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Neuro (M2) > Alzheimer's / Parkinson's Drugs > Flashcards

Alzheimer's / Parkinson's Drugs Flashcards

1
Q

Low levels of what are associated w/ AD? (2 things)

High levels of what are associated w/ AD? (2 things)

A
  • AD associated w/ reduction in Ach and nicotinic receptors
  • Increased levels of homocysteine are associated w/ increased risk of AD
  • Chronic / overactive glutamatergic activity may play a role in AD. Glutamate stimulates NMDA receptors → increased neuronal Ca → neuronal damage
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2
Q

Role of AchE in AD

A

AchE acts as a chaperone, accelerating the formation of amyloid fibrils by forming stable complexes w/ A-beta

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3
Q

Role of Apo E4 in AD

A

Apo E4 binds to A-beta, making it insoluble, promoting plaque formation.

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4
Q

Role of ERAB in AD

What does it stand for?

A

Endoplasmic reticulum associated binding protein

Enhances neurotoxic effects of A-beta

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5
Q

Normal / abnormal functions of tau

A

Tau protein normally stabilizes association of alpha / beta tubulin dimers. Hyperphosphorylation → paired helical fragments → neurofibrillary tangles.

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6
Q

2 main strategites to improve AD outcomes

A

1) increase Ach levels by blocking metabolism

2) decrease NMDA receptor-mediated glutamatergic signaling.

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7
Q 
Donepezil
Use
Mechanism
Adverse rxns
Precaution
A
  • Use – sx management for mild / moderate AD. Pxs show modest improvement in cognition / memory.
  • Mechanism – reversible AchE inhibitor. Binds to enzyme via hydrogen bonds. Has greater affinity for CNS AchE than plasma BuChE (butyryl cholinesterase; aka pseudocholinesterase)
  • Adverse rxns – generally well-tolerated
  • Precaution – GI bleeding: increases Ach-mediated acid secretion
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8
Q 
Rivastigmine
Use
Mechanism
Adverse rxns
Precautions
Comparison to donepezil
A
  • Use – mild / moderate AD and mild / moderate dementia associated w/ Parkinson’s
  • Mechanism – Pseudo-irreversible inhibitor of AchE (dissociates slowly) via carbamylation. 10x greater affinity for CNS AchE than Donepezil. Dose-related effects.
  • Adverse rxns – generally well tolerated (adverse rxns diminish over time)
  • Precautions – GI bleeding
  • Advantage over donepezil – no liver dysfunction due to no CYP involvement and more selective for CNS AchE
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9
Q 
Galantamine
Use
Mechanism
Pharmacokinetics
Metabolism
Precautions
A
  • Use – Improves cognitive sxs in mild / moderate AD
  • Mechanism – reversible, competitive inhibitor of AchE. 53x selective for CNS. Positive allosteric modulator of nicotinic receptors.
  • No dose-related effects.
  • Metabolism – CYP2D6 and CYP3A4. Excreted via urine.
  • Precautions – GI bleeding, renal failure (metabolites are excreted in urine), and hepatic disease
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10
Q 
Memantine
Use
Mechanism
Pharmacokinetics
Adverse rxns
Precaution
A
  • Use – Tx moderate / severe AD
  • Mechanism – Noncompetitive low-affinity antagonist at NMDA glutamate receptor slows intracellular Ca accumulation to prevent neurotoxicity. Inhibits low-grade, chronic “leak” of NMDA receptors. When full-fledged glutamatergic signal comes though, drug is knocked out of the way and allows for normal function.
  • Pharmacokinetics – active renal secretion (exceeds GFR)
  • Adverse rxns – none. Excellent tolerability.
  • Precaution – renal failure
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11
Q

Characteristics of Parkinson’s

Cause of death

A

Bradykinesia, muscular rigidity, resting tremor, impaired balance
Some pxs exhibit cognitive decline (PD dementia; more common in males > 70 y/o)
Eventual progression to akinetic state w/ death ensuing from complications of immobility.

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12
Q

How does Ach and DA affect GABA? What is the case in PD?

What other NT’s are involved in PD?

A

Ach stimulates GABA neurons.
DA inhibits GABA.
PD often has too much Ach and not enough DA function.
Often see decrease in DA transporters as well as DA itself
Other monoamine NT’s are affected as well. Loss of DA, NE, and 5HT function throughout the brain, not just SN.

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13
Q

What percentage of DA neurons in SN are lost before sxs begin?

A

80%

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14
Q

4 general strategies to restore neurochemical balance in PD

A
  • Increase DA levels by stimulating DA biosynthesis (L-DOPA precursor)
  • Increase DA levels by blocking metabolism
  • Directly stimulate DA receptors w/ DA agonists
  • Block CNS Ach receptors w/ muscarinic antagonists
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15
Q 
Levodopa-Carbidopa
Use
Mechanism
Adverse rxns
Precautions
A
  • Use – 1st line tx for PD.
  • Mechanism – Carbidopa inhibits DOPA decarboxylase (enzyme that converts LDOPA to DA in periphery), allowing for more LDOPA to enter brain b/c DA does not cross BBB, allowing for lower doses of LDOPA, more rapid titration, and minimized side effects. Carbidopa does not cross BBB.
  • Adverse rxns – dose-related and more common in elderly.
  • CNS: dyskinesias (due to excess DA; head bobbing, gnawing, tics, grimaces, ballismus, rhythmic foot or hand movements, bruxism, tongue movements; 80%); anxiety, nightmares, euphoria, insomnia, anorexia, nervousness, memory loss, psychosis (20%; tx with low doses of atypical antipsychotic agents)
  • Precautions
  • Melanoma
  • Narrow-angle glaucoma
  • Abrupt DC
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16
Q

Entacopone
Use
Mechanism
Adverse rxns

A
  • Use – adjunct to levodopa-carbidopa
  • Mechanism – selective / reversible inhibitor of COMT, prolonging half life and duration of action of LDOPA
  • Adverse rxns
  • Similar to levodopa-carbidopa (above)
  • May cause orange pee
  • B/c COMT is blocked, other drugs w/ catecholamine structure are blocked from being degraded → large concentrations in blood: isoproterenol, epinephrine, etc.
17
Q 
Silegiline
Use
Mechanism
Metabolism
Adverse rxns
A
  • Use – PD, off-label antidepressant
  • Mechanism – Noncompetitive, irreversible antagonist at MAO-B (main form in brain) which is main metabolizer of DA
  • Metabolism – methamphetamine is a metabolite
  • Adverse rxns
  • Adjunctive use w/ levodopa can potentiate dose-related effects
  • CNS: anxiety, confusion, insomnia, mania
  • CV: orthostatic hypotension, arrhythmias
  • GI: pain, NVD
  • Edema in legs / feet
18
Q

What is best PD therapy for elderly people?

What about younger pas?

A

LDOPA-carbidopa is go-to therapy for elderly people.

DA agonists are better for younger pxs

19
Q

Special effect of DA agonists

A

DA agonists protect DA neurons. Less cell death.

20
Q

Pramipexole
Use
Mechanism
Adverse rxns

A
  • Use – May be used alone or as adjunct to levodopa-carbidopa for PD
  • Mechanism – Synthetic DA agonist at D2 and D3 receptors.
  • Adverse rxns
  • CNS: dizziness, drowsiness, insomnia, asthenia, hallucinations, SLEEP ATTACKS (suddenly fall asleep in the middle of something; careful w/ driving)
  • GI: NV, constipation
  • CV: orthostatic hypotension
21
Q

Ropinirole
Use
Mechanism
Adverse rxns

A
  • Use – Used alone or in combo w/ levodopa-carbidopa for PD. Also used for moderate / severe restless legs syndrome.
  • Mechanism – DA agonist acting on D2 and D3 receptors.
  • Adverse rxns
  • CNS: dizziness, drowsiness, insomnia, asthenia, neuralgia, hallucinations, SLEEP ATTACKS
  • CV: syncope, edema, orthostatic hypotension
  • Causes fewer dyskinesias than levodopa
22
Q

Bromocriptine
Use
Mechanism
Adverse rxns

A
  • Use – PD, neuroleptic malignant syndrome, hyperprolactinemia, and acromegaly. Used alone or w/ levodopa.
  • Mechanism – Ergot-derived DA agonist at D2 receptors. Partial agonist at D1 receptors.
  • Adverse rxns
  • CNS: headache, dizziness, drowsiness, fatigue, confusion, hallucinations, agitation
  • GI: NV, cramps
  • CV: syncope, orthostatic hypotension, RAYNAUD’S SXS, ERYTHROMELALGIA
23
Q

3 muscarinic Ach receptor antagonists used for PD

A
  • Trihexyphenidyl – mainly specific for CNS receptors
  • Benztropine – fewer cognitive side effects than trihexyphenidyl but may cause anxiety
  • Diphenhydramine (Benadryl) – H1 blocker w/ significant antimuscarinic effects
24
Q

Amantadine
Use
Mechanism
Adverse rxns

A
  • Use – 2nd line tx for PD. Originally used as antiviral for influenza A
  • Mechanism – unknown
  • Adverse rxns
  • CNS: dizziness, insomnia, anxiety, depression, drowsiness, agitation
  • GI: nausea, xerostomia, diarrhea, constipation
  • CV: orthostatic hypotension, edema
25
Q

Rasagiline
Use
Mechanism
Adverse rxns

A
  • Use – Used alone or w/ levodopa for PD.
  • Mechanism – Irreversible MAO-B inhibitor
  • Well tolerated

Neuro (M2) (34 decks)

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