Pharmacology of Movement Disorders

Question 1

Based on the pathophysiology of parkinson disease, patients may be treated with what 2 general classes of drugs?

Answer 1

Dopamine agonists and/or anticholinergic agents

Question 2

______ is one of the first-line treatments for parkinsons because it is the immediate metabolic precursor to dopamine. It enters the CNS via ____________; dopamine itself cannot cross the BBB

Answer 2

Levodopa; L-amino acid transporter (LAT)

Question 3

What is often co-administered with levodopa and why?

Answer 3

Carbidopa (a DOPA decarboxylase inhibitor that does not cross BBB)

Results in reduced peripheral metabolism, increased half-life, and increased levodopa available for entry into the brain. Thus, the daily requirements for levodopa are reduced

Also decreases incidence of GI side effects from levodopa including anorexia, nausea, and vomiting

Question 4

Describe the “wearing-off” phenomenon that can occur during long-term treatment of PD with levodopa

Answer 4

Each dose effectively improves mobility for period of time (1-2 hrs), but rigidity and akinesia return rapidly at the end of the dosing interval

Increasing the dose and frequency of administration can improve symptoms, but this is often limited by the development of dyskinesias (distortion or impairment of volutary movement)

Question 5

Adverse effects of levodopa

Answer 5

GI: anorexia, nausea, vomiting (lessened when +carbidopa)

Cardio: postural hypotension (improves with duration of tx), hypertension with large doses, or in combo with nonselective MAOIs or sympathomimmetics

Dyskinesias: most frequently choreoathetosis of face and distal extremities

Behavioral effects: depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria

Question 6

What are some options for the behavioral effects seen with levodopa therapy?

Answer 6

Atypical antipsychotic agents (clozapine, olanzapine, quetiapine, risperidone)

Question 7

What is the on-off phenomenon sometimes associated with levodopa therapy? What is an option to alleviate this?

Answer 7

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

Subcutaneous injections of apomorphine may provide temporary benefit to those patients with severe off-periods

Question 8

Parkinsons patients taking ___________ may experience hypertensive crisis when combined with levodopa

Answer 8

Monoamine oxidase A inhibitors

Question 9

In what patients is levodopa contraindicated?

Answer 9

Psychotic patients

Patients with angle-closure glaucoma

Patients with hx of melanoma (levodopa is a precursor to melanin)

Use with caution in pts with active peptic ulcer d/t possibility of GI bleeding

Question 10

Clinical use of dopamine receptor agonists in parkinsons patients

Answer 10

Lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy

Can be administered in addition to carbidopa-levodopa therapy, may help with end-of-dose akinesia or on-off phenomenon

Question 11

Ergot alkaloid derivative that is a D2 agonist; also approved for tx of endocrine disorders (hyperprolactinemia, prolactin-secreting adenoma, acromegaly)

Answer 11

Bromocriptine

Bioavailability 28% (extensive first-pass metabolism with CYP3A4) with peak plasma concentration w/i 1-3 hours; 15 hour half life

Question 12

Preferential affinity for D3 receptors; also approved for tx of moderate-to-severe primary restless leg syndrome

Answer 12

Pramipexole

Peak plasma concentration reached in 2 hours with half life of 8 hours; 90% excreted unchanged in the urine [renal insufficiency may require dose adjustment]

Question 13

Preferential affinity for D2 receptors; also approved for the tx of RLS

Answer 13

Ropinirole

CYP450 metabolism (primarily CYP1A2); peak plasma concentration reached in 1-2 hours with a half-life of 6 hours

Question 14

Adverse effects associated with dopamine receptor agonists

Answer 14

GI: anorexia, nausea, and vomiting can occur (reduced if taken with meals); constipation, dyspepsia, and symptoms of reflux esophagitis

Cardio: postural hypotension, digital vasospasm, peripheral edema, cardiac arrhythmias

Dyskinesias: similar to those introduced by levodopa; reversed by reducing total dose

Mental disturbances: confusion, hallucinations, delusions (more severe than with levodopa) — clears when meds are stopped

Question 15

Contraindications to using dopamine receptor agonists

Answer 15

Patients with a hx of psychotic illness, recent MI, or with active peptic ulceration

Contraindicated in pts with peripheral vascular disease d/t vasoconstricting effects

Question 16

There are 2 forms of monoamine oxidase:

MAO-A preferentially metabolizes ______ and ______

MAO-B preferentially metabolizes _____ and _______

_______ and ________ are metabolized equally by MAO-A and MAO-B

Answer 16

NE; serotonin

Phenylethylamine; benzylamine

Dopamine; tryptamine

Question 17

Selective irreversible MAO-B inhibitor (inhibits MAO-A at high doses); slows the breakdown of dopamine and prolongs the antiparkinsonian effects of levodopa; may reduce mild on-off or wearing-off phenomena

Utilized as adjunctive therapy in pts with declining or fluctuating responses to levodopa

Answer 17

Selegiline

10% bioavailability with peak plasma concentrations within an hour

Question 18

Selegiline may be contraindicated in patients taking what meds?

Answer 18

Meperidine, tricyclic antidepressants, or SSRIs (risk of serotonin syndrome)

Question 19

Irreversible inhibitor of MAO-B; more potent than Selegiline and used as a neuroprotective agent and for early symptomatic treatment of PD

Answer 19

Rasagiline

Question 20

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

Answer 20

Catechol-O-methyltransferase (COMT)

Question 21

COMT inhibitors such as _____ and ______ prolong the activity of levodopa by inhibiting its peripheral metabolism, which decreases clearance and increases bioavailability

These drugs may be helpful in pts receiving levodopa who have developed response fluctuations

Answer 21

Tolcapone; entacapone

Question 22

Of the COMT inhibitors, ______ is central and peripheral acting, may cause an increase in liver enzyme levels, and has been associated (rarely) with death from acute hepatic failure

______ is peripheral acting only

Answer 22

Tolcapone

Entacapone

Question 23

Side effects associated with COMT inhibitors

Answer 23

Orange discoloration of urine, diarrhea, abdominal pain, and sleep disturbance

Question 24

MOA of apomorphine

Answer 24

Dopamine agonist at dopamine D2 receptors; injected subcutenously for quick, temporary relief of off-periods of akinesia in patients on dopaminergic therapy (clinical benefits within 10 mins)

Question 25

Adverse effects associated with apomorphine

Answer 25

Nausea, dyskinesias, drowsiness, sweating, hypotension, injection site bruising

Question 26

What antiemetic is usually given as a pre-treatment to apomorphine therapy?

Answer 26

Trimethobenzamide

Question 27

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

Answer 27

Amantadine

Half life of 2-4 hours; peak plasma concentrations in 1-4 hours; excreted mostly unchanged in the urine

Benefits may be short-lived

Question 28

Adverse effects of amantadine

Answer 28

Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion

Headache, heart failure, postural hypotension, urinary retention, and GI disturbance

Livedo reticularis

Question 29

What vascular condition is caused by amantadine, and what is it characterized by?

Answer 29

Livedo reticularis — characterized by purplish mottled discoloration of skin, usually on legs

Question 30

Amantadine should be used with caution in patients with hx of what 2 conditions?

Answer 30

Seizures or heart failure

Question 31

Clinical use of anticholinergic drugs in pts with PD

Answer 31

Centrally acting mAChR antagonists may improve tremor and rigidity, but have little effect on bradykinesia

Question 32

What anticholinergic drugs are used in pts with PD?

Answer 32

Benztropine
Biperiden
Orphenadrine
Procyclidine
Trihexyphenidyl

Question 33

Adverse effects of anticholinergic drugs used for PD

Answer 33

Sedation, mental confusion, constipation, urinary retention, blurred vision

Question 34

What medications are used to treat tremor?

Answer 34

Metoprolol and propranolol in tremors where B1-receptors have been implicated

Primidone (anti-epileptic)

Topirimate (serotonin receptor agonist)

Alprazolam (benzodiazepine)

IM injection of botulinum toxin A

Question 35

Although Huntington disease only rarely justifies pharmacological therapy (no current therapy slows disease progression), drugs that impair dopaminergic neurotransmission often alleviate chorea — what are some examples?

Answer 35

Reserpine
Tetrabenazine
Olanzapine
Phenothiazines (perphenazine)
Butyrophenones (haloperidol)

Question 36

What are the most predictive and effective pharmacologic agents used to treat tics? What are their adverse effects?

Answer 36

Neuroleptic antipsychotics = tetrabenzaine, haloperidol, pimozide

However, they cause extrapyramidal syndromes, weight gain, sedation, irritability, and various phobias

Question 37

Since neuroleptic antipsychotics are not always the first choice for tics due to their side effect profile, what is the other option?

Answer 37

Alpha-adrenergic agents like clonidine or guanfacine

In some cases botulinum toxin A injection at the tic site

Question 38

Pharmacologic treatment of restless leg syndrome

Answer 38

Symptoms may resolve with correction of coexisting iron-deficiency anemia (if present) and often respond to dopamine agonists, levodopa, diazepam, clonazepam, or opiates

Also non-ergot dopamine agonists pramipexole and ropinirole, and alpha-2-delta calcium channel ligands (gabapentin and pregabalin)

Question 39

What is the only drug to have any impact on ALS, shown to prolong survival by a few months?

What is its MOA and potential adverse effects?

Answer 39

Riluzole

Inhibits glutamate release and blocks postsynaptic NMDA- and kainite-type glutamate receptors and inhibits voltage-dependent Na+ channels

Adverse effects are nausea and weakness

Question 40

Medication used for Wilson disease that acts as a chelating agent that forms a stable complex with copper and is readily excreted by the kidney

Answer 40

Penicillamine

Question 41

Adverse effects associated with penacillamine (used for Wilson disease)

Answer 41

Nausea, vomiting, nephritic syndrome, myasthenia, optic neuropathy, and various blood disorders

Question 42

Drug used in Wilson disease that reduces intestinal absorption of copper and can be prescribed in addition to penicillamine

Answer 42

Potassium disulfide

Question 43

_____ (chelating agent); ______ and _______ (increase fecal excretion of copper by decreasing GI absorption) are also useful for Wilson disease

Answer 43

Trientine; zinc acetate; zinc sulfate

Question 44

A patient who has been treated for Parkinson disease for about a year presents with purplish, mottled changes to her skin. How would you describe these findings, and what drug is the most likely cause of this cutaneous response?

Answer 44

Livedo reticularis; amantadine

Question 45

A 72 y/o male with a 3-year hx of Parkinson disease is prescribed trihexyphenidyl as an adjunct to levodopa/carbidopa. What is the most likely purpose or action of this drug as part of the overall drug treatment plan?

A. To counteract sedation that is likely to be caused by other meds
B. To help correct further the dopamine-ACh imbalance that accounts for parkinsonian signs and symptoms
C. To manage cutaneous allergic responses that are so common with typical antiparkinson drugs
D. To prevent the development of manic/hypomanic responses to other antiparkinson drugs
E. To reverse tardive dyskinesias if the parkinsonism was induced by an antipsychotic drug

Answer 45

B. To help correct further the dopamine-ACh imbalance that accounts for parkinsonian signs and symptoms

Question 46

About one year ago you diagnosed schizophrenia in a 23-year-old otherwise healthy man. As a result of intensive psychotherapy, careful titration of chlorpromazine (DA antagonist; used in the treatment of schizophrenia) dosages, and remarkably good compliance with drug and other therapies, he is well enough to return to work. Several months later, at a scheduled visit, you observe numerous signs and symptoms of drug-induced parkinsonism, and the patient reports rather distressing symptoms of akathisias (restlessness, jitteriness, etc). However, typical manifestations of schizophrenia seem to be well controlled. What drug could be added that will most likely alleviate the motor and subjective parkinsonian responses, and pose the lowest risk of causing schizophrenia signs and symptoms to reappear?

A. COMT inhibitor
B. Centrally acting cholinesterase inhibitor
C. Benztropine
D. Levodopa or levodopa + carbidopa
E. Levodopa + carbidopa

Answer 46

C. Benztropine