Flashcards in Lecture 12 - Parkinson's Disease Drugs Deck (56)
Parkinson's disease is a _____ disorder
When do symptoms usually appear?
60 yrs old
List 5 symptoms of Parkinson's
-shrinkage of handwriting
List 4 voluntary motor pathways
List 4 involuntary motor pathways
What is parkinson's caused by?
by the loss of neurons in the substantia nigra and thus, the loss of dopamine innervation of striatum (part of the basal ganglia)
When do parkinson's symptoms occur?
when about 70% of nigrostriatal neurons are lost
Abnormal signalling leads to ??
Describe the normal path of neurons
GABA neurons are inhibited by dopamine and stimulated by acetylcholine
Describe the path of neurons in parkinson's disease
dopaminergic neurons die, leaving a relative excess of ACh
Describe the path of neurons in huntington's disease
GABA neurons die as well as some ACh neurons
Symptoms amenable to drug therapy
-early treatment for 'neuronal sparing'
Discuss pharmacologic targets for parkinson's
-increase Da signalling in brain
-decrease cholinergic activity (striatal muscarinic receptors)
-decrease peripheral dopamine effects at D1/D2 dopamine receptors
-decrease peripheral L-dopa metabolism
dopamine receptors are ______
D1 subfamily members
Describe D1 subfamily
D1 subfamily members
Describe D2 subfamily
Striatum has what kind of dopamine receptors
What kinds of medication would be used to treat the first appearance of parkinson's
MAO B inhibitors
Describe the disposition characteristics of L-dopa
-rapid absorption from the small intestine by aromatic amino acid transport system
-peak plasma concentration 1-2 hr after ingestion
-plasma half life = 1-3 hrs
Bioavailability issues with L-dopa
-metabolism in intestine, blood, and peripheral tissues
-concurrently ingested food (protein, iron)
-only 1% actually enters the brain
Therapeutic effects of L-dopa
-reduces rigidity and bradykinesia
-improves motor function and speech
-return of facial expression
-first choice drug for improving motor function
Side effects of L-dopa
-nausea and vomiting
-hypotension and cardiac arrhythmias
-dyskinesias (abnormal involuntary movements)
-can have an on-off effect
-psychosis, schizophrenia-like behaviour, hallucinations
An adjunct to L-dopa = ?
How does carbidopa work?
-inhibits dopa decarboxylase (DDC or aromatic L-amino acid decarboxylase AADC)
-does not cross BBB
-reduces the amount of L-dopa required and thus, reduces the adverse effects of L-dopa
Describe standard adjunct therapy for parkinson's
L-dopa + carbidopa = Sinemet
L-dopa + bensarazide = Prolopa
Another adjunct to L-dopa = ?
-primarily for treating later stage parkinsons' disease
-selective and reversible inhibitor of peripheral COMT
-reduces peripheral metabolism of L-dopa
-does not cross BBB
-this leads to increased conversion of L-dopa to dopamine in the brain
Entacapone - used to treat problems associated with long term therapy of L-dopa (wearing off/ on-off effects)
-can enhance adverse effects of L-dopa, such as dyskinesias, nausea, psychosis and confusion
Sinemet + entacapone = ?
roprinirole/pramipexole are selective _______
dopamine agonists at D2/D3 receptors
peak plasma concentration ?
1-3 hours after ingestion
plasma half life
Therapeutic effects of roprinirole/pramipexole
-act on D2 and D3 receptors in and outside of the corpus striatum
-improves depressive symptoms
-may be combined with L-dopa to treat "on-off" effects
Side effects of dopamine agonists (including roprinirole/pramipexole)
-action on D2 receptors outside of the corpus striatum - dyskinesia
-activates other CNS D1-D3 receptors
-suppresses prolactin secretion
-suppresses growth hormone release
-visual and auditory hallucinations
-trihexyphenidyl HCl and benzatropine mesylate
-selective for muscarinic ACh type 1 receptor (M1R)
-not first line therapy
-used mainly in young patients with severe tremor
-inhibition of striata cholinergic activity
-improves tremor but not rigidity
-not recommended in elderly
MAO-A metabolizes ?
NE and 5-HT
MAO-B metabolizes ?
Selegiline is an ?
irreversible MAO-B inhibitor
Bioavailability issues with Selegiline ?
-negligible bioavailability after oral ingestion
-very rapid absorption (peak conc. < 1 hr)
-plasma half-life about 2 hr
Therapeutic issues with Selegiline
-relatively selective inhibition of MAO-B
-enhances effects of L-dopa
-may be useful to manage the on/off effect
-increased death rate compared to L-dopa when used as first treatment for the mild disease
Selegiline side effects
-not to be used with other MAO-I drugs
Selegiline is superseded by _______
Explain: Selegiline is superseded by rasagiline
-less production of amphetamine-like by-products
-useful in patients with depression and/or cognitive decline
Amantadine is a ??
bioavailability issues with amantadine
-not absorbed from the stomach (variable)
-half life of 12-14 hrs with normal renal function
-virtually complete excretion by the kidney (renal function)
Amantadine - therapeutic effects
-increases dopamine release in the CNS
-only of short-term benefit (<6 mo)
-sometimes used together with L-dopa
Side effects of Amantadine (similar to L-dopa)
-livedo reticularis (reddish-blue netlike mottling of the skin)
slide 35 - important
moderate/severe disability and age 70-75+ years or with significant comorbidity including cognitive impairment = ??
begin levodopa +/- COMTI
mild/moderate motor disability and no cognitive impairment = ??
begin dopamine agonist
mild motor disability and no cognitive impairment = ??
begin MAO-B inhibitor