431 Lec 34

Understand the area/ signaling pathway of the brain impacted most significantly that leads to PD and why

•Associated with deficit of dopamine

•Characterized by destruction of DA containing neurons in the substantia nigra leading to DA deficiency in nerve terminals in corpus striatum

Be able to recognize the three main contributors to the cause of PD.

Genetic component

Oxidative Metabolism component

Environmental Neurotoxins component

Know how alpha-synuclein may be involved in PD.

•Can aggregate and form donuts then attach to neuron membrane and make a whole leading to calcium flux leading to toxicity

•can aggregate and attach to mitochondria

•block proteosomes

•overprodced leading to block release of dopamine, causing dopamine toxicity

Know what other genes are involved and how their dysfunction can lead to PD.

DJ1- inhibits aggregation of alpha syn nuclein

PINK1- protein kinase thats responsible for mitochondrial health

Parkin- responsible for tagging misfolded proteins to be broken down

LRRK- kinase, mutations in this gene lead to lewy bodies and neuronal death in PD

Be able to recall at which points in the dopamine biosynthesis or catabolism pathways reactive intermediates may be generated and how this relates to PD

Recognize what environmental neurotoxins we discussed are likely to cause PD and which one is not

\
Rotenone, Cyperquat, Paraquat

Rotenone (most likely), Cyperquat, Paraquat (least likely- does not bind mitochondrial complex 1)

\
MPTPS causes severe parkinsons syndrome

Understand the correlation between mitochondrial complex 1 inhibition and PD

Important in the electron shuffling of mitochondria- inhibiting it is bad for the mitochondria which is essential to cells

Know how dopamine is biosynthesized from L-tyrosine, and what enzymes and co-factors are involved.

Does dopamine cross the BBB?

No

Does L-DOPA cross the BBB?

Yes

Know how carbidopa works mechanistically and how it is used to treat symptoms of PD. You do not need to know the arrow pushing mechanism but the general concepts are important.

Inhibits the conversion of LDOPA to dopamine in the periphery because we want LDOPA to cross the BBB BEFORE it gets converted to dopamine

\
Carbidopa does not cross BBB

Understand at what stage of PD using L-DOPA is most appropriate and why.

Early on use of LDOPA increases life expectancy

Needs vitamin B6

Know how dopamine receptor agonists are used in PD (what do they do and what stage of disease are they most useful)?

Enzymes to convert LDOPA don’t work→ bring in molecules that mimic dopamine action at the receptor

\
Usually used at nigrostriatal degeneration (fewer nerve terminals lef tot convert LDOPA to DA)

How do DA agonists differ from L-DOPA in duration of action and side effect profile?

Longer duration of action than L Dopa and may be less likely to produce on off effects and dyskinesias but can produce other adverse effects:

→ nausea

→vomiting

→Sedation

→Hallucination

→psychiatric disturbances

Apomorphine

Dopamine receptor agonist

Nonselective

No oral bioavailability

Controls motor dysfunction in PD

\
Agonizes D1 & D2

Crosses BBB

Bromocriptine

Selective D2 agonist

Orally active

Extensive liver metabolism

Inhibits prolactin release from pituitary cells which exclusively expressed D2 receptors

Mirapex/(S)- pramipexole & ropinirole/Requip

Both commonly prescribed for PD

First line treatment sometimes before LDOPA

D2 receptor agonists

\
Side effects: initial nausea, vomiting, postural hypotension, fatigue

Hallucinations, delusions, confusion- esp in elderly dementia patients with PD

How are monoamine oxidase inhibitors used in PD (what is their mechanism of action)?

Inhibition of MAO could increase DA concentrations because MAO turns dopamine into DOPAL

What MAOIs are NOT used in PD and why?

Long acting nonselective are contraindicated in combination with LDOPA due to risk of inducing hypertensive crisis and delirium

Know the structure/name and mode of action of Selegiline/deprenyl in PD.

Irreversible, MAO B selective

Reduces dosages needs of LDOPA

N-dealkylated by CYPs to L methamphetamine

\
L methamphetamine metabolized to L amphetamine→ vasoactive activity → associated with cardiovascular and psychiatric side effects

Azilect/rasagiline in PD

•Irreversible, MAOB selective

•Reduces dosage needs of LDOPA

•Ndealkylated by CYPS

•Not vasoactive

•1mg.day dose is neuroprotective

Safinamide/Xadago

MAOI

Multiple MOA:

→ reversible MAOB selective inhibitor

→Blocks sodium and calcium ion channels

→Inhibits glutamate release

\
Add on therapy: Reduces dosage needs of LDOPA

Oral

\
Contraindications:

Patients with severe liver impairment

Patients with retinal disorders

Preggo and breast feeding

In combination with other MAOIs/SSRIs/tyramine containing foods

Know the Catechol O-Methyltransferase (COMT) pathways relevant to PD.

COMT can degrade LDOPA to different intermediates before it turns into dopamine

Entacapone/Comtun

Reversible COMT inhibitor

Short duration of action

**Works only in periphery**

Severe diarrhea

Tolcapone/Tasmar

Reversible COMT inhibitor

Long duration of action

**Works in brain and periphery**

Hepatic toxicity

Severe diarrhea

What is a common side effect of Entacapone/Comtun and Tolcapone/Tasmar?

Severe diarrhea

Know the components and utility of Stalevo.

Entacapone- Peripheral reversible COMT inhibitor

Carbidopa- Aromatic L amino acid decarboxylase inhibitor

L-Dopa- Precursor to DA synthesis

\
Helpful to:

→Replace equivalent dosage of individual components

→Help with wearing off effects of L-Dopa/carbidopa alone

Adamantine/symmetrel

Adjunct therapy

Antidyskinetic (helps with sudden uncontrolled movements)

Causes release of DA and NE from storage vesicles

Blocks reuptake of DA

NMDA glutamate receptor antagonist

Benzatropine/Cogentin

Adjunct therapy

Muscarinic antagonist (relaxes muscle to avoid spasm)

Control extrapyrimidal effects well so still used despite adverse events

Nourianz

Adjunct therapy with LDOPA/Carbidopa

For treating “off time” in PD

Adenosine A2A receptor antagonist

Metabolized by CYP3A4

Patients with renal failure may need to adjust dose down

what molecule is this

tyrosine

what is this

LDOPA

what is this

Dopamine

what is this

Carbidopa