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Pharm III Unit I > 8 Parkinson's and Alzheimer's > Flashcards

8 Parkinson's and Alzheimer's Flashcards

1
Q

What is the pathophysiology of Parkinson’s disease?

A

Loss of Dopamine (DA) neurons in the substantia nigra pars compacta

Decreased DA neurotransmission in basal ganglia

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2
Q

4 major clinical features of Parkinson’s disease

A

Bradykinesia - slowness of movement

Muscle rigidity (cogwheel rigidity) - esp elbows and knees

Resting tremor

Impairment of postural balance, gait

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3
Q

Secondary Sx of Parkinson’s disease

A

Dementia/cognitive deficits, depression, anxiety, difficulty speaking

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4
Q

What is the most common etiology of Parkinson’s?

A

Idiopathic

Not as genetically linked as Alzheimer’s but research into Parkin gene and alpha-synuclein gene as possible markers

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5
Q

What is MPTP?

A

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Street drug —> late stage Parkinson’s basically overnight

Being used in animal studies for Parkinson’s research

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6
Q

Symptoms of Parkinson’s become apparent once _______% of the DA neurons in the substantia nigra have been lost

A

70-80%

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7
Q

What are Lewy bodies?

A

Intracellular aggregation of alpha-synuclein and other proteins (histological sign of Parkinson’s)

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8
Q

Why does a section of the substantia nigra in a Parkinson’s patient appear less pigmented than a normal brain?

A

Because DA is a precursor for melanin, so loss of DA neurons means loss of pigmentation as well

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9
Q

How is the nigrostratal and basal ganglia circuitry disturbed in Parkinson’s?

A

Loss of DA neurons in SNPC

—> Over-activity of indirect pathway and under-activity of direct pathway

—> Increased GABA input into thalamus

—> Decreased glutamate input into cortex

—> Inability to control movement

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10
Q

Why are anticholinergics used as an adjunct in Parkinson’s treatment?

A

The DA neurons normally inhibit GABA in the corpus striatum at the same time as cholinergic interneurons enhance GABA activity

In Parkinson’s the loss of DA inhibition means over excitation of GABA by ACh, so anticholinergics are used to balance it out

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11
Q

What are the different targets for drugs used to treat Parkinson’s?

A

Increase brain DA levels (L-dopa)

Inhibit DA metabolism in the brain (MAO-B and COMT)

Stimulate brain DA D2 receptors (dopamine agonists)

In the periphery, inhibit the conversion of L-dopa to DA (Carbidopa) and the metabolism of L-dopa by COMT

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12
Q

What drug is used to increase DA levels?

A

L-Dopa (Levodopa, Dopar, Larodopa)

L-3,4-dihydroxyphenylalanine

“Replacement” Therapy

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13
Q

Why do we give L-dopa rather than dopamine for replacement therapy?

A

Dopamine does not cross BBB

L-Dopa readily crosses BBB is is then converted to DA in the neuron

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14
Q

Peripheral effects of L-Dopa

A

Nausea and vomiting

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15
Q

Clinical uses of L-Dopa

A

Improvement of PD symptoms for 3-4 years (esp Bradykinesia)

Not all patients respond well (or can tolerate) - ~33%

Effectiveness of L-dopa will go down over time, so other drugs need to be added eventually

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16
Q

Why does L-dopa get less effective over time?

A

Does not affect progression of DA neuron degeneration

Once you’ve lost enough DA neurons, it just doesn’t matter how much L-dopa you add

As effectiveness of L-dopa goes down, have to add other drugs

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17
Q

L-dopa is not as effective in _________ Parkinson’s

A

Drug-induced (MPTP)

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18
Q

What are the pharmacokinetics of L-dopa?

A

Orally administered - absorption is delayed by food, amino acids

Short half-life - needs to be taken 3-4x/day

Need high doses b/c only 1-3% gets into the CNS

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19
Q

What is Sinemet?

A

Combo of L-Dopa and Carbidopa

Carbidopa inhibits the dopa-decarboxylase enzyme that converts L-dopa to DA in the periphery, but doesn’t cross the BBB

SO, peripheral conversion is inhibited but not in the brain

Decreases the dose of L-dopa needed and decreases peripheral effects (N/V)

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20
Q

Side effects of L-dopa/Carbidopa

A

Tend to increase as disease progresses

GI: N/V
• Divided doses will help decrease GI effects
• Avoid antiemetics that block DA D2 receptors (Prochlorperazine)

CV: postural hypotension, arrhythmias, HTN

Dyskinesia develop over time - treat by reducing L-dopa

Behavioral: depression, anxiety, agitation, sleep problems
• Psychosis possible - treat with atypical antipsychotics

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21
Q

What is the On-Off Phenomenon?

A

Fluctuations in clinical response

Occurs in patients on successful L-dopa therapy

“On” = improved mobility

“Off” = akinesia (due to falling drug levels)

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22
Q

What can you do to avoid the On-Off phenomenon?

A

Increase frequency of doses
Improve absorption of L-dopa (diet), sustained release
Add another drug (MAO-I, DA agonist)

Apomorphine (Apokyn) used as “rescue” - fast acting DA2 receptor agonist

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23
Q

Drug interactions possible with L-dopa

A

MAO-A Inhibitors - may cause hypertensive crisis

Pyridoxine (Vit B6) - increases peripheral metabolism of L-dopa, which decreases its effectiveness

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24
Q

Which drugs can cause a hypertensive crisis when paired with L-dopa?

A

MAO-A inhibitors

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25
Q

Which supplement will increase the peripheral metabolism of L-dopa, decreasing it’s effectiveness?

A

Pyridoxine (Vit B6)

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26
Q

Contraindications for L-dopa

A

Psychosis***

Closed angle glaucoma - increases intraocular pressure

Cardiac disease

Active peptic ulcer - can increase GI bleeding

Malignant melanoma - L-dopa is a precursor of melanin

L-dopa toxicity

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27
Q

What are the MAO-b inhibitors used to inhibit DA metabolism?

A

Selegiline (Deprenyl)

Rasagiline (Azilect)

Safinaminde (Xadago)

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28
Q

MOA for MAO-B inhibitors

A

Inhibits MAO-B in CNS —> reduces striata metabolism of DA

Does not affect peripheral metabolism of DA by MAO-A

May inhibit progression of PD by decreasing free radicals produced during DA metabolism

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29
Q

Adverse effects of MAO-BIs

A

Insomnia (Amphetamine like metabolites) - take in morning and noon to decrease likelihood

Severe hypertension if combined with other MAOIs (Phenelzine)

Will increase the side effects of L-dopa in late stage disease

Do NOT combine with meperidine - can lead to stupor, rigidity, agitation, hyperthermia, possible serotonin syndrome

Serotonin syndrome possible if combined with TCAs/SSRIs

30
Q

Your patient is on a MAO-B inhibitor and complains of insomnia. What should you advise them to do?

A

Take it in the morning or at noon to decrease the likelihood

31
Q

Why shouldn’t you combine MAO-BI’s with meperidine?

A

Can lead to stupor, rigidity, agitation, hyperthermia, possible serotonin syndrome

32
Q

MAO-BIs + TCA or SSRI = __________

A

SEROTONIN SYNDROME

33
Q

MOA for COMT inhibitors

A

Catecholamines-O-methyl transferable metabolizes DA and L-dopa

Inhibiting COMT prevents metabolism of DA and L-Dopa

34
Q

_______ inhibits COMT in CNS and periphery, but _______ inhibits COMT in periphery only

A

Tolcapone (Tasmar)

Entacapone (Comtan)

35
Q

Which PD drug has been associated with death from hepatic failure?

A

Tolcapone (Tasmar) - inhibits COMT in CNS and periphery

36
Q

How does Entacapone work?

A

Inhibits COMT in periphery only, increasing pool of L-dopa available for transport into the brain

37
Q

What is Stalevo?

A

Combo of L-dopa/Carbidopa/entacapone

38
Q

Side effects of COMT inhibitors

A

Dyskinesia, confusion, nausea, hypotension, abdominal pain, sleep disturbances, ORANGE COLOR IN URINE

39
Q

Which PD drugs work by acting directly on DA D2 receptors

A

DA Receptor Agonists

Bromocriptine (Parlodel)
Ropinirole (Requip)
Pramipexole (Mirapex)

Because these drugs act directly on the receptors, they continue to be effective as the disease progresses

40
Q

What are the benefits of using DA receptor agonists?

A

They continue to be effective as the disease progresses

Used in combo with L-dopa during ‘on-off’ periods

Lower incidence of response fluctuations and dyskinesias

41
Q

What awesome side effect do you get with Bromocriptine (Parlodel)

A

Erythromelalgia - swollen, itchy, red feed

It’s because it’s an ergot derivatives, so it can cause vasospasms

42
Q

Your patient has a mutation in DDC and cannot synthesize DA. How do you treat them?

A

Bromocriptine

43
Q

PD drugs that may cause narcolepsy

A

The newer DA agonists (Ropinirole and Pramipexole)

44
Q

Newer DA agonists (Ropinirole and Pramipexole) are useful in…

A

Monotherapy in mild PD

Soothing response to L-dopa in late PD

45
Q

DOC for restless leg syndrome (RLS)

A

Ropinirole

Relatively pure DA D2 agonist

46
Q

Why does Pramipexole have an FDA warning?

A

Possible heart failure

47
Q

Which DA receptor agonist is available as a transdermal patch?

A

Rotigotine (Neupro)

Can be used for either PD or restless leg syndrome

Helps with patient compliance

48
Q

Drug used for temporary relief (“rescue”) of off-periods in patients on optimized L-dopa therapy

A

Apomorphine (Apokyn)

Typically injected

49
Q

Side effects of Apomorphine (Apokyn)

A

NAUSEA - patient should take an antiemetic prior to introduction (trimethobenzamide)

Avoid antiemetics that target the serotonin system (Ondansetron) —> severe HTN, LOC

Avoid antiemetics that block DA D2 receptors (Prochlorperazine)

50
Q

Side effects of DA agonists

A

GI: Anorexia, N/V - take with meals

CV: postural hypotension (beginning of treatment); ergot derivatives = digital vasospasm, decrease dose; cardiac arrhythmias (d/c)

Dyskinesia

Mental disturbances

Erythromelalgia (Bromocriptine)

Decreased release of Prolactin

51
Q

Antiviral used for influenza that also increases the release of DA and possibly inhibit DA reuptake

A

Amantadine (Symmetrel)

Used to treat early or mild cases of PD

52
Q

What is livedo reticularis?

A

Reddish/blue spotting of skin

Can be caused by Amantadine (Symmetrel)

53
Q

What is buzzwordy side effect of Amantadine (Symmetrel)?

A

Livedo reticularis - reddish/blue spotting of the skin

Other side effects:
Restlessness
Depression
Irritability
Insomnia
Agitation
Confusion
Hallucinations
Peripheral edema (give diuretics)
54
Q

Your PD patient took too much Amantadine (Symmetrel). What are you worried about?

A

Toxic psychosis and convulsions

55
Q

MOA for anticholinergics used in PD treatment

A

Muscarinic receptor antagonists restore DA/ACh balance in striatum

Provides modest anti-Parkinson action

Improves rigidity, tremor but little effect on bradykinesia

Used in early/late stages as adjunct to DA therapy

56
Q

What anticholinergics are used for PD adjunct therapy?

A

Benztropine (Cogentin)

Trihexyphenidyl (Artane)

57
Q

Side effects of Benztropine (Cogentin) and Trihexyphenidyl (Artane)

A

Anticholinergics!

Constipation, urinary retention, blurred vision, sedation, confusion

If d/c, do so gradually

58
Q

What will increase the effects of anticholinergics used for PD?

A

TCAs and antihistamines

59
Q

Alternative treatments for Parkinson’s

A

Neuroprotection - antioxidants, anti-apoptotic agents

Pallidotomy - decrease activity of globus pallidus

Transplants of fetal neurons or patient-derived stem cells

Gene therapy

Deep brain stimulation

60
Q

Over 50% of dementia is caused by….

A

Alzheimer’s Disease

61
Q

Risk factors for Alzheimer’s

A

Age

Genetics (more so than PD)

Gender (females more at risk)

Lack of education

Head injury

62
Q

Symptoms of Alzheimer’s

A

Mild
• Confusion, memory loss
• Routine tasks become difficult
• Personality, judgement impaired

Moderate
• Difficulty with ADLs, sleep disturbance
• Anxiety, agitation
• Don’t know family anymore

Severe
• Loss of speech
• Incontinence

63
Q

Alzheimer’s disease is characterized by…

A

Neuritic plaques (ß-Amyloidosis) - insoluble, fibrous protein aggregations outside the neurons

Neurofibrillary tangles (Tau proteins) inside the neurons

64
Q

Alzheimer’s leads to the degeneration of _______ neurons

A

Cholinergic neurons originating int he basal nucleus of Meynert and projecting to the cerebral cortex and hippocampus

These are the neurons involved in memory and cognition

65
Q

What is the major class of drugs used to treat Alzheimer’s?

A

Cholinesterase Inhibitors

Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Reminyl)

Inhibit metabolism of ACh —> increased amount of ACh in the nerve terminal

66
Q

Pharmacokinetics of cholinesterase inhibitors

A

Well absorbed and readily penetrate the CNS

Metabolized by CYP450s

67
Q

Peripheral cholinergic side effects of cholinesterase inhibitors

A

GI primarily
N/V/D
Stomach cramps

68
Q

All three cholinesterase inhibitors used in Alzheimer’s block acetylcholinesterase, but only _________ inhibits the ACh autoreceptor to reduce reuptake

A

Galantamine

69
Q

What is Memantine (Namenda)?

A

NMDA receptor antagonist (channel blocker)

Blocks the pathological activation of NMDA receptors and reduces excitotoxic effect of glutamate to slow degeneration

Used for late-stage Alzheimer’s in combo with AChE-I’s

70
Q

Side effects of Memantine (Namenda)

A

Agitation, insomnia, urinary incontinence, UTI, and diarrhea

Competes for renal tubular secretion so monitor dose in patients with renal impairment

71
Q

Memantine (Namenda) is contraindicated in patients also taking…

A

Meperidine, dextromethorphan

72
Q

If your patient is unfortunate enough to have both PD and Alzheimer’s, what should you not give them?

A

Memantine (Namenda), because it may increase side effects of L-dopa

Pharm III Unit I (9 decks)

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