Drugs in parkingsons Flashcards
What are the symptoms of parkinsons disease?
PROBLEM WITH PLANNING AND INITATION OF MOVEMENT.
Ataxia – rigidity, bradykinesia
Resting tremor (3-7Hz)
Cognitive (memory, attention, loss of inhibition.)
Postural instability
Eventually dementia
Second most common neurodegenerative disease (~1% in over-60s). Incurable, progressive, not (directly) lethal; life expectancy 10-15 years
WITH MEDICATION THE MOVEMENT CAN IMPROVE.
SOMETIMES, IF YOU WERE TO THROW A BALL AT SOMEONE WITH PARKINSONS, THEY WOULD BE ABLE TO CATCH IT BECAUSE OTHER INFLUENCES ARE INVOLVED.
DOPMAINE
DIRECT HAVE D1 RECEPTORS THESE INCREASE ACTIVITY OF THE NUERONS
INDIRECT HAVE D2, AND THESE DECREASE ACTIVITY OF THESE NUERONS
What do you need to do to treat parkinsons
Treatment is management of symptoms:
Increase dopamine production
Decrease dopamine breakdown
Mimic dopamine
One issue is that dopamine does not cross the blood/brain barrier.
L- DOPA
Dopamine (DA) does not cross the blood/brain barrier
However, its metabolic precursor, L-DOPA (a.k.a levodopa), does.
Converted to DA in nerve terminals = increased release
DA is formed from tyrosine via the metabolite L-DOPA (levodopa), by the enzymes tyrosine hydroxylase and DOPA decarboxylase. It is then loaded into terminals.
Bear in mind that dopamine is also present in the periphery (e.g. GI tract, pancreas, some blood vessels). This means all the metabolic machinery for DA synthesis and catabolism is present in the periphery, too. Consequently ingestion of L-DOPA results in very substantial amounts of it converted into DA in the periphery before it can access the CNS.
As a result, carbidopa and benserazide are used to inhibit the peripheral metabolism of L-DOPA, allowing a tenth of the dose and also minimising side effects. They block DOPA decarboxylase; the key to their function is they do not enter the CNS: if they did, they would be useless.
SO THEY ARE GOING TO STOP THE BREAKDOWN OF L-DOPA IN THE PERIPHERY BUT NOT IN THE BRAIN !!!
What is gold standard parkinsons treatment
Carbidopa
Primary PD treatment. Highly effective in ~80% of patients initially, but drops to about ~30-40% effective by 5 years.
Therefore, if someone has symptoms and you can treat them with something else first, you should do that; therefore, you should save L-DOPA treatment for when it’s going to be most effective.
Adverese effects of Co-careldopa / co-beneldopa
Involuntary movements, confusion - schizophrenia-like effects, postural hypotension, “on-off” effects: rapid fluctuations in clinical state, nausea / vomiting. These normally reduce after a few weeks.
Needs to be taken 3-4 times daily
MAO-B & COMT
Monoamine oxidase B (MAO-B)
Catechol-O-methyltransferase (COMT)
tHESE Break down dopamine !
Selective MAO-B inhibitors
To specifically target DA we favour MAO-B selective drugs.
Side effects are similar to L-DOPA; although with some sympathomimetic activity as they increase NA as well as DA in the periphery and CNS.
CAN BE PRESCRIBED ON ITS OWN (WITHOUT L-DOPA)
L-DOPA + COMT inhibitors
HAS TO BE PRESCRIBED WITH L-DOPA!!!These aren’t commonly used; they are often given at the end of treatment.
Catechol-O-methyl transferase (COMT) does not just metabolise DA, it also metabolises L-DOPA. Inhibition this drug in the periphery allows more L-DOPA to reach the CNS, and can also be used to reduce the L-DOPA dose about 30%. Tolcapone also crosses the blood-brain barrier. This is still useful, because it will also prevent L-DOPA breakdown to 3-OMD in the CNS (so more can be converted to DA) and DA breakdown. However, mostly, it is their action in the periphery that matters.
Dopamine receptor agonists
- Improve the mimicking of dopamine D2 receptors.
- Pramipexole, ropinirole; rotigotine (transdermal patch)
Antimuscarinics
Some of the interneurones in the striatum are cholinergic. ACh in the striatum inhibits MSNs through Gi/o-linked M2 and M4 receptors.
As antipsychotic medications would be counteracted by drugs increasing DAergic activity, their iatrogenic motor side effects might be controlled by antimuscarinics – although of course bearing mind the problems with even more anticholinergic side effects.
other drugs
Eventually, with enough progression, no pharmacology is effective.
Only option then is surgical.
