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

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Flashcards in Pharmacotherapy for Parkinson's Disease (Week 4--Melega) Deck (33):
1


Hyperkinetic movement disorders


Characteized by excess of movement

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

Ex: Huntington's disease

2


Hypokinetic movement disorders

Characterized by decreased movement

Tremor, rigidity, bradykinesia

Ex: Parkinson's disease

3


Parkinsonism


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

4


Is Parkinson's Disease treatable?


Yes, highly treatable

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

5


Where does PD usually manifest first?


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

6


Three primary symptoms of PD


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

7

Goal of pharmacological therapies for PD


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)

8

Dopamine synthesis and storage


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

9


Dopamine receptors


All G-protein coupled

D1, D5 increase adenylyl cyclase activity

D2, D3, D4 inhibit adenylyl cyclase activity

10


Levodopa (L-DOPA)


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!

11


Why can't we just administer tyrosine or dopamine?


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!

12


How is L-DOPA metabolized in the periphery?


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

13


Carbidopa


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

Increases L-DOPA bioavailability

14


Sinemet


L-DOPA + carbidopa

15


Major adverse effects of L-DOPA


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

16


Dyskinesias


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

17


Dopamine agonists

 

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

 

18


Ergot alkaloids


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

19


What is apomorphine (Apokyn) used for?


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

20


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


Sleep disorder

Psychiatric effects

Nausea/vomiting

Postural hypotension

Lower incidence of dyskinesia compared to L-DOPA

21


Irreversible MAO-B inhibitors


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

22


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


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

23


Muscarinic receptor antagonists to treat PD


Trihexyphenidyl, benztropine

Weak efficacy and limited clinical utility but mostly for tremor

Less effective than L-DOPA

Competitive inhibition of ACh, decreasing ACh

24


COMT inhibitor


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!

25


Which drugs should we use first to treat PD?


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)

26


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


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

27


Drug-induced Parkinsonism


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

28

MPTP


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

29


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


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

30


How can we use PET imaging to track DOPA?


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)

31


Other treatments besides drugs for PD


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)

32


When to use which drugs


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

33


Amantadine

"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

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