Pharmacotherapy for Parkinson's Disease (Week 4--Melega)

Question 1

Hyperkinetic movement disorders

Answer 1

Characteized by excess of movement

Uncontrollable and rapid motor acts that intrude into normal flow of motor activity

Ex: Huntington’s disease

Question 2

Hypokinetic movement disorders

Answer 2

Characterized by decreased movement

Tremor, rigidity, bradykinesia

Ex: Parkinson’s disease

Question 3

Parkinsonism

Answer 3

Set of symptoms similar to those of PD that may be related to side effects associated with DA antagonists (antipsychotic drugs) or environmental toxin exposure

Question 4

Is Parkinson’s Disease treatable?

Answer 4

Yes, highly treatable

But treatments still treat symptoms (just very well!) and don’t cure the disease

Question 5

Where does PD usually manifest first?

Answer 5

PD starts in the medulla (or pontine tegmentum) and olfactory bulb/anterior olfactory nucleus and THEN progresses to substantia nigra

Question 6

Three primary symptoms of PD

Answer 6

1) Resting tremor
2) Muscle rigidity
3) Bradykinesia (slowness or inability to initiate movement)

Other symptoms: stooped posture, loss of arm swinging when walking, shuffling gait, problems speaking and writing (micrographia), masklike face (loss of facial expressions/movements), depression, autonomic dysfunction

Question 7

Goal of pharmacological therapies for PD

Answer 7

Produce more output from striatal dopaminergic neurons:

1) Increase DA synthesis capacity (Levodopa)
2) Activate post-synaptic receptors (ropinirole, pramipexole)
3) Inhibit DA metabolism (selegiline, rasagiline, COMT inhibitor)
4) Alter interaction/balance with other NTs (ACh-DA balance: trihexyphenidyl, benztropine)
5) Dopamanie releasers (amantadine?)
6) Peripherally inhibit L-DOPA metabolism (carbidopa)

Question 8

Dopamine synthesis and storage

Answer 8

Tyrosine –> Tyrosine hydroxylase creates L-DOPA –> DOPA decarboxylase creates dopamine –> MAO degrades dopamine into DOPAC –> COMT degrades DOPAC into HVA

Tyrosine transported in, turned to L-DOPA which enters vesicle via VMAT, then released into synaptic cleft then re-uptake by dopamine transporter (DAT), then degraded in the presynaptic terminal to DOPAC by MAO

Question 9

Dopamine receptors

Answer 9

All G-protein coupled

D1, D5 increase adenylyl cyclase activity

D2, D3, D4 inhibit adenylyl cyclase activity

Question 10

Levodopa (L-DOPA)

Answer 10

Give L-DOPA (an amino acid, and precursor to dopamine) because it can be transported across the BBB via transporter for large neutral amino acids (LNAA) and turned into dopamine

However, L-DOPA is extensively metabolized, so have to administer carbidopa too to make sure not all L-DOPA broken down in periphery!

Question 11

Why can’t we just administer tyrosine or dopamine?

Answer 11

Can’t give tyrosine because it will be used for protein synthesis and not creating L-DOPA

Can’t give dopamine because it won’t get across the BBB so won’t be therapeutic for PD!

Question 12

How is L-DOPA metabolized in the periphery?

Answer 12

95% of L-DOPA (po) is metabolized in the periphery

COMT, AAAD, MAO all degrade L-DOPA in periphery

AAAD turns it to dopamine

COMT turns it to 3-O-methyl-L-DOPA or HVA

MAO turns it to DOPAC

Question 13

Carbidopa

Answer 13

Peripheral decarboxylase inhibitor (NO CNS actions, does not cross BBB!)

Increases L-DOPA bioavailability

Question 14

Sinemet

Answer 14

L-DOPA + carbidopa

Question 15

Major adverse effects of L-DOPA

Answer 15

Early: nausea, vomiting, emotional depression/psychosis, orthostatic hypotension

Late: end of dose/”wearing off” periods, on/off periods (sudden loss of symptom control) irrespective of L-DOPA levels

Years of chronic L-DOPA: dyskinesias

Question 16

Dyskinesias

Answer 16

Induced by L-DOPA administration (drug-induced, not natural!)

Can develop in 50-90% of patients

Involuntary movements that are typically choreiform (quick, jerky, purposeless) or dance-like in character but may involve dystonia, myoclonus (clonic spasm or twitching of muscles), other movement disorders

Virtually any part of body may be involved

Question 17

Dopamine agonists

Answer 17

Apomorphine: D1/D2 agonist; short-acting 40min half life (to provide “rescue” 4-8 min after injection)

Ropinirole: D2/D3 agonist; 6h half life

Pramipexole: D2/D3 agonist; 8-12h half life

Question 18

Ergot alkaloids

Answer 18

Isolated from fungus Claviceps purpurea on rye and wheat

Ergotism can cause nausea, diarrhea, vasoconstriction, smooth muscle contraction, gangrene, hallucinations, delirium and seizures

Acts as agonist at serotonin, dopamine, and alpha 1 receptors

Causes uterine contraction, vasoconstriction, dopamine agonist activity

Question 19

What is apomorphine (Apokyn) used for?

Answer 19

Rapid “rescue” within 4-8 min after injection for undermedicated or “frozen” state

Acute, intermittent treatment of hypomobility, “end of dose wear off” and unpredictable “on/off” episodes of PD

Adverse effects: nausea, vomiting, hypotension

Question 20

Major adverse effects of dopamine receptor agonists (apomorphine, ropinirole, pramipexole)

Answer 20

Sleep disorder

Psychiatric effects

Nausea/vomiting

Postural hypotension

Lower incidence of dyskinesia compared to L-DOPA

Question 21

Irreversible MAO-B inhibitors

Answer 21

MAO-B is present in striatum and metabolizes dopamine so if we can block this we’ll have more dopamine

Selegiline, rasagiline

Potential serious drug interactions (potentiate SSRIs, TCAs)

Metabolism by MAO-A (both central and peripheral) unaffected

Note: MAO inhibitors also raise serotonin levels

Question 22

Why would we want to change ACh levels in treating PD?

Answer 22

In PD, dopamine deficit results in excessive ACh function because you lose a “balance” between DA and ACh

Question 23

Muscarinic receptor antagonists to treat PD

Answer 23

Trihexyphenidyl, benztropine

Weak efficacy and limited clinical utility but mostly for tremor

Less effective than L-DOPA

Competitive inhibition of ACh, decreasing ACh

Question 24

COMT inhibitor

Answer 24

Entacapone

Inhibits COMT in periphery only, increasing bioavailability of L-DOPA (only given with L-DOPA)

Prolongs duration of L-DOPA response (1.7x)

Note: similar idea to carbidopa!

Question 25

Which drugs should we use first to treat PD?

Answer 25

Main line agents: Sinamet (L-DOPA + carbidopa), ropinirole and pramipexole (DA agonists), rasagiline and selegiline (MAO-B inhibitors)

Lower efficacy/second line or adjuvants: Benztropine and trihexyphenidol (anticholinergics), amantadine (DA reuptake inhibitor), entacapone (COMT inhibitor)

Question 26

Compare/contrast L-DOPA, DA agonist, MAO inhibitor

Answer 26

L-DOPA: sinamet most effective, long-term use commonly associated with dyskinesia, pulsatile DA stimulation

DA agonist: ropinirole and pramipexole very effective, reduces risk of dyskinesia because continuous rather than pulsatile DA stimulation as with L-DOPA

MAO inhibitor: selegiline and rasagiline may have neuroprotective and anti-apoptotic effects on dopamine neurons

Begin with monotherapy and then may progress to polypharmacy

Question 27

Drug-induced Parkinsonism

Answer 27

Drugs that reduce DA activity in striatum

Reversible (but may take weeks/months after drug is stopped)

Reserpine depletes brain catecholamines and induces PD symptoms

Antipsychotics (neuroleptics) that block DA receptors

DA antagonists exacerbate PD

Question 28

MPTP

Answer 28

Contaminant created by accident when drug dealers were trying to make a meperidine analog (MPPP)

MPTP produced PD pathology in drug users in early 1980s

MPTP is lipid soluble so crosses BBB, metabolized by MAO-B to MPP+ which is re-uptaken by DAT into dopaminergic terminals, diffuses into mitochondria, inhibits oxidative phosphorylation and causes cell death in DA SNc cells which causes PD

Question 29

Is there a time limit on effectiveness of drugs to treat PD?

Answer 29

Yes, after 3-5 years of medication (L-DOPA especially), becomes less effective and causes dyskinesia

Question 30

How can we use PET imaging to track DOPA?

Answer 30

Add 18F to L-DOPA to create FDOPA which is metabolized like DOPA so we can see L-DOPA levels

18FDOPA injected into patient in trace amount –> FDOPA uptaken into brain and into DA nerve terminals –> FDOPA converted to FDA (fluorodopamine) by AAAD and stored in vesicles

Interpretation of PET images based on 18F accumulation that is presumed proportional to AAAd activity (assessment of DA synthesis capacity)

Question 31

Other treatments besides drugs for PD

Answer 31

Surgery: radiofrequency lesion (pallidotomy), deep brain stimulation (subthalamic nucleus)

Clinical studies in progress: intrastriatal viral vector therapy (genes for tyrosine hydroxylase, AA decarboxylase), infusion of neurotrophic factors (GNDF)

Question 32

When to use which drugs

Answer 32

L-DOPA is most effective for PD symptoms and is effective in treating first symptoms

Dopamine agonists used initially in individuals <65 years old

Early treatment may include antimuscarinics and/or amantadine, or MAO-B inhibitors

Question 33

Amantadine

Answer 33

“Dopamine releaser” actually blocks DA reuptake

Mechanisms of action might also include NMDA-antagonist (what does that do…?)

Amantadine can be used as early monotherapy for PD, but also later on in therapy because can treat dyskinesias

Also used in HD to treat movement disorders