Case 7 - medications and treatment

Question 1

what is the traditional first line of treatment in PD

Answer 1

levodopa - L-dopa

Question 2

what is the mechanism of levodopa

Answer 2

dopamine itself cannot cross the BBB
L dopa can and once it has, it is converted into dopamine by DOPA carboxylase.
it is also concerted to dopamine once it is inside the pNS, and it is thought that this may be responsibke for some of the side effects of this drug
it is thought that dopamine essentially floods the synapses, and this combined with the reduced amount of endogenous dopamine is enough to reduce the clinical consequences of PD

Question 3

what does Levodopa increase

Answer 3

the amount of free dopamine in the brain, and compensate for the usual loss of dopamine

Question 4

what is the problem with levodopa

Answer 4

their efficacy tends to decrease over time, thus you should only give it to them when you feel the PD is adversely affecting life to great enough extent

Question 5

when is Levodopa usually given

Answer 5

12 months after diagnosis

Question 6

what is the normal dosage of L-dopa

Answer 6

naturally very short acting
taken with food to avoid nausea and vomiting
usually doses are sound 800mg /24 hr in divided doses, but get up to this level gradually

Question 7

what is levodopa usually given with

Answer 7

carbidopa, entacapone or benserazide

Question 8

why is it given with something else

Answer 8

decrease L-dopa metabolism and thus prolong the half life of L-dopa

these also reduce the dose needed by about 90&

Question 9

what are the side effects of levodopa

Answer 9

nausea
Dyskinesias - these usually occur in the face and limbs, and usually occur at the peak therapeutic effect, this the link between therapeutic and high dose is fine
Hypotension
Arrhythmia
Psychosis - increased dopamine levels in the brain
Compulsive behaviour
Gambling
Spending
Inappropriate sexual behaviour

Question 10

what is the on-off effect

Answer 10

this is related to the fluctuating plasma concentration of Ldopa. the effect is seen more often the longer the drug has been used. it is also seen in untreated patients. this usually occurs at the ‘end of dose’. you can reduce the on-odd effect with slow release L-dopa. often the on-off effect can never be eliminated once to has occured

Question 11

how much of a levodopa dose actually crosses the BBB

Answer 11

10%

Question 12

what happens to the remaining levodopa

Answer 12

susceptible to conversion to dopamine In the periphery leading to side effects

Question 13

how do you counteract the conversion of levodopa in the pNS

Answer 13

inhibitors that reduce the breakdown of dopamine in the PNS, called peripheral dopa decaerboxylase inhibitors (carbidopa and benserazide) are given. in combination with levodopa to reduce peripheral conversion that would otherwise devour most of the dose given

Question 14

what does the addition of dopa decarboxylase do

Answer 14

maximises the bioavailability of dopamine in the brain, decreases side effects, and allows a lower dose of levodopa to be used

Question 15

what two enzymes break down dopamine

Answer 15

MAO
COMT

Question 16

what is another therapeutic strategy to do with MAO

Answer 16

introduce an MAO inhibitor in too the synapse, which interrupts the action of the MAO enzyme and prevents the breakdown of dopamine in the synapse.

this allows more dopamine to remain in the synapse and increases the likelihood that it will bind to the postsynaptic membrane

Question 17

what features of PD respond best to levodopa

Answer 17

bradykinesia and rigidity.

Question 18

what is the loss of dopamine due to

Answer 18

protein misfolding, aggregation and toxicity

defective proteolysis

mitochondrial dysfunction

oxidative stress

Question 19

how does L-dopa lead to dyskinesias

Answer 19

at the disease progresses and dopaminergic neurones continue to be lost in the substantia nigra, l-dopa becomes ineffective for treating the motor symptoms

as medication becomes less effective, off periods may occur when the levodopa dose has worn off and movement is again difficult until another dose is given

Question 20

what are ropinirole and pramipexole

Answer 20

selective D3 agonists

they have decreased risk of dyskinesias, and they appear to not exhibit the long term diminished effectiveness as seen with L dopa

Question 21

who are D3 agonists used in

Answer 21

first line treatment in younger patients

Question 22

what are the side effects of ropinirole and pramipexole

Answer 22

drowsiness
hallucinations
nausea

Question 23

what is bromocriptine

Answer 23

a selective D2 agonist
has a long half life so does not need to be given as often as L dopa

Question 24

what are the side effects of bromocriptine

Answer 24

hallucinations
hypotension
nausea
fibrosis
drowsiness

Question 25

what is selegilene

Answer 25

inhibits MAO-B selectively MAO-B metabolises dopamine thus this helps increase the level of dopamine in the brain

Question 26

what may MAO-B inhibitors do in early stage PD

Answer 26

may help slow down the progression of the disease

Question 27

why is MAO-B used in conjunction with Ldopa

Answer 27

helps to reduce the dose of L dopa which in turn reduces the side effects and increases the long term effectiveness of L dopa

Question 28

what are the side effects of selegilene

Answer 28

postural hypotension

Question 29

how do MAO-B inhibitors increase the level of dopamine

Answer 29

by blocking its metabolism. they inhibit the MAO-B enzyme responsible for breaking down dopamine. alone can improve motor symptoms and delay the need for levodopa. can be used between the on-off period with levodopa

Question 30

what drug type releases dopamine

Answer 30

amantadine

Question 31

what does amantadine do

Answer 31

used as an adjunct to Ldopa it is a weak antagonist of the NMDA type glutamate receptors that increase dopamine release and blocks dopamine re uptake into the synapse

Question 32

what are examples of anticholinergics

Answer 32

orphenadrine and atropine

Question 33

what do anticholingergics do

Answer 33

many of the motor symptoms of PD are the result of over activity of ACh releasing neurones, because their dopamine inhibition has been lost anticholinergics can reduce this overactivity and thus reduce the motor signs as seen in PD

Question 34

what do they essentially do to the muscle nerve connections

Answer 34

anaesthetise the muscle nerve connections to reduce intend motor symptoms and rigidity

Question 35

what is deep brain stimulation

Answer 35

surgical intervention that utilises an implantable pulse generator as a waveform generator and power source. the neurostimulator controls the flow of current to specific brain regions through an attachment to an implantable DBS lead. each DBS lead has multiple contacts and therefore many possible parameter configurations. the optomisation of possible settings, which may number into the thousands when considering the range of pulse widths, frequencies, amplitudes and configurations of anodes and cathodes, can provide critical determinant for therapeutic success or failure

Question 36

what is involved in the DBS procedure

Answer 36

two stage process involved in stereo static frame, with the patient under sedation yet awake for a 30 minute 3D MRI to locate the coordinates of the deep Brain target. after determining the target in the operating room, a path for the very fine metal electrodes is selected that will reach the target the DBS electrode is placed, and electrical impulses are sent to see which placement gives the best reduction in tremors, while monitoring for other unwanted side effects in speech or numbness

Question 37

what is the second procedure

Answer 37

performed under general anaesthetic to place. small battery pouch containing the stimulator pulse generator under the collar bone. from there, a wire is passed under the skin up the neck and behind the ear where it re emerges and is attached to the stimulator wire in the brain. observed for several weeks and then it is turned on. depending on the targeted area or the brain, one or more sides may be targeted

Question 38

what is involved in Sinamet

Answer 38

carbidopa and levodopa

Question 39

factors of a person with a good sinamet profile

Answer 39

shows dramatic improvement in response to sinamet experiences a dramatic difference between off and on states appears near normal in the on state spends most of the day pff

Question 40

what are the symptoms most commonly helped by DBS

Answer 40

dyskinesias and tremor

Question 41

what does DBS not help

Answer 41

swallowing problems softness of speech constipation drooling memory difficulties

Question 42

what is benserazide

Answer 42

peripherally acting DOPA decarboxylase inhibitor this is combined with levodopa to reduce peripheral side effects

Question 43

what can benserazide not do

Answer 43

cannot cross the BBB and so doesn't prevent the effects of leopdopa in the brain