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Pharmacology Test 1 > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

Neuropathology of Parkinsons

A
  • loss of dopaminergic (DA) neurons in the susbstantia nigra pars compacta (SNpc) in the basal ganglia
  • accumulation of Lewy bodies, primary structural component of which is protein alpha-synuclein
  • dopamine is progressively lost
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2
Q

MPTP

A
  • caused PD (environmental cause)

- oxidized to free radical

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3
Q

PD Treatment

A
  • exogenous dopamine precursor
  • inhibitors of dopamine metabolism
  • dopamine agonists
  • increased dopamine release or re-uptake
  • inhibit dopamine degredation
  • ** dopamine can’t cross blood brain barrier ***
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4
Q

Levodopa (L-Dopa)

A
  • most effective agent for PD treatment
  • Levodopa CAN cross blood brain barrier (unlike dopamine)
  • ** L-Dopa -> Tyrosine -> Dopamine ***
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5
Q

Levodopa Pharmacokinetics

A
  • rate and extent of absorption dependent upon
  • – rate of gastric emptying
  • – time of exposure to degradative enzymes of gastric and intestinal mucosa
  • ORAL*
  • absorbed rapidly from small intestine by active transport
  • peak plasma 1-2 hrs after oral dose
  • t1/2 = 1-3 hours
  • transported into brain by active transport system
  • – competitive to other stuff
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6
Q

Levodopa Metabolism in peripheral tissues

A
  • by L-aromatic amino acid decarboxylase -> Dopamine
  • ** BAD: does NOT enter CNS; can be used elsewhere***
  • ** Inhibited by Carbidopa ***
  • by catechol-O-methyltransferase -> 3-O-methyl-dopa
  • – 15-hr t1/2
  • – competes with levodopa for transport into brain
  • ** if administered alone, only about 1-3% of dose enters CNS
  • ** peripheral metabolism produces side effects
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7
Q

Carbidopa

A
  • L-aromatic amino acid decarboxylase inhibitor
  • does not itself penetrate blood-brain barrier
  • increases amount of Levadopa available to enter CNS
  • allows REDUCED DOSAGE of levadopa which reduces peripheral side effects
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8
Q

Sinemet

A

Levadopa + Carbidopa
fixed concentrations
1:4 and 1:10 where 1=25 mg

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9
Q

Levadopa used alone

A
  • very little enters CNS; many side effects due to peripheral metabolism
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10
Q

Sinemet use results

A
  • w/ carbidopa: less dopamine in pheriphery = decreased side effects
  • more dopamine reaches CNS
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11
Q

Adverse Effects of Levadopa Therapy

GI EFFECTS

A
  • if given without carbidopa, 80% of patients experience
  • – anorexia
  • – nausea
  • – vomiting
  • stimulation of emetic center located in brain stem

** combination with carbidopa reduces side effects so 20% of patients **

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12
Q

Adverse Effects of Levadopa Therapy

CARDIOVASCULAR EFFECTS

A
  • Arrhythmias
  • Postural hypotension
  • Hypertension: if very high doses of levodopa is taken or if taken with MAO-A inhibitors
  • together with MAO-A inhibitors may cause life threatening hypertensive crisis
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13
Q

Low dopamine : __________

High dopamine: __________

A

Low dopamine = hypotension

High dopamine = hypertension

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14
Q

Therapeutic/Adverse Effects of Levodopa Therapy

CNS

A

Desired: decrease in tremor, rigidity, bradykinesia

Undesired:

  • abnormal involuntary movements (dyskinesias)
  • psychological disturbances: confusion, hallucination, anxiety
  • – conventional anti-psychotic agents are effective but worsen PD
  • – “atypical” antipsychotics do NOT worsten symptoms and can be used
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15
Q

Levadopa Drug Interactions

A
  • Pyridoxine
  • MAO-A ( or nonselective MAO ) inhibitors accentuate peripheral effects of catecholamines (can lead to hypertensive crisis)
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16
Q

Levadopa Contraindications

A
  • pyschotic patients
  • angle-closure glaucoma
  • active peptic ulcer must be managed carefully (GI bleeding)
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17
Q

Long Term Effects of Levodopa Therapy

A
  • Response fluctuations
  • – 50% of patients after 5 years of therapy
  • – 70% of patients after 15 years of therapy
  • Honeymoon: symptoms completely disappear for a few years
  • Endo-of-Dose: deterioration or wearing-off (predictable)
  • On-off phenomenon (unpredictable)
  • usually adjunctive therapy is required
18
Q

PD Increase side effects with long term use

A
  • dyskinesias

- psychiatric disturbances

19
Q

Endo-of-Dose Deterioration

A

(predictable)

  • nigrostriatal dopamine system still has ability to retain dopamine, so effects outlast drug lifetime
  • eventually buffering capacity (ability to hold dopamine) is lost, and motor state fluctuates dramatically (wearing off phenomenon)
  • each dose of Levadopa effectively improves mobility for 1-2 hours, but symptoms return rapidly at the end of the dosing interval
20
Q

On/Off Phenomenon

A

(unpredictable)

  • patients fluctuate between having no apparent effects of medication (off) and having effects of medication (on)
  • mechanism unknown
  • for severe off-periods if not responding to other measures apomorphine can be used
21
Q

Apopmorphine

A

for severe off-periods if not responding to other measures apomorphine can be used

22
Q

Tolcapone

A

catechol-O-methyltransferase inhibitor
- central and peripheral effects
-increase bioavailability of levodopa
- lead to more steady levels of levodopa in peripheral tissues and allow reduction of levodopa use
- used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
* use only if patient is not responding to entacapone*
(can cause hepatotoxicity)

23
Q

Entacapone

A

catechol-O-methyltransferase inhibitor

  • peripheral effects
  • increase bioavailability of levodopa
  • lead to more steady levels of levodopa in peripheral tissues and allow reduction of levodopa use
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
24
Q

Stalevo

A

levodopa/carbidopa/entacapone

entacapone preferred over tolcapone because no incidence of hepatotoxicity

25
Q

Dopamine Agonists

A
  • directly effect dopamine receptors
  • less effective in decreasing symptoms
  • don’t compete at brain blood barrier
  • less incidence of side effects
  • longer t1/2 compared to levodopa
  • no potential toxic metabolites
26
Q

Why decreased side effects with dopamine agonists

A

can target specific receptors; different dopamine receptors are expressed in different areas of the brain

27
Q

Dopamine Agonist types

A
  • Ergot derivatives

- Non-ergot derivatives

28
Q

Bromocriptine

A

dopamine agonist; ergot derivative

  • well absorbed orally
  • plasma t1/2 of 3-7 hours
  • used as monotherapy in patients with mild-disease
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
29
Q

Ropinirole

A

dopamine agonist; non-ergot derivative

  • metabolized by CYP1A2; drugs metabolized by liver may significantly reduce clearance
  • used as monotherapy in patients with mild disease
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
30
Q

Pramipexole

A

dopamine agonist; non-ergot derivative

  • excreted largely unchanged in urine
  • used as monotherapy in patients with mild disease
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
31
Q

Rotigotine

A

dopamine agonist; non-ergot agonist
- administered as a once-daily transdermal PATCH allowing continuous absorption leading to less serum fluctuation as compared to oral administration several times a day

32
Q

Apomorphine

A

dopamine agonist

  • available as a subcutaneous injection to treat OFF episodes in patients with advanced PD
  • is RAPIDLY TAKEN UP in the brain, leading to quick clinical benefit
33
Q

MAO-B

A
  • metabolizes dopamine selectively; is mostly found in CNS

* ** want to selectively target B to target dopamine in CNS system ONLY! ***

34
Q

MAO-A

A
  • metabolizes norepinephrine, serotonin, and dopamine; in addition to CNS, also found in live and GI tract
35
Q

MAO-B Inhibitors

A

Selectively target MAO-B

36
Q

Selegiline

A

MAO-B Inhibitor

  • selective irreversible MAO-B inhibitor (AT HIGH DOSES INHIBITS A AS WELL)
  • decreases breakdown of dopamine
  • used as monotherapy in patients with mild disease
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
37
Q

Rasagiline

A

MAO-B Inhibitor

  • selective irreversible MAO-B inhibitor (MORE SLECTIVE than Selegiline) (at higher doses does still inhibit MAO-A)
  • decreases breakdown of dopamine
  • does not produce amphetamine metabolites
  • used as monotherapy in patients with mild disease
  • used in combination with levodopa/carbidopa for patients with advanced PD who have developed response fluctuations
38
Q

Which MAO-B Inhibitor is more effective

Selegiline or Rasagiline?

A

Rasagiline: more selective

39
Q

What is unique about Rasagiline/Selegiline

A

POSSIBLE MECHANISM OF NEUROPROTECTIVE EFFECT

  • decrease synthesis of toxic metabolites
  • neuroprotection by reducing oxidation of dopamine
40
Q

Anti-Cholinergics

dNtK specific names

A
  • intentionally causes acetylcholine pathway to deteriorate
  • reduce acetylcholine signaling, thus somewhat restoring the balance between dopamine and acetylcholine
  • may improve tremor and rigidity
  • little effect on bradykinesia
  • if fail to respond to one drug try another (trial and error to figure out which respond best to)
41
Q

Amantadine

A

antiviral agent

  • mechanism is unclear
  • benefits short-lived
  • – may favorably influence bradykinesia, rigidity, and tremor
  • – antidyskinetic properties
  • used as monotherapy in mild cases or adjunct

Pharmacology Test 1 (8 decks)

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