Parkinson's Disease Flashcards
Neuropathology of Parkinsons
- 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
MPTP
- caused PD (environmental cause)
- oxidized to free radical
PD Treatment
- 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 ***
Levodopa (L-Dopa)
- most effective agent for PD treatment
- Levodopa CAN cross blood brain barrier (unlike dopamine)
- ** L-Dopa -> Tyrosine -> Dopamine ***
Levodopa Pharmacokinetics
- 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
Levodopa Metabolism in peripheral tissues
- 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
Carbidopa
- 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
Sinemet
Levadopa + Carbidopa
fixed concentrations
1:4 and 1:10 where 1=25 mg
Levadopa used alone
- very little enters CNS; many side effects due to peripheral metabolism
Sinemet use results
- w/ carbidopa: less dopamine in pheriphery = decreased side effects
- more dopamine reaches CNS
Adverse Effects of Levadopa Therapy
GI EFFECTS
- 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 **
Adverse Effects of Levadopa Therapy
CARDIOVASCULAR EFFECTS
- 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
Low dopamine : __________
High dopamine: __________
Low dopamine = hypotension
High dopamine = hypertension
Therapeutic/Adverse Effects of Levodopa Therapy
CNS
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
Levadopa Drug Interactions
- Pyridoxine
- MAO-A ( or nonselective MAO ) inhibitors accentuate peripheral effects of catecholamines (can lead to hypertensive crisis)
Levadopa Contraindications
- pyschotic patients
- angle-closure glaucoma
- active peptic ulcer must be managed carefully (GI bleeding)
Long Term Effects of Levodopa Therapy
- 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
PD Increase side effects with long term use
- dyskinesias
- psychiatric disturbances
Endo-of-Dose Deterioration
(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
On/Off Phenomenon
(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
Apopmorphine
for severe off-periods if not responding to other measures apomorphine can be used
Tolcapone
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)
Entacapone
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
Stalevo
levodopa/carbidopa/entacapone
entacapone preferred over tolcapone because no incidence of hepatotoxicity
Dopamine Agonists
- 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
Why decreased side effects with dopamine agonists
can target specific receptors; different dopamine receptors are expressed in different areas of the brain
Dopamine Agonist types
- Ergot derivatives
- Non-ergot derivatives
Bromocriptine
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
Ropinirole
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
Pramipexole
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
Rotigotine
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
Apomorphine
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
MAO-B
- metabolizes dopamine selectively; is mostly found in CNS
* ** want to selectively target B to target dopamine in CNS system ONLY! ***
MAO-A
- metabolizes norepinephrine, serotonin, and dopamine; in addition to CNS, also found in live and GI tract
MAO-B Inhibitors
Selectively target MAO-B
Selegiline
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
Rasagiline
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
Which MAO-B Inhibitor is more effective
Selegiline or Rasagiline?
Rasagiline: more selective
What is unique about Rasagiline/Selegiline
POSSIBLE MECHANISM OF NEUROPROTECTIVE EFFECT
- decrease synthesis of toxic metabolites
- neuroprotection by reducing oxidation of dopamine
Anti-Cholinergics
dNtK specific names
- 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)
Amantadine
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
