Movement Disorders Pharm Flashcards by Maren Osterholt

Which 4 drugs are Dopamine receptor agonists?

Apomorphine
Bromocriptine
Pramipexole
Ropinirole

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What 2 drugs are Monoamine oxidase inhibitors?

Rasagiline
Selegiline

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What are the 2 Catechol-O-methyltransferase inhibitors?

Entacapone
Tolcapone

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What are the 5 anticholinergic drugs used for movement disorders?

Benztropine
Biperiden
Orphenadrine
Procyclidine
Trihexyphenidyl

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

Striatum (caudate and putamen)

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

Excitatory

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How does Levodopa enter the CNS?

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

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What is the MOA of Levodopa?

Agonist at dopamine (D) receptors

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What is the absorption of Levadopa like?

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

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

What effects will this decrease and increase?

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

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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What are the adverse GI effects of levadopa?

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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What are the cardiovascular effects of levodopa?

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

How common?

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

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

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

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

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

Subcutaneous injections of apomorphine (DA receptor agonist)

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Levodopa is contraindicated in patients taking which drug?

May cause what adverse effect?

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

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Levodopa is contraindicated in which patients?

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

Dopamine receptor agonists

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

Bromocriptine

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

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

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Which CYP metabolizes Bromocriptine?

CYP3A4 (extensive first pass metabolism, bioavailabilty 28%)

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Which Dopamine receptor agonist has preferential affinity for D3 receptors?

Pramipexole

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

Moderate-to-severe Restless Leg Syndrome (RLS)

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

Ropinirole

Which CYP metabolizes Ropinirole?

CYP450 (**primarily CYP1A2**)

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

- Anorexia, nausea, and vomiting (reduced if taken **before** meals) - Constipations, dyspepsia, and sx's of reflux esophagitis

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

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

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

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

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

- Confusion, hallucinations, delusions - Other psychiatric rxns are **more severe** than with levodopa and clear during withdrawl of medication

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

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

What are the 2 forms of monoamine oxidase and what does each preferentially metabolize? Which 2 compounds are metabolized equally by each?

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

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

- 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

What is the bioavailability of Selegiline (aka deprenyl)?

10% bioavailability

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

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

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

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

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

**Nonselective** MAO inhibitor

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

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

COMT inhibitors (tolcapone and entacapone) are used in conjunction with levadopa for what? May be helpful in which patients?

- **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**

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

- **Tolcapone** is central and peripheral acting - **Entacapone** is peripheral acting only

What is a possible negative side effect of Tolcapone?

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

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

- **Orange** discoloration of the urine - Diarrhea, abdominal pain, and sleep disturbances

What is the MOA of Apomorphine?

Dopamine agonist at **D2 receptors**

How is Apomorphine administered and for what?

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

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

Trimethobenzamide (antiemetic)

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

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

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

Amantadine

Amantadine should be used with caution in which patients?

Hx of seizures or heart failure

What are the anticholinergic drugs (benztropine, biperiden, ophenadrine, procyclidine, trihexyphenidyl) used for in PD? Which receptor do they target?

- **mAChR antagonists** may **IMPROVE** **tremor** and **rigidity** - **Not much** effect on **bradykinesia**

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

- 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

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

- Metoprolol - Propranolol

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

Primidone

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

- **Topirimate** (serotonin receptor agonist) - **Alprazolam** (benzodiazepine) - Intramuscular injections of **botulinum toxin A**

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

- Reserpine - Tetrabenazine

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

- Neuroleptic antipsychotics: **pimozide** - Cause extrapyramidal syndromes, weight gain, sedation, irritability, and various phobias

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

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

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

Iron-deficiency anemia

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

Riluzole

What is the MOA of Riluzole used in the treatment of ALS? Major adverse effects?

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

Which drugs may be used in the treatment of Wilson disease? How does each drug work?

- **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)

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

- Nausea and vomiting - Nephritic syndrome - Myasthenia - Optic neuropathy - Various blood disorders \*After remission pts may require a maintenance dose