Drugs for Parkinson's Flashcards
A progressive disorder of movement that occurs most commonly in the elderly
Parkinson’s Disease
The result of loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) in the basal ganglia
Parkinson’s Disease (PD)
In PD dopamine is progressively lost, the effect of acetylcholine is relatively
Increased
Parkinson’s Disease is diagnosed at an advanced stage of approximately
80% cell loss
In PD there is a late appearance of symptoms - probably because of adaptive increase in dopamine receptors until the effect
“Max out”
MPTP is metabolized to the free radical, MPP+, which produces oxidative stress resulting in
Cell Death
Lead to the hypothesis that metabolism of dopamine could lead to the same effect via production of free radicals
MPTP Toxicity
The goal of treatment in PD is to facilitate
Dopaminergic Neurotransmission
The single most effective agent in treatment of PD
Levodopa (L-Dopa)
Is normally synthesized from L-tyrosine
L-Dopa
L-dopa is largely inert and unlike dopamine, it can cross the
Blood-brain barrier
The rate and extend of Levodopa absorption is dependent upon the rate of gastric emptying and
pH of gastric juice
Absorbed rapidly from small intestine by active transport system
-Competitive with aromatic amino acids
L-Dopa
High protein meal will delay absorption and reduce peak plasma concentration of
L-Dopa
The peak plasma concentration of L-Dopa is reached 1-2 hours after oral dose and the plasma half-life is
1-3 hours
An L-aromatic amino acid decarboxylase inhibitor
Carbidopa
Increases the fraction of levodopa that remains unmetabolized and available to enter the CNS
-Does not itself penetrate the blood-brain barrier
Carbidopa
Allows reduced dosage of levodopa which reduces peripheral side effects
Carbidopa
A Carbidopa + Levodopa combo drug with a 1:4 and 1:10 ratio of carbidopa : levodopa
Sinemet
If Levodopa is given without peripheral decarboxylase inhibitor (carbidopa) then 80% of patients experience
Anorexia, Nausea, and Vomiting
Combination with carbidopa reduces GI effects to occurrence in
20% of patients
Can also cause arrhythmias and postural hypertension
L-Dopa
Markedly accentuates levodopa actions and may precipitate a life-threatening hypertensive crisis
Administration with nonspecific MAO inhibitors
Enhances extracerebral metabolism of levodopa
Pyridoxine (B6)
Accenuate peripheral effects of L-dopa and can cause hypertensive crisis
MAO-A inhibitors
L-dopa is contraindicated in
Psycotic patients and patients with angle-closure glaucoma and active peptic ulcer
What percentage of patients will experience response fluctuations after 5 years of L-dopa therapy?
50%
What percentage of patients will experience response fluctuations after 15 years of L-dopa therapy?
70%
Long term use of L-dopa can result in an increase in the side effects of
Dyskinesias and psychiatric disturbances
In early PD, the duration of the beneficial effects of levodopa exceeds the plasma lifetime of the drug, because the nigrostriatal dopamine system retains some capacity to
Store and Release Dopamine
After the long-term use of levodopa therapy this “buffering“ capacity is lost, and the patient’s motor state may fluctuate dramatically with each dose of levodopa. This is called the
Wearing Off Phenomenon
Each dose of levodopa effectively improves mobility for 1-2 hours, but symptoms return rapidly at the end of the
Dosing Interval
Patients fluctuate rapidly between having no apparent effects of medication (“off”) and having effects of medication (“on”)
The unpredictable O/Off phenomenon
Off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility, but often of marked
Dyskinesia
For severe off-periods if not responding to other measures, we can use
Apomorphine
What are the two COMT inhibitors used to treat PD?
Tolcapone and entacapone
Has central and peripheral effects
Tolcapone
Has peripheral effects only
Entacapone
Adjunct to levodopa/carbidopa allowing reduction of levodopa dose
COMT inhibitors
Prolongs plasma half-life of levodopa and increases availability of levodopa to brain
Inhibition of COMT
Approved for patients with late PD who have developed response fluctuations
COMT inhibitors
Concurrent use with a non-specific MAO inhibitor could severely limit metabolism of levodopa and is contraindicated
COMT inhibitors
Can cause an increase in aminotransferase and transaminase activity which results in hepatotoxicity
Tolcapone
Is not associated with hepatotoxicity
Entacapone
Are secondary pharmacologic therapies of PD
Dopamine agonists like pramipexole, ropinrole, bromocriptine, and pergolide
Agonists selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than
Levodopa
A D2 agonist that is an ergot derivative
Bromocriptine
A non-ergot derivative D2 agonist
Ropinirole
A non-ergot derivative D3 agonist
Pramipexole
Could be used as monotherapy in patients with mild disease
- Well absorbed orally
- Plasma hlf life of 3-7 hours
Bromocriptine
Has similar affects to levodopa but more severe hallucinations than with levodopa alone
Bromocriptine
Metabolized by CYP1A2, so drugs that are metabolized by the liver may significantly reduce clearance
Ropinirole
Excreted largely unchanged in urine
Pramipexole
Has the RARE side effect of uncontrollable tendency to fall asleep at inappropriate times; requires discontinuation of medication
Ropinirole and pramipexole
Administered as a once-daily transdermal patch allowing continuous absorption leading to less serum fluctuation as compared to oral administration several times a day
Rotigotine
In addition to producing adverse side effects seen with other DA receptor agonists, application site reactions (erythema [redness] and pruritis [itching]) were reported in 37% of patients in clinical studies
Rotigotine
Available as a subcutaneous injection to treat “off” episodes in patients with advanced PD
-Mostly interacts with D2 receptors
Apomorphine
Rapidly taken up in the brain leading to clinical benefit that begins within 10 min of injection
Apomorphine
Causes emesis (vomiting/nausea) and requires pretreatment with antiemetic trimethobenzamide 3 days before initial treatment and continued for at least 2 months of therapy, if not indefinitely
Apomorphine
Contraindicated with antiemetics of the 5HT3 receptor class. Causes severe hypotension and loss of consciousness
Apomorphine
Metabolizes dopamine selectively
MAO-B
Metabolizes norepinephrine, serotonin, and dopamine; also found in liver and GI tract
MAO-A
Irreversible MAO-B inhibitor => B selective at 10 mg/day or less (at higher doses also inhibits MAO-A)
Selegiline
Retards breakdown of dopamine in striatum without inhibiting peripheral metabolism of catecholamines
Selegiline
Should not be taken together with analgesic meperidine - stupor, rigidity, agitation, and hyperthermia (mechanism is unknown), tramadol, methadone, cyclobenzaprine, St. John’s wort
Selegiline
More selective MAO-B inhibitor than selegiline
-Does not produce amphetamine metabolites
Rasagiline
Retards breakdown of dopamine in striatum without inhibiting peripheral metabolism of catecholamines
Rasagiline
Studies suggest that rasagiline and selegiline might have a
Neuroprotective effect
Provide neuroprotection by reducing the oxidation of dopamine
Selegiline and Rasagiline
Mechanism is unclear but may cause:
- Increase in dopamine release
- Blocking of dopamine reuptake
- Increase in dopamine synthesis
Amantidine (antiviral)
May favorably influence bradykinesia, rigidity, and tremor
-It also has antidyskinetic properties
Amantidine
Amantidine overdose may cause acute toxic
Psycosis
