Case 7 - medications and treatment Flashcards
what is the traditional first line of treatment in PD
levodopa - L-dopa
what is the mechanism of levodopa
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
what does Levodopa increase
the amount of free dopamine in the brain, and compensate for the usual loss of dopamine
what is the problem with levodopa
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
when is Levodopa usually given
12 months after diagnosis
what is the normal dosage of L-dopa
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
what is levodopa usually given with
carbidopa, entacapone or benserazide
why is it given with something else
decrease L-dopa metabolism and thus prolong the half life of L-dopa
these also reduce the dose needed by about 90&
what are the side effects of levodopa
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
what is the on-off effect
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
how much of a levodopa dose actually crosses the BBB
10%
what happens to the remaining levodopa
susceptible to conversion to dopamine In the periphery leading to side effects
how do you counteract the conversion of levodopa in the pNS
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
what does the addition of dopa decarboxylase do
maximises the bioavailability of dopamine in the brain, decreases side effects, and allows a lower dose of levodopa to be used
what two enzymes break down dopamine
MAO
COMT
what is another therapeutic strategy to do with MAO
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
what features of PD respond best to levodopa
bradykinesia and rigidity.
what is the loss of dopamine due to
protein misfolding, aggregation and toxicity
defective proteolysis
mitochondrial dysfunction
oxidative stress
how does L-dopa lead to dyskinesias
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
what are ropinirole and pramipexole
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
who are D3 agonists used in
first line treatment in younger patients
what are the side effects of ropinirole and pramipexole
drowsiness
hallucinations
nausea
what is bromocriptine
a selective D2 agonist
has a long half life so does not need to be given as often as L dopa
what are the side effects of bromocriptine
hallucinations
hypotension
nausea
fibrosis
drowsiness
what is selegilene
inhibits MAO-B selectively
MAO-B metabolises dopamine thus this helps increase the level of dopamine in the brain
what may MAO-B inhibitors do in early stage PD
may help slow down the progression of the disease
why is MAO-B used in conjunction with Ldopa
helps to reduce the dose of L dopa which in turn reduces the side effects and increases the long term effectiveness of L dopa
what are the side effects of selegilene
postural hypotension
how do MAO-B inhibitors increase the level of dopamine
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
what drug type releases dopamine
amantadine
what does amantadine do
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
what are examples of anticholinergics
orphenadrine and atropine
what do anticholingergics do
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
what do they essentially do to the muscle nerve connections
anaesthetise the muscle nerve connections to reduce intend motor symptoms and rigidity
what is deep brain stimulation
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
what is involved in the DBS procedure
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
what is the second procedure
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
what is involved in Sinamet
carbidopa and levodopa
factors of a person with a good sinamet profile
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
what are the symptoms most commonly helped by DBS
dyskinesias and tremor
what does DBS not help
swallowing problems
softness of speech
constipation
drooling
memory difficulties
what is benserazide
peripherally acting DOPA decarboxylase inhibitor
this is combined with levodopa to reduce peripheral side effects
what can benserazide not do
cannot cross the BBB and so doesn’t prevent the effects of leopdopa in the brain
