Neuro-pharmacology Flashcards
(41 cards)
Describe the tremor seen in Parkinson’s disease.
Pill rolling, resting tremor. Decreases upon movement but returns 6-9 seconds following the cessation of movement.
Describe the rigidity seen in PD.
Cog wheeling at the wrist and lead pipe rigidity in the forearms.
Apart from tremor and rigidity, what are the other two motor, clinical features of Parkinson’s
Bradykinesia (shuffling steps and mask like fascies). Postural instability (increasing falls risk).
Give some non-motor manifestations of Parkinson’s.
- Mood changes/ Cognitive changes. If these occur alongside parkinsonian motor symptoms = Dementia with Lewy Bodies.
- Urinary Incontinence
- Sleep problems + daytime somnolence (esp. later in the course).
- Pain on stiff side.
Pathological Features in Parkinson’s Disease
- Synucleinopathy - deposition of Synuclein in the brain as Lewy Bodies.
- Loss of neurones at ‘substantia nigra pars compacta’. A 50% pigment loss is reuquired to give symptoms as, in the early stages of neurone die-off, other parts of the basal ganglia increase the expression of dopamine receptors and the remaining neurones produce it at a greater speed.
What scanning modality can demonstrate the loss of dopaminergic neurones?
DAT Scanning - a nuclear medicine study that uses a radioactive tracer to look at dopamine reuptake. This is not a diagnostic test, however.
How does low dopamine impact on the circuits within the basal ganglia?
Less dopamine means less inhibition of the striatum. If this inhibition is decreased than more ACh is produced which is excitatory to the motor areas of the cortex and spinal cord. This results in the EXTRA PYRAMIDAL movement defects that are seen in PD.
Describe the synthetic pathway of dopamine, NA and Adrenaline
L-tyrosine –> L-dopa -(dopa decarboxylase)->Dopamine –> Noradrenaline –> Adrenaline.
What is the significance of Dopa-Decarboxylase in the treatment of PD?
It exists in the periphery (outside the BBB) so if we gave L-dopa (Dopamine itself cannot cross BBB) on its own without a Dopa-Decarboxylase inhibitor such as Carbidopa it would all be used up in the periphery and not cross to the brain where it has its effects.
What is dopamine broken down to?
What are the two enzymes responsible?
Broken down to Homovallinic acid.
Monoamine Oxidase and Catechol - O - methyltransferase are responsible for breaking it down.
Why does the efficacy of L-dopa decline over the course of the disease?
Parkinson’s is a progressive disease so neurones in SNPC are lost over time. It is in these neurones that L-dopa is converted to dopamine so the fewer of these there are the less conversion and the less symptomatic relief is seen.
How is L-dopa handled in the intestines?
90% is broken down here. That which is absorbed must compete with AA’s for active transport so absorption will be poorer if taken with a high protein meal.
How does its PK affect dosing?
It has a short half life of about 2hrs so the drug has to be taken 4-6x a day.
In all, what % of levo-dopa administered enters the CNS?
How does L-dopa get into the brain?
1%, that that isn’t peripherally broken down/converted to dopamine has to compete with AA’s again to enter brain.
What are Co-Careldopa and Co-beneldopa?
These are both combinations of L-dopa with a peripheral DOPA decarboxylase inhibitor such as carbidopa. This inhibitor also decreases any side effects which may be caused from circulating dopamine.
What are some of the problems with L-DOPA delivery?
Needs to be taken 4-6x daily or patients risk ‘freezing’ . Some modified release preparations are available. They exist only in tablet forms, the most accessible form is dispersible but this is still unhelpful in very bad cases of the disease.
What is the side effect burden of L-dopa like?
Minimal side effects given the efficacy of the drug. Can cause nausea and vomiting- this can be managed with the D2 antagonist Domperidone. Can also cause hypotension, tachycardia and psychosis.
What are some of the issues that come up with L-dopa as the disease progresses?
Its efficacy decreases, patients can find their treatment wears off quickly leading to an ‘on/off’ effect. Can also cause dystonia (muscles twisting the body into strange positions). Dystonia can be the result of both under and over dosing so a good history is required.
DDI’s with L Dopa
Mixing with Vitamin B6 (Pyridoxine) can decrease efficacy as B6 increases the peripheral conversion of L dopa.
Older (typical) antipsychotics have dopamine blocking effects so can exacerbate symptoms).
Non-parkinsonian MOAI’s (as used in depression historically) can cause hypertensive crises.
Important types of dopamine agonists used in treating Parkinson’s.
Non-ergot derived drugs (Ropinirole)
Patch drugs (Rotigotine)
SC drugs such as Apomorphine.
Advantages of directly acting dopamine agonists.
Fewer motor complications (e.g. dyskinesias such as choreo-athetosis) and may have neuroprotective effects.
Disadvantages of directly acting dopamine agonists.
May lead to issues with impulse control. They are less efficacious than L-dope in early disease and they are more likely to cause psychiatric side effects (hallucinations, confusion). Have side effects of nausea and hypotension just like L dopa.
What function does Monoamine Oxidase B have in the brain?
It metabolises and breaks down dopamine, predominantly in dopamine containing regions of the brain.
Name a Monoamine Oxidase Type B inhibitor.
Selegiline
Rasagaline
