Pharmacotherapy for Parkinson's Disease (Week 4--Melega) Flashcards
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
Hypokinetic movement disorders
Characterized by decreased movement
Tremor, rigidity, bradykinesia
Ex: Parkinson’s disease
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
Is Parkinson’s Disease treatable?
Yes, highly treatable
But treatments still treat symptoms (just very well!) and don’t cure the disease
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
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
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)
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
Dopamine receptors
All G-protein coupled
D1, D5 increase adenylyl cyclase activity
D2, D3, D4 inhibit adenylyl cyclase activity
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!
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!
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
Carbidopa
Peripheral decarboxylase inhibitor (NO CNS actions, does not cross BBB!)
Increases L-DOPA bioavailability
Sinemet
L-DOPA + carbidopa
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
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
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
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
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
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
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
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
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
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!
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)
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
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
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
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
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)
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)
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
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
