Dopamine Enhancing Agents Flashcards by Beth Cocker

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

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Secondary therapeutic goal in PD

Decrease endogenous ACh action

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Why worry about ACh?

ACh has an overall stimulating effects on muscle contraction (while DA inhibits muscle contracting so not enough = tremor)

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So what happens in PA?

Not enough DA to counteract ACh

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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

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So L-dopa works how?

It is decarboxylated to DA

L-dopa is transported across BBB via large neutral amino acid transporter (LAT)

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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

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Levodopa SE

Nausea
Dyskinesias
Hallucinations, postural hypoTN

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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

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Levodopa Absorption

Bioavailablity of 30% but doubled when given with a decarboxylase inhibitor
Delayed/reduced with food

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Levodopa Metabolism and Excretion

M: Liver/gut/kidney
E: Kidneys

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Decarboxylase Inhibitor =

Carbidopa

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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

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Carbidopa Brands

Sinernel
Rytary
Lodosyn (monotherapy)

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Carbidopa helps to

Relieve nausea and other side effects of Levadopa

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COMT Inhibitors do what?

Diminish response fluctuations
Adjunct to L-dopa/carbidopa
Blocks L-DOPA to 3-o-MD

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COMT Inhibitors Drugs

Talcapone (Tasmar)

Entacapone (Comtan)

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Talcapone Brand

Tasmar

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Talcapone MOA

Inhibits COMT centrally and peripherally

Long duration of action

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Talcapone SE

jaundice, upset stomach, extreme tiredness, hepatotoxicity

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Talcapone Black Box Warning

Risk of potentially fatal, acute fulminant liver failure so requires blood test

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Talcapone Use

Only used in patients not responding to other treatments

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Entacapone Brand

Comtan

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Entacapone MOA

Inhibits COMT peripherally

Preferred over Tolcapone

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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) ```

Dopamine Enhancing Agents Flashcards

(76 cards)