Drugs For Movement Disorders DSA Flashcards Preview

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Flashcards in Drugs For Movement Disorders DSA Deck (50):
1

List levodopa and combos

Levodopa
Carbidopa
Levodopa + carbidopa
Levodopa + carbidopa + entacapone

2

List dopamine receptor agonists

Apomorphine
Bromocriptine
Pramipexole
Ropinirole

3

List monoamine oxidase inhibitors

Rasagiline
Selegiline

4

List catechol-O-methyltransferase inhibitors

Entacapone
Tolcapone

5

List anticholinergic drugs

Benztropine
Biperiden
Orphenadrine
Procyclidine
Trihexyphenidyl

6

List miscellaneous agents

Metoprolol, propranolol
Riluzole
Primidon
Topirimate
Alprazolam
Botulinum toxin A
Reserpine, tetrabenazine
Olanzapine
Perphenazine
Haloperidol, pimozide
Clinidine, guanfacine
Diazepam, clonazepam
Penicillamine
Potassium disulfide
Trientine
Zinc acetate, zinc sulfate

7

Describe intro and background of movement disorders

Neurodegenerative disorderds are characterized by progressive and irreversible loss of neurons from specific regions of brain
Examples that manifest as abnormalities in control of movement include Parkinson disease (PD) and Huntington disease (HD)
Alzheimer disease and amyotrophic lateral sclerosis (ALS) are also neurodegenerative disorders but result in impaired memory and cognitive ability (Alzheimer) and muscular weakness (ALS)
Pharmacological treatment is limited mostly to symptomatic treatments that do not alter course of underlying disease

8

Describe tremor

Involuntary trembling or quivering
Consists of rhythmic oscillatory movement around a joint and is best characterized by its relation to activity
Tremors may be due to genetic causes, lesions of brainstem or cerebellum, drug and alcohol toxicity

9

Describe postural tremor

Tremor of a part during maintenance of sustained posture (outstretched upper limb when holding a cup)

10

Describe essential tremor

Tremor of a part during movement (outstretched upper limb when lifting a cup
Termed intention tremor

11

Describe parkinsonian tremor

Consists of slow, regular movements of hands and sometimes lower limbs, neck, face, or jaw
Typically stops upon voluntary movement of the part and is intensified by stimuli such as cold, fatigue, and strong emotions
Tremor at rest is characteristic of parkinsonism

12

Describe chorea

Occurrence of a variety of continual, rapid, highly complex, jerky, dyskinetic movements that look well coordinated but are actually involuntary
May be hereditary (as in HD) or may occur as a complication of a number of general medical disorders and of therapy with certain drugs

13

Describe tics

Involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization, experienced as irresistible although it can be suppressed for some length of time
Occurrence is exacerbated by stress and diminished during sleep or engrossing activities
Tics may be psychogenic or neurogenic in origin and are classified as either simple (eye blinking, shoulder shrugging, coughing, grunting, snorting, or barking) or complex (facial gestures, grooming motions, coprolalia, echolalia, or echokinesis)
Maybe single or multiple and transient or chronic
Patients with Gilles de la Tourette syndrome experience tics

14

Describe Parkinson disease

Clinical syndrome consisting of four cardinal features
1. Bradykinesia (slowness and poverty of movement)
2. Muscular rigidity
3. Resting tremor (usually abates during voluntary movement)
4. Impairment of postural balance leading to disturbances of gait and falling

15

Describe pathophysiology of Parkinson disease

Pathological hallmark of PD is a loss of pigmented, dopaminergic neurons of substantia nigra, with appearance of intracellular inclusions known as Lewy bodies
Although progressive loss of dopaminergic neurons occurs during normal aging, patients with PD lose 70-80% of dopaminergic neurons
Under normal conditions, dopaminergic neurons originating in substantia nigra inhibit GABAergic output from striatum (caudate and putamen), while cholinergic neurons exert an excitatory effect on GABAergic neurons
Selective loss of dopaminergic neurons in patients with PD results in disinhibition of GABAergic neurons and distributed movement
Based on this, PD patients may be treated with dopamine agonists and/or anticholinergic agents

16

Describe basic pharmacology of Levodopa (L-dopa)

Immediate metabolic precursor to dopamine
Enters CNS via an L-amino acid transporter (LAT) (dopamine does not cross BBB)
MOA: agonist at dopamine (D) receptors. D2 receptor most inovled in benefits of antiparkisonism drugs (though D1 and D3 receptors do appear to play a role but to a lesser degree)
Rapidly absorbed fro small intestine with a peak plasma concentration usually between 1-2 hours after oral dose (half-life usually between 1-3 hours)
Only 1-3% of administered levodopa actually enters brain unaltered (remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine)
Coadministration of leveodopa with a DOPA decarboxylase inhibitor that does not cross BBB (carbidopa) results in reduced peripheral metabolism, increased plasma levels, increased half-life, and increased levodopa available for entry into brain)
Coadministration may reduce daily requirements of levodopa by approximately 75%

17

Describe clinical use of levodopa

Approved for use in Parkinsonian syndrome (idiopathic Parkinson disease, postencephalitic parkinsonism, symptomatic parkinsonism)
Does not stop progression of PD but does lower mortality rate when initiated early in disease
Best results occur during first few years of treatmet
Wearing-off phenomenon can occur during long-term treatment, where each dose of levodopa effectively improves mobility for a period of time (1-2 hrs), but rigidity and akinesia return rapidly at end of closing interval
Increasing dose and frequency of administration can improve symptoms, but this is often limited by development of dyskinesias (distortion or impairment of voluntary movement)
1/3 of patients respond very wll, 1/3 respond less well, and 1/3 are either unable to tolerate medication or do not respond at all

18

Describe adverse GI effects of levodopa

Levodopa given in absence of peripheral decarboxylase inhibitor causes anorexia, nausea, and vomiting in roughly 80% of patients
Combo of levodopa/carbidopa causes less frequent and less troublesome GI side effects in only 20% of patients
Vomiting can be attributed to activation of chemoreceptor trigger zone located in brainstem but outside BBB
Occasionally, individuals will require larger doses of carbidopa to minimize the GI side effects, and administration of supplemental carbidopa alone may be beneficial

19

Describe adverse CV effects of levodopa

Postural hypotension (frequently asymptomatic) can occur but often diminishes with continuing treatment
Hypertension can occur when taking large doses of levodopa or levodopa in combination with nonselective monoamine oxidase inhibitors or sympathomimetics
Increases in cardiac arrhythmias are rare and can be attributed to presence of increased peripheral catecholamine synthesis

20

Describe adverse effects of dyskinesia due to levodopa

Can occur in 80% of patients
Choreoathetosis (movement of intermediate speed, between quick, flitting movements of chorea and the slower, writhing movements of athetosis) of face and distal extremities is most common presentation
Development is dose-related, but there is individual variation in dose required to produce dyskinesias

21

Describe adverse effects on behavior of levodopa

Depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, other mood/personality changes
Atypical antipsychotic agents (clozapine, olanzapine, quetiapine, risperidone) are able to help counteract behavioral complications

22

Describe fluctuations in response of levodopa

Can occur due to timing of dose (wearing off phenomenon) or due to reasons unrelated to dose timing (on-off phenomenon)

23

Describe on-off phenomenon

Off-periods of marked akinesia alterante over course of a few hours with on-periods of improved mobility but often marked dyskinesia
Subcutaneous injections of apomorphine may provide temporary benefit to pts with severe off-periods

24

Describe drug interactions and contraindications of levodopa

Patients taking monoamine oxidase A inhibitors (or within 2 weeks of discontinuation) may experience hypertensive crisis when combined with levodopa
Contraindicated in psychotic patients, patients with angle-closure glaucoma (levodopa can be given to pts with well-controlled open-angle glaucoma), patients with a history of melanoma or with suspicious undiagnosed skin lesions (levodopa is a precursor of skin melanin), use with caution in patients with active peptic ulcer due to possibility of GI bleeding

25

Describe dopamine receptor agonists

Use in patients with PD is associated with a lower incidence of response fluctuations and dyskinesias that occur with long-term levodopa therapy
Generally, patients who don't respond well to levodopa don't respond well to dopamine agonists
Can be administered in addition to levodopa/carbidopa and in patients who are taking levodopa and who have end-of-dose akinesia or on-off phenomenon

26

Describe bromocriptine

Ergot alkaloid derivative that is a D2 agonist
Also approved for treatment of endocrine disorders (hyperprolactinemia, prolactin secreting adenomas, acromegaly)
Bioavailability 28% with peak plasma concentration usually attained within 1-3 hours
Half-life approximately 15 hours
Extensive first-pass metabolism (CYP3A4 primarily)

27

Describe pramipexole

Preferential affinity for D3 receptors
Also approved for treatment of moderate-to-severe primary Restless Leg Syndrome (RLS)
Peak plasma concentration reached in 2 hours with a half-life of 8 hours
90% of pramipexole is excreted unchanged in urine (individuals with renal insufficiency may require dose adjustment)

28

Describe ropinirole

Preferential affinity for D2 receptors
Also approved for treatment of RLS
Metabolized by hepatic CYP450 enzyme (primarily CYP1A2)
Coadministration with agents that are also metabolized by CYP1A2 may reduce clearance of ropinirole
Peak plasma concentration reached in 1-2 hours with a half-life of 6 hours

29

Describe adverse GI effects of dopamine receptor agonists

Anorexia, nausea, and vomiting
Symptoms reduced if agents are taken with meals
Constipation, dyspepsia, and symptoms of reflux esophagitis

30

Describe adverse CV effects of dopamine receptor agonists

Postural hypotension, especially at initiation of therapy
Bromocriptine may cause digital vasospasm during long-term treatment
Presence of peripheral edema and cardiac arrhythmias may indicate need to discontinue therapy

31

Describe adverse dyskinesias of dopamine receptor agonists

Similar to those introduced by levodopa.
Reversed by reducing total dose

32

Describe mental disturbances by dopamine receptor agonists

Confusion, hallucinations, delusions, other psychiatric reactions
More severe with dopamine agonists than with levodopa
Clear during withdrawal of medication

33

Describe miscellaneous adverse effects of dopamine receptor agonists

Headache, nasal congestion, increased arousal, pulmonary infiltrates, and pleural and retroperitoneal fibrosis with bromocriptine use
Rarely, patients who are taking pramipexole or ropinirole may feel uncontrollable tendency to fall asleep at inappropriate times

34

Describe contraindications to using dopamine receptor agonists

Patients with a history of psychotic illness, recent myocardial infarction, or with active peptic ulceration
Bromocriptine is contraindicated in patients with peripheral vascular disease (vasoconstricting effects)

35

Describe the two forms of monoamine oxidase

MAO-A preferentially metabolizes norepinephrine and serotonin
MAO-B preferentially metabolizes phenylethylamine and benzylamine
Dopamine and tryptamine are metabolized equally by MAO-A and MAO-B

36

Describe selegiline (deprenyl)

Selective irreversible MAO-B inhibitor (inhibits MAO-A at high doses)
Slows breakdown of dopamine and prolongs antiparkinsonian effects of levodopa, may reduce mild on-off or wearing-off phenomena
Used as adjunctive therapy in patients with declining or fluctuating response to levodopa
10% bioavailability with peak plasma concentrations within an hour
Caution recommended or contraindicated in patients taking meperidine, tricyclic antidepressants, or serotonin reuptake inhibitors (risk of serotonin syndrome acute effects)

37

Describe rasagiline

Irreversible inhibitor of MAO-B, more potent than selegiline
Used as neuroprotective agent and for early symptomatic treatment of PD

38

Why must the combined administration of levodopa and a nonselective MAO inhibitor be avoided?

May lead to hypertensive crisis due to peripheral accumulation of norepinephrine

39

Describe catechol-O-methyltransferase (COMT) inhibitors

COMT metabolizes levodopa to 3-O-methyldopa, which competes with levodopa for transport across the intestinal mucosa and blood-brain barrier
COMT inhibitors (tolcapone and entacapone) prolong activity of levodopa by inhibiting its peripheral metabolism, which decreases clearance and increases bioavailability
May be helpful in patients receiving levodopa who have developed response fluctuations
Tolcapone has both central and peripheral effects, whereas entacapone has peripheral effects only
Tolcapone may cause an increase in liver enzyme levels and has been associated, rarely, with death from acute hepatic failure (use in USA requires signed patient consent)
Side effects are often due to levodopa, but also include orange discoloration of urine, diarrhea, abdominal pain, and sleep disturbances

40

Describe apomorphine

MOA: dopamine agonist that appears to act by stimulating postsynaptic dopamine D2 receptors in caudate-putamen
Injected subcutaneously for quick, temporary relief of off-periods of akinesia in patients on dopaminergic therapy (clinical benefits within 10 minutes)
Adverse effects include nausea (can pretreat with antiemetic trimethobenzamide), dyskinesias, drowsiness, sweating, hypotension, and injection site bruising

41

Describe amantadine

Antiviral agent whose MOA in prakinsonism is unknown (may potentiate dopaminergic function by influencing synthesis, release, or reuptake of dopamine)
Half-life 2-4 hours, peak plasma concentrations reached in 1-4 hours, excreted mostly unchanged in urine
Benefits may be short-lived
Adverse effects include restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion (all of which can be mediated by discontinuation), as well as headache, heart failure, postural hypotension, urinary retention, and GI disturbances
May cause livedo reticularis, a vasculard condition characterized by a purpilsh mottled discoloration of skin, usually on legs
Use with caution in patients with a history of seizures or heart failure

42

Describe anticholinergic drugs

Centrally acting mAChR antagonists are available to treat patients with PD
MAChR antagonists may improve tremor and rigidity but have little effect on bradykinesia
Benztropine, biperiden, orphenadrine, procyclidine, trihexyphenidyl
Patients are given a low dose of drug, which is titrated upwards in amount until benefit occurs or adverse effects limit use
If one agent is unsuccessful, trial with a different agent is warranted and may be successful
Adverse effects include common peripheral anticholinergic effects (sedation, mental confusion, constipation, urinary retention, blurred vision)

43

Describe treatment for tremor

B1-receptors have been implicated in some tremors, and these tremors respond well to metoprolol and propranolol
Symptomatic tremor can be controlled by antiepileptic drug primidone in smaller doses than those used to treat seizures
Topirimate (serotonin receptor agonist) has shown to be effective
Alprazolam (benzodiazepine) and intramuscular injections of botulinum toxin A have been effective in some patients

44

Describe Huntington disease

Autosomal dominant inherited disorder caused by an abnormality in chromosome 4 and is characterized by progressive chorea and dementia that usually begin in adulthood
Development of chorea is most likely due to imbalance of dopamine, acetylcholine, and GABA in basal ganglia that results in overactivity of dopaminergic nigrostriatal pathways
Movement disorder of HD per se only rarely justifies pharmacological therapy (no current therapy slows disease progression)

45

Describe treatment of Huntington disease

Drugs that impair dopaminergic neurotransmission often alleviate chorea (reserpine, tetrabenazine, olanzapine, phenothiazines such as perphenazine, butyrophenones such as haloperidol), while durgs that activate dopaminergic signaling exacerbate it
GABA, glutamic acid, decarboxylase (enzyme that synthesizes GABA), and choline acetyltransferase are markedly reduced in basal ganglia of patients with HD, but pharm approaches to increase central GABA and acetylcholine activity have been unsuccessful
Reserpine (irreversible) and tetrabenazine (reversible) are agents that block the vesicular monoamine transporter and deplete cerebral dopamine stores. The effects of tetrabenzine resemble reserpine but with less peripheral activity and shorter duration of action
Most therapy is for patients who are depressed, irritable, paranoid, anxious, or psychotic
1. Antidepressants with substantial anticholinergic profiles can exacerbate chorea
2. Fluoxetine is effective for depression and irritability; carbamazepine is effective for depression

46

Describe treatment of tics

Most predictive and effective approach are neuroleptic antipsychotics (tetrabenzaine, haloperidol, pimozide). Because of their tendency to cause extrapyramidal syndromes, weight gain, sedation, irritability, and various phobias, they are not always first choice
Alpha-adrenergic agents (clonidine, guanfacine) are effective and cause fewer long-term adverse effects
In some cases, injection of botulinum toxin A at site of problematic tics is beneficial

47

Describe treatment of restless leg syndrome

Unknown cause
Symptoms may resolve with correction of coexisting iron-deficiency anemia (if present) and often respond to dopamine agonists, levodopa, diazepam, clonazepam, or opiates
Non-ergot dopamine agonists pramipexole and ropinirole are only drugs approved by FDA for RLS and are considered first-line treatment in patients with daily symptoms

48

Describe treatment of amytrophic lateral sclerosis (ALS)

Riluzole is only drug to have any impact on survival in ALS, which has been shown to prolong survival by a few months
MOA: inhibits glutamate release and blocks postsynaptic NMDA-and kainite-type glutamate receptors and inhibits voltage-dependent Na+ channels, though precise mechanism in treatment of ALS is unclear
Major adverse effects are nausea and weakness

49

Describe Wilson disease

Recessively inherited disorder of copper metabolism that is characterized by
1. Biochemically: reduced ceruloplasmin (major copper-carrying protein in blood) concentrations
2. Pathologically: markedly increased concentration of copper in brain and viscera
3. Clinically: signs of hepatic and neurologic dysfunction (tremor, choreiform movements, rigidity, hypokinesia, dysarthria, and dysphagia)

Frequency is 1 in 30,000 with a carrier rate of 1 in 90

Treatment includes agents that reduce serum copper levels and low-copper diet (high copper foods: calf liver, turnip greens, cashews, molasses, spinach)

50

Describe treatment of Wilson disease

Penicilamine
MOA: chelating agent that forms a stable complex with copper and is readily excreted by kidney
Adverse effects: nausea, vomiting, nephritic syndrome, myasthenia, optic neuropathy, and various blood disorders
After remission, patients may require maintenance dose

Potassium disulfide reduces intestinal absorption of copper and can be prescribed in addition to penicillamine

Trientine (chelating agent)
Zinc acetate and zinc sulfate (increase fecal excretion of copper by decreasing GI absorption)