • Nausea and vomiting
  • Nephritic syndrome
  • Myasthenia
  • Optic neuropathy
  • Various blood disorders

*After remission pts may require a maintenance dose

#US Neuro 2 Depression COPY ahmed (17 decks)

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