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Neurology Week 2 > Pharmacotherapy for Movement Disorders > Flashcards

Pharmacotherapy for Movement Disorders Flashcards

1
Q

What are some agents used to tx Parkinson’s disease?

A

L-Dopa (levodopa); L-DOPA/carbidopa (Sinemet)

Dopamine receptor agonists: Bromocriptime, pramipexole, ropinirole, and apomorphine

Enhancement of dopamine release: Amantadine

Antimuscarinics: Benztropine, Diphenhydramine, and Trihexyphenidyl

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2
Q

What drugs that decrease dopamine metabolism can be used for Parkinson’s tx?

A

MAO-B: Selegiline, Rasagiline

COMT: Entacapone, Tolcapine

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3
Q

What agents are used to tx Huntington Disease?

A

VMAT Inhibitors-DA depleting agents: Reserpine, tetrabenazine

Dopamine D2 receptor antagonistsL

Chlorpromazine, haloperidol

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4
Q

Parkinson disease

A

A progressive movement disorder affecting 1.5 million people in the U.S. with an average onset of 55 yrs (~10% of cases present before 40 yo)

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5
Q

Parkinson consists of what 4 primary clinical features?

A

Bradykinesia (slowness of movement)

Muscular rigidity (increased muscle tone and resistance)

resting tremor (abates during voluntary movement)

Postural instability and impaired gait

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6
Q

What causes idiopathic PD?

A

unknown, although exposure to neurotoxins or generation of free radicals are thought to contribute

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7
Q

T or F. There is a genetic component of PD

A

T. AD forms of the disease lie in mutations of the gene encoduing a-synuclein (a synaptic protein), LRRK2 (leucine-rich repeat kinase 2), parkin (a ubiquitin hydrolase), and UCHL1 (also involved in ubiquitin mediated protein degradation)

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8
Q

PD has been associated with environmental factors such as:

A

infection with encephalitis, stroke, trauam, MPTP, and antipsychotic drug tx

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9
Q

The hallmark neurological feature of PD is:

A

selective loss of the pigmented (neuromelanin) neurons in the substantia nigra pars compacta

most symptoms dont appear until striatal DA neuron levels decline by at least 70-80%

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10
Q

The basal ganglia consists of severl subcortical nuclei that participate in movement control. These nuclei are interconnected to form 2 pathways that form a feedbakc loop to the cortex. What are they?

A

direct pathway (cerebral cortex, striatal neurons (SNpc), SN para reticulata/edial globus pallidus, thalamus, cerebral cortex)

indirect pathway (cerebral cortex, striatal neurons (SNpc), lateral globus pallidus, subthalmic nucleus, SN para reticulata/edial globus pallidus, thalamus, cerebral cortex)

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11
Q

What is the net effect of the direct pathway? Indirect?

A

Direct: increased thalamic output

Indirect: less thalamic output

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12
Q

Describe the direct pathway of striatal control

A

the substantia nigra pars compacta synapses with the striatum via excitatory D1 receptors to project to the direct pathway while inhibiting the indirect pathway neurons in the striatum via D2 receptor binding (thus, under normal conditions the SN pars compacts favors the direct pathway)

However in PD, activity of the indirect pathway predominates

D2 receptor activation appears to be the most important in gating the balance of the two pathways

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13
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A
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14
Q
A
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15
Q

Describe the metabolism of dopamine

A

1) tyrosine is converted to dopa via tyrosine hydroxylase
2) dopa is converted to dopamine via who fucking cares (aka aromatic-L-amino acid decarboxylase)

Dopamine is then packaged into vesicles that merge with the presynaptic membrane or broken down to DOPAC via MAO

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16
Q

What happens to dopamine in a synaptic cleft?

A

binds to postsynaptic membrane or

converted to 3MT via COMT and then to HVA via MAO

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17
Q

T or F. DA cannot cross the BBB into the CNS

A

T.

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18
Q

______, the immediate precursor to DA, is the single msot effective tx of PD

A

L-DOPA (levodopa)

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19
Q

How does L-DOPA work?

A

it replenishes DA stores in the remaining DA terminals in the striatum

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20
Q

Describe the pharmacokinetics of LevoDOPA

A

L-DOPA is readily absorbed from the GI tract (dependent on gastric emptying), plasma concentrations peak fast (1-2hrs) and the t1/2 is brief (1-3 hrs)

It is heavily (99%) converted in the periphery and brain to DA by L-aromatic amino acid decarboxylase (L-AAD) and then principally excreted in the urine as HVA and DOPAC

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21
Q

T or F. L-DOPA must be given in high doses when used alone

A

T. Therefore, it is often coadministered with carbidopa, a L-AAD inhibitor that cant cross the BBB, thus prolonging the half-life of L-DOPA, reducing the amount of L-DIOA needed to be given by up to 75% and reducing side effects due to reduced levels of peripheral DA

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22
Q

What are the major AEs of L-DOPA monotherapy?

A

GI (anorexia, N/V)- tends to decrease with repeated use

CV (arrhythmias, tachycardia, ventricular extrasystoles, a. fib)- incidence tends to be low except in those predisposed. Orthostatis hypotension common

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23
Q

What are the major AEs of L-DOPA/carbidopa therapy?

A

Behavioral (depression, anxiety, delusion, agitation, etc.) Use antipsychotics

Dyskinesias (chorea, myoclonus, tics, tremor (intentional))

24
Q

What are the DDIs of DA replacement therapy?

A

vitB6 (pyridoxine) increases L-DOPA metabolism, thus decarboxylase inhibitors are also needed. L-DOPA should not be given to pts on MAO-A inhibitors due to hypertensive crises. Given before meals due to competition with L-amino acids in food for transporters in GI tract

25
Q

What are the contraindications of DA replacement therapy?

A

psychotic pts

glaucoma (angle-closure)

cardiac disease

peptic ulcer

melanoma

26
Q

Tx with L-DOPA is often effective for how long?

A

3-5 yrs (thus, it is often delayed until symptoms of PD become impairing)

27
Q

What is the rationale of dopamine agonist therapy for tx of PD?

A

principally activate D2 receptors to reduce activation of the indirect pathway

28
Q

What are the advantages of dopamine agonist therapy for tx of PD?

A

does not need to be converted to active compount, there are no potentially txoci metabolities, it does not compete with other substances for GI absorption or across BBB

May be more selective, thereby reducing adverse reactions

29
Q

T or F. DA agonists have become the preferred therapeutic strategy for early PD

A

T. May be used in combo with LDOPA in advanced PD, may reduce ‘on-off’ phenomenom of response

30
Q

What are the current DA receptor agonists in use for PD?

A

Bromocriptine - D2 agonist/partial D1 agonist

Apomorphine- D1/D2 agonist

Pramipexole- D2 selective, may also act as free radical scavenger]

Ropinirole- D2 selective, metabolized by CYP1A2

31
Q

Enhancement of DA relase is also sued to tx PD. Explain

A

Amantadine (an antiviral agent is used)- mechanism unknown, but appears to enhance release and possibly DA synthesis, and may also inhibit DA uptake (effects are modest and short-lived)

Possible interaction with NMDA receptors

32
Q

Describe the pharmacokinetics of Amantadine

A

peak plasma conc (1-4 hrs). T1/2= 2-4 hrs

Excreted primarily in urine

33
Q

What are the major AEs of amantadine?

A

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

Overdose may produce psychosis

34
Q

Amantadine is contrandicated in pts with what?

A

Hx of seizures or heart failure

35
Q

What is Selegiline?

A

a selective MAO-B inhibitor that retards the breakdown of DA. Metabolities includes amphetamine and methamphetamine which increase DA release (may be neuroprotective and reduce PD progression by inhibiting MAO-B-mediated free radical formation)

NOTE: Rasagiline is a new, more potent inhibitor of MAO-B approved for combined therapy with levodopa in late-stage PD or alone in early PD

36
Q

What are the indications of Selegiline?

A

used primarily in pts whose responsiveness to L-DOPA has declines. Little effect when given alone

37
Q

DDIs of Selegiline?

A

dont take with meperidine, TCAs, or SSRIs

38
Q

AEs of Selegiline?

A

may potentiate the AEs of L-DOPA

39
Q

What are some selective inhibitors of COMT used to tx PD?

A

Entacapone and tolcapone

40
Q

How do Entacapone and tolcapone work?

A

they prolong the action of L-DOPA (increased L-DOPA bioavailabilty), and reduce the production of 3OMD which may compete with L-DOPA for transport carriers in GI and BBB

41
Q

What are the indications of Entacapone and tolcapone?

A

helpful in reducing fluctuation in responses to L-DOPA

42
Q

Pharmacokientics of Entacapone and tolcapone?

A

both rapdily absorbed, highly protein bound, t1/2= 2 hrs

43
Q

More on Entacapone and tolcapone

A

Tolcapone has both central and peripheral effects, while entacapone is strictly peripheral

Entacapone is preferred as tolcapone may result in increased liver enymes and hepatic fialure

44
Q

Muscarinic antagonists are used to block colinergic activation in the striatum, widely used prior to the advent of L-DOPA therap and used in early PD or as an adjunct to L-DOPA. What are the main drugs used?

A

Benzatropine (Cogentin)

Diphenhydramine

Trihexyphenidyl (Artane)

45
Q

What are the main AEs of antimuscarinics used for PD tx?

A

drowsiness, mental slowness, inattention, mood changes, delusions, etc.

dry mouth, blurred vision, mydriassis, urinary retnetion, N/V, constipation, tachycardia, palpations, arrhythmias, increased itnraocular pressure

46
Q

Antimuscarinics used for PD tx are contraindicated in who?

A

pts with prostatic hyperplasia, OBD, glaucoma. Avoid concomitant use of drugs with antimuscarinic effects (i.e. TCAs or antihistamines)

47
Q

What channels control the pacemaking activity in substantia nigra dopamine neurons?

A

CaV1.3 subtypes of L-type Ca2+ channels

48
Q

What is Huntington disease?

A

AD inherited disorder (incidence 8:100,000) causing both motor and cognitive deficits

49
Q

What are the symptoms of HD?

A

Chorea which is jerky, random, uncontrollable, rapid movements. Typically, abnormal movements begin at the extremities. As the disease, progresses there is a general lack of coordination and involuntary movements become more severe, causing an unsteady gait, loss of facial expression, speech, and ability to swallow

Cognitive deficits include slowing of mental processing, and reductions in memory (not of actual events, but of how to process or acquire new info)

Early symptoms may also include mood swings, depression, etc.

50
Q

What causes HD?

A

IT15 gene (4p16.3) that encodes a 384 kDA protein (3144 aa) known as huntingtin (htt), which has a cytoplasmic distribution.

In the normal htt, the N-terminal region of the protein contains 19-34 glutamine (Q) residues, which is encoded by the nucleotides cytosine-adenine-guanosine (CAG). In mutant htt, this sequence is expanded anywhere from 40-100x. For this reason, the disease is often known as polyglutamine expansion, or a trinucleotide repeat disease.

51
Q

T or F. In HD, the length of the CAG repeat is positively correlated with a severity of the disease and the age of onset (typically 35-40 yo).

A

T. In those with a polyglutamine length of 35-39 generally have a later onset form of the disease

52
Q

What does htt do?

A

the normal cellular function for htt is not known, but its thought that it may regulate organelle transport, protein trafficking, and energy metabolism. Mutant htt is thought to be a ‘gain of function’ mutant that also allows it to become a transcriptional regulator

53
Q

What is the pathophys of HD?

A

Mutant htt causes a loss of cholinergic neurons in the striatum but a greater and earlier loss is observed in the striatal medium spiny GABAergic neruons which project to the GPe (indirect pathway) thus decreasing the output of the indirect pathway

54
Q

Tx for HD is predominatly symptomatic and is aimed at what?

A

alleviating the depression seen with the disease (fluoxetine and carbamazepine used frequently)

55
Q

How else is HD tx?

A

drugs used to tx HD associated-chorea include central dopamine depleting agents such as reserpine and tetrabenazine (dopamine antagonists such as chlorpromazine and haloperidol tend to be useful too)

The MOA is thought to reside in their ability to block D2 receptors. As D2 receptor activity is normally inhibitory to the indirect pathway, this will tend to increase activity in this pathway restoring the balance between the direct and indirect pathways

Neurology Week 2 (14 decks)

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