Drugs & other treatments for PD Flashcards
What is the aim of current drug treatments for PD
- aim to restore DA/Ach imbalance
- Reduce cholinergic transmission
- Boost dopaminergic transmission
Loss of DA dis-inhibits striatal cholinergic interneurones. What is the consequence of this?
- increase striatal Ach levels
- Activation of Gq-coupled muscarinic ACh receptors in the striatum
- Further increases overactivity of indirect pathway
- Contributes to symptoms of tremor
Outline the use of anticholinergic drugs/muscarinic receptor antagonists
-eg benzhexol, benzatropine
-Only effective against tremor(~30% of pts)
-Minimal effect against bradykinesia and rigidity
SIDE EFFECTS:
-central eg confusion, mood changes
-Peripheral eg constipation, blurred vision, dry mouth
* useful if sialorrhoea is a problem
Outline the possible sites of dopaminergic drug intervention
- Synthesis eg levodopa
- Storage
- Release
- Receptors eg Apomorphine (DA agonist; d1/d2 receptors)
- Reuptake
- Degradation eg MAO-B inhibitors
What is the function of dopa decarboxylase?
-Converts levodopa to dopamine
What is the function of MAO-B?
Breaks down dopamine into 3 metabolites, one such being DOPAC
What is the function of COMT
- catechol-O-methyl transferase
- enzyme
- degrades catecholamines including DA
- one of the metabolites of this is HVA
Outline the use of Levodopa in PD
- Natural DA precursor which, unlike DA can cross the BBB
- L-DOPA is converter to DA. reaction catalysed by DDC
- But L-DOPA is ~90% converted by DDC in intestinal wall. To overcome this it is co-administered with peripherally-acting DDC inhibitors {CARBIDOPA- as sinemet or BENSARAZIDE as madopar}
- L-DOPA is ~5% metabolised by plasma COMT. To overxcome this COMT inhibitor ENTACAPONE may be used
- Ensure majority of L-DOPA enters brain unchanged
- Conversion by DDC inside monoaminergic neurones produces DA
- Also thought to happen inside serotonergic neurones (5-HT) (we know this because if you give L-DOPA in the very late stages where you don’t really have any DA neurones remaining you can still have efficacy
- So when you get an L-DOPA response it’ll never be completely the same physiologically as DA itself cos you might get release of DA from other types of neurones itself
State the therapeutic effects of L-DOPA
- L-DOPA with carbidopa/benserazide raises striatal DA levels
- Activity normalised in direct (D1R stim) and indirect (D2R stimulation) pathways
- Improves rigidity, bradykinesia, facial expression, speech & handwriting in ~80% pts
What are the acute side effects of L-DOPA
- Nausea: due to remaining peripheral DA receptor activation
- Peripheral DA receptor antagonist domperidone given as adjunct (need to ensure this doesn’t get into the brain otherwise the L-DOPA would be useless)
- Postural hypotension (esp. in pts on anti-hypertensive drugs)
- Psychological: hallucinations, confusion, insomnia or nightmares
What are the side effects with chronic L-DOPA ?
Within 3 years of starting L-DOPA therapy around 1/3 pts develop:
- )MOTOR FLUCTUATIONS(‘ON/OFF’ EFFECT& wearing off)
- Rapid fluctuations in clinical state. Freezing may last mins or hours
- Related to plasma fluctuations in L-DOPA?
- Related to limited storage of DA as degeneration progresses - ) LEVODOPA-INDUCED DYSKINESIA (LID)
- Excess,hyperkinetic involuntary movements (choreic or dystonic)
- Thalamocortical feedback is increased above normal
- Face&limbs mostly affected but trunk & neck susceptible too
- Mechanism uncertain but plasticity(of corticostriatal pathway?)involved
- Amantadine (NMDA-type glutamate receptor blocker i.e antagonist): only drug providing relief
What drug is the ONLY drug currently available to provide relief against dyskinesias?
-AMANTADINE
Outline the use of Dopamine receptor agonists in PD
- eg bromocriptine, lysuride, ropinirole, pramipexole
- Produce effects mainly through activation of striatal D2 receptors
- Not activated by progressive neurodegeneration
- Acute side effects -as for L-DOPA
- Lessened chronic side effects as it has a longer half life than L-DOPA so less plasma fluctuation, less on/off effect and reduced incidence of dyskinesia
- Often used as 1st line treatment in younger pts BUT less effective than L-DOPA in relieving symptoms, so L-DOPA needed eventually
- Used as adjuncts to lower L-DOPA dose when L-DOPA required
State alternative routes of drug administration to circumvent dyskinesia
- )ROTIGOTINE (DA agonist) PATCH: effective as monotherapy in early PD
- Apply new patch every 24hrs
- Slow, stable release stops fluctuations in plasma levels and stops dyskinesias happening - ) DUO-DOPA: intraduodenal pump to provide L-DOPA infusion (no subcutaneous formulation)
- Doesn’t look like a long term solution for many people
Outline the use of MAO-B inhibitors in PD pts
- eg selegiline, rasagiline
- MAO-B is principal route of DA metabolism in DA rich brain regions
- usually DA will be metabolised to DOPAC (& free radicals)
- MAO-B inhibitors block DA metabolism
- Often used as an adjunct to lower L-DOPA dose required
- SIDE EFFECTS: unlike non-selective MAO inhibitors, selegiline doesn’t inhibit peripheral tyramine metabolism so NO CHEESE REACTION
- May be used as monotherapy in early stage PD
