Drugs & other treatments for PD Flashcards

1
Q

What is the aim of current drug treatments for PD

A
  • aim to restore DA/Ach imbalance
  • Reduce cholinergic transmission
  • Boost dopaminergic transmission
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Loss of DA dis-inhibits striatal cholinergic interneurones. What is the consequence of this?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Outline the use of anticholinergic drugs/muscarinic receptor antagonists

A

-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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Outline the possible sites of dopaminergic drug intervention

A
  • Synthesis eg levodopa
  • Storage
  • Release
  • Receptors eg Apomorphine (DA agonist; d1/d2 receptors)
  • Reuptake
  • Degradation eg MAO-B inhibitors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the function of dopa decarboxylase?

A

-Converts levodopa to dopamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the function of MAO-B?

A

Breaks down dopamine into 3 metabolites, one such being DOPAC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the function of COMT

A
  • catechol-O-methyl transferase
  • enzyme
  • degrades catecholamines including DA
  • one of the metabolites of this is HVA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Outline the use of Levodopa in PD

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

State the therapeutic effects of L-DOPA

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the acute side effects of L-DOPA

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the side effects with chronic L-DOPA ?

A

Within 3 years of starting L-DOPA therapy around 1/3 pts develop:

  1. )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
  2. ) 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What drug is the ONLY drug currently available to provide relief against dyskinesias?

A

-AMANTADINE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Outline the use of Dopamine receptor agonists in PD

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

State alternative routes of drug administration to circumvent dyskinesia

A
  1. )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
  2. ) DUO-DOPA: intraduodenal pump to provide L-DOPA infusion (no subcutaneous formulation)
    - Doesn’t look like a long term solution for many people
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Outline the use of MAO-B inhibitors in PD pts

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the cheese reaction?

A
  • An acute attack of hypertension that can occur in a person taking a MAOI drug who eats cheese
  • Caused by an interaction of the MAOI with tyramine, formed in ripe cheese when bacteria provide an enzyme that reacts with the AA tyrosine in the cheese
17
Q

Outline neuroablative surgery (‘otomy’)

A
  • Very popular prior to L-DOPA
  • Now used in medically-refractory pts only
  • A stereotaxic thermolytic lesion (uni or bilateral) is made in part of basal ganglia motor loop to restore normal thalamocortical feedback
    a. )THALAMOTOMY( tremor-dominant cases)
    b. )PALLIDOTOMY(improves rigidity & brady kinesia)
    c. )SUBTHALAMOTOMY(improves rigidty,bradykinesia &LIDs- levodopa induced dyskinesias)
18
Q

What are the disadvantages of ablative therapy?

A
  • Irreversible

- Risk of visual impairment (if optic tract damaged); intracerebral haemorrhage; mild speech &cognitive impairment

19
Q

Outline deep brain stimulation (DBS)

A
  • High frequency stimulation to ‘switch off’ or normalise firing of motor loop nuclei(this process is like depolarising block where you go beyond the threshold)
  • Mechanism likely involves depolarising block of nerve conduction
  • Advantage over lesioning as procedure is REVERSIBLE &graded
  • Subthalamic nucleus (STN)(becomes overactive in PD)- preferred region
20
Q

Outline the pathophysiological changes in basal ganglia circuitry in PD

A
  • Direct pathway underactive, indirect pathway overactive

- Thalamocortical feedback is reduced, evoking motor defects

21
Q

Outline the surgical procedure for subthalamic DBS

A
  • Improved imaging technology now means surgery can be performed confidently with patient under anaesthesia
  • Patient controls stimulation using a pacemarker attached via wires implanted under skin to the indwelling electrode
22
Q

State the failings of current treatments

A
  • Only treat some of the symptoms (postural imbalance left unaffected)
  • Side effects: very disabling in some cases eg dyskinesia (anti-dyskinetic agents being investigated)
  • Do not address the progressive degeneration (Neuroprotective and neurorestorative treatments being investigated)
23
Q

Why is L-DOPA not usually used as first line in younger pts?

A
  • Bad side effects (hyperkinetic/dyskinesias)
  • Better to give a muscarinic antagonist eg if the pt has a tremor its better to tackle this first
  • When starting to show signs of bradykinesia better to give something that’ll work on the endogenous DA eg MAOB inhibitors as first line to maintain their own DA levels
  • Avoid turning to L-DOPA until you really need to
  • Different in elderly; more likely to use L-DOPA as first line cos they have a shorter life span left, so it’s better to use the best drug available.