Dopamine Enhancing Agents Flashcards
How do we increase dopaminergic action in striatum?
Augmentation of the synthesis of brain DA Stimulation of DA release Direct stimulation of DA receptor Decreasing DA reuptake Decreasing metabolism of DA and DOPA
Secondary therapeutic goal in PD
Decrease endogenous ACh action
Why worry about ACh?
ACh has an overall stimulating effects on muscle contraction (while DA inhibits muscle contracting so not enough = tremor)
So what happens in PA?
Not enough DA to counteract ACh
Why can’t you administer DA?
It is completely destroyed during digestion
It cannot be absorbed by the gut wall
Must be given IV and even then it can’t cross BBB
So L-dopa works how?
It is decarboxylated to DA
L-dopa is transported across BBB via large neutral amino acid transporter (LAT)
L-dopa half life and problems
0.5-2 hrs
Has to compete with neutral amino acids so don’t take it with lots of proteins
Also rapid peripheral decarboxylation so always given with an inhibitor
Levodopa SE
Nausea
Dyskinesias
Hallucinations, postural hypoTN
Long-term treatment with levodopa leads to
Motor complications
- Waring off and response fluctuations
- Dyskinesias (involuntary movements)
- Feeling stuck to the floor
- Therapeutic window becomes narrower with longer treatment
Levodopa Absorption
Bioavailablity of 30% but doubled when given with a decarboxylase inhibitor
Delayed/reduced with food
Levodopa Metabolism and Excretion
M: Liver/gut/kidney
E: Kidneys
Decarboxylase Inhibitor =
Carbidopa
Decarboxylase Inhibitor MOA
Inhibits the peripheral metabolism of L-dopa to DA which increases amount of levadopa which increase the amount of DA in the brain
Carbidopa Brands
Sinernel
Rytary
Lodosyn (monotherapy)
Carbidopa helps to
Relieve nausea and other side effects of Levadopa
COMT Inhibitors do what?
Diminish response fluctuations
Adjunct to L-dopa/carbidopa
Blocks L-DOPA to 3-o-MD
COMT Inhibitors Drugs
Talcapone (Tasmar)
Entacapone (Comtan)
Talcapone Brand
Tasmar
Talcapone MOA
Inhibits COMT centrally and peripherally
Long duration of action
Talcapone SE
jaundice, upset stomach, extreme tiredness, hepatotoxicity
Talcapone Black Box Warning
Risk of potentially fatal, acute fulminant liver failure so requires blood test
Talcapone Use
Only used in patients not responding to other treatments
Entacapone Brand
Comtan
Entacapone MOA
Inhibits COMT peripherally
Preferred over Tolcapone
Carbidopa + Levodopa + Entacapone =
Stalevo
Entacapone SE
Nausea
Orthostatic hypotension
0 Less severe
Entacapone + MAOI?
Only selegiline
MAO-A
Preferentially deaminates serotonin, epinephrine and NE leading to unwanted serious side effects
MAO-B
Resonsible for oxidative deamination of DA in the brain
So is MAOB or A more desired?
MAO-B should be selectively inhibited
MAO-B Inhibitors
Selegiline (Eldepryl, Emsam, Zelapar)
Rasagiline (Azilect)
Selegiline
Eldepryl
Emsam
Zelapar
Selegiline is what type of inhibitor?
Irreversible MAO-B Inhibitor
Low dose verse high dose Selegiline
Low: MAOB
High: both A and B
Selegiline Use
1st drug of choice in pts under 65
Monotherapy in early PD
Adjunct in advanced PD
Metabolites of Selegiline
Amphetamine and methamphetamine
Selegiline SE
Anxiety and insomnia
Hallucinations
Selegiline Drug Interactions
Meperidine (serotonin syndrome, CV instability)
Transdermal patch and orally disintegrating pill of selegiline?
Reduce 1st pass metabolism and limits the formulation of metabolites so there are less side effects
Rasagiline brand
Azilect
Rasagiline MOA
irreversible MAO-B Inhibitor
Rasagiline upside
Not metabolized to amphetamines so less side effects
Rasagiline use
Monotherapy in early or adjunct with levadopa in advanced PD
Ergot derivatives that are Dopamine Receptor Agonists
Bromocriptine
- Rarely used nowadays bc they are older
Most common Dopamine Receptor Agonists
Pramipexole
Rapirnirole
Define Indirect Pathway
Inhibits movement
Define Direct Pathway
Enables movement
What does Dopamine do to the pathways?
It inhibits the indirect pathway (blocks inhibition of movements) and stimulates the direct pathway (increase movement)
So how do dopamine agonist work?
Directly stimulates dopamine receptors
Dopamine Agonists upsides
Longer half lives
No toxic metabolites
No competition for transporter
Dopamine Agonist Uses
Initial therapy esp in young and adjunct to levadopa
Monotherapy dopamine agonist
Ropinirole and pramipexole
Dopamine agonists SE
N/V Dizziness Drowsiness/somnolence Confusion hallucinations Dyskinesias with levadopa Fibrosis (ergots)
Ropinirole brand
Requip
Ropinrole MOA
D2 class receptor selectivity 6 hr half life and last 8-24 hours
Ropinirole SE
Somnolence
Hallucination/confusion
Orthostatic hypotension
Ropinirole Use
Treating on/off effects
Pramipexole Brand
Mirapex
Pramipexole MOA
D2 class receptor selectivey
8 hr half life
90% bioavailability
Pramipexole AE
N
Somnolence
Sleepiness (sudden falling asleep)
Apomorphine brand
Apokyn
- Oldest and most potent dopamine agonist
Apomorphine Use
SC injection Rescue medication (pts with irregular off periods)
Apomorphine SE
Highly nauseating
Orthostatic hypotension
Rotigotine Brand and dosage form
Neupro
- Transdermal patch
Rotigotine MOA
Selective D2 receptor agonist
halflife 5-7 hrs
Rotigotine Use
PD and restless leg syndrome
Anti-cholinergic agent MOA
Anti-PD blcoks msucarinic receptors or inhibit DA reuptake
DA depletion leads to increased cholinergic activity (tremor)
Decreased dopaimine leads too
Inhibited ACh through D2
Increased ACh which leads to tremor
Muscarinic receptor antagonists?
Benzlropine (Cogentin)
Trihexyphenidyl (Artane)
Anticholinergic agent Use
Tremor
Anticholinergic agents + older pts
Worsening dementia so CI in alzheimer’s
Anticholinergic SE
Dry mouth Constipation Urinary retention Sedation/confusion Delirium
Amantadine brand
Symmetrel
Amantadine MOA
Antiviral drug used for flu
Enhances DA release and inhibits its reuptake
Has anticholinergic properties
Blocks NMDA receptors
Amantadine Use
Mild PD
Amantadine SE
Confusion Dizziness Hallucinations Dry mouth Livedo reticularis (mottling of skin)
