Term
| PD is a disease characterised by... |
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Definition
| impaired volutary movements |
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Term
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Definition
Symptoms include:-
Tremor at rest
Abnormal posture
Bradykinesia (slow initiation of movements)
Muscle rigidity (resistance to movement)
Signs include:-
Shuffling gait
Inability to perform skilled tasks
Blank facial expression
Speech impairment |
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Term
| Voluntary movement is controlled by |
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Definition
signals from the motor cortex that travel down the PYRAMIDAL TRACTS (pathways in the brainstem and spinal cord) to initiate motoneurone activity.
These signals are fine tuned by
influences from EXTRAPYRAMIDAL
regions e.g. the BASAL GANGLIA. |
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Term
| PD is associated with dysfunction of the... |
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Definition
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Term
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Definition
| consists of five nuclei :- striatum (caudate nucleus and caudate putamen), Globus pallidus (defined as internal (GPi) and external (GPe) regions, Subthalamic nucleus, substania nigra (pars reticulata (SNr ventral and pale coloured) and pars compacta (SNc, dorsal and which gives the nucleus its name because of its dark colour). |
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Term
| Nigrostriatal dopamine pathways runs from... |
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Definition
| the Substantia Nigra to the striatum (caudate nucleus and caudate putamen) |
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Term
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Definition
| degeneration of dopamine containing cells in the substantia nigra of the basal ganglia - in which symptoms of PD are only seens after above 70% of the nigrostriatal dopamine content is lost (this is estimated to take 8 years or more from the onset of degeneration). |
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Term
| Dopamine and normal function of the basal ganglia... |
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Definition
Basal ganglia output is via the GPi / SNr and mediates
tonic inhibition of the thalamo-cortical motor pathway.
The striatum modulates GPi / SNr output via
a direct pathway (inhibitory / GABA)
an indirect pathway (STN, excitatory / glutamate) |
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Term
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Definition
Inhibtion of GPi/SNr output by the direct pathway is reduced.
excitation of the GPi/ SNr by the indirect pathway is increased.
Thus, output of the basal ganglia is increased, leading to excessive inhibition of the thalamus. |
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Term
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Definition
approx. 5% have been associated with inheritable genetic traits (mutation).
Idiopathic (of unknown causes) - >95% late onset are sporadic.
For both types - postmoterm evidence suggest a mitochondrial impairement might be responsible for dopamine neurone cell death. The oxidative stress theory? |
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Term
| The oxidative stress theory is based on the idea of ____ |
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Definition
| Oxidative stress - excessive production of reactive oxygen species (ROS) - e.g. H2O2, oxygen and hydroxyl free radicals - occuring when oxidative phosphorylation (ATP production is compromised). ROS damage important cellular components such as DNA, enzymes and membrane lipids and subsequently lead to apoptosis of the cell. |
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Term
| On what basis is MPTP effects a line of evidence for the oxidative stress theory in PD? |
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Definition
| -effects of MPTP - first appeared as a toxic contaminant of designer drug - causes a selective degeneration of dopaminergic neurons in the SNc and PD-like symptoms. MPTP is converted to MPP+ in glial cell (toxic metabolite)by MAO-B. MPP+ is transported by the dopamine transporter into dopamine containing cells (dopaminergic neuron). This accumulates in the mitochondria and inhibits complex I (a enzyme involved in oxidative phosphorylation). This is proposed to result in the production of neurotoxic ROS. N.B. MTPT DOES NOT CAUSE PD as people are not generally exposed to in. However, it has been speculated that environmental toxins might be involved. |
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Term
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Definition
| Research has shown that at low doses, rotenone a commonly used pesticide also acting by inhibition of mitochondrial complex I, can induce parkinson like symptoms in animal models. Unlike MPTP, this is associated with the appearance of lewy bodies. Many other naturally occuring compounds and synthetic pesticides are inhibitors of complex I, further supporting the environmental toxin hypothesis. |
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Term
| Why is alpha-synuclein speculated to be involved in causation of PD? |
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Definition
| also thought accumulation of synuclein that forms lewy bodies promotes excessive production of ROS. SYnuclein is though to be important in the packaging of dopamine into vesicles, thus the aggregation of synuclein may impair this function leading to excessive cytoplasmic dopamine concentrations, that when metabolised produces the ROS which promote cell death. |
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Term
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Definition
PD is associated with the appearance of
spherical deposits in cells of the substantia nigra and brainstem
called “Lewy bodies” |
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Term
| Generally, what is the three main ways current PD treatment act by? |
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Definition
| Drugs that facilitate dopaminergic neurotransmission alleviate the symptoms, but none yet target the underlying pathology. 1. Facilitation of synthesis and release of endogenous dopamine (L-dopa) 2. Direct acting dopaminergic agonists. 3. Inhibitors of dopamine metabolism. |
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Term
| L-dopa mechanism of action ... |
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Definition
| The metabolic precursor of dopamine and is the most effective treatment for PD. Requires it to cross the blood-brain barrier and transporter into dopaminergic neurons in order for it to be active, where in is converted to dopamine by dopadecarboxylase. |
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Term
| Pharmacokinetics of L-dopa... |
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Definition
| L-dopa is rapidly absorbed from the stomach giving peak plasma levels of 1-3 hours after an oral dose. The plasma half-life is short (1-3hours) due to extensive metabolism by peripheral dopa decarboxylase in the gut wall, plasma and peripheral tissues. Dopamine itself cannot cross the blood-brain barrier, therefore only aprx 1% of administer L-dopa reaches the brain. |
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Term
| How could we increase the effectiveness of oral L-dopa? |
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Definition
| L-dopa can be combined with inhibitors of peripheral metabolism to allow lower and less frequent doses to be uses. dopa decarboxylase inhibitors e.g. carbidopa, benserazide. CARBIDOPA DOES NOT CROSS THE BLOOD BRAIN BARRIER. |
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Term
| Effects of L-dopa/carbidopa (sinement) treatment? |
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Definition
| rapidly alleviates tremor, rigidity and bradykinesia. Its effectiveness probably steming from its ability to act equally through the direct D1 receptor and indirect D2 receptor mediated pathways. |
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Term
| How does L-dopa-induced dyskineasia occur? |
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Definition
Motor complications develop 10 years after L-dopa therapy in approx. 80% of patients. L-dopa-induced dyskinesia
– involuntary writhing movements. Usually develop within 2 years of continous L-dopa treatment. They are associated with high L-dopa plasma levels which are required to combat rigidity. L-dopa induced dykinesia is thought to occur through excessive inhibition of the neurons in the indirect pathway (Striatum - GPe). This causes disinhibition of the GPe, subsequent overinhibition of the STN and a consequent reduced excitatory drive to the GPi/SNr, resulting in reduced output of from the basal ganglia, which is thought to accompany excessive excitatory drive of the cortical motor areas. |
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Term
| How does the unwanted "on-off effect" as a result of continous treatment of L-dopa occur? |
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Definition
| Early stages of PD respond well to L-dopa between doses (symptoms effectively allieviates even when plasma L-dopa levels have fallen. However as disease progresses, the benefits of L-dopa wear off before the next dose and the patients flutate been ON ("good anti-parkinsons effect) and OFF (poor control of symptons). Thus higher doses and more frequent doses are required to control ridigity and bradykinesia but this also results in more severe dyskinesia. THUS NARROWING OF MARGING BETWEEN THERAPEUTIC BENEFITS AND UNWANTED EFFECTS BECOMES PROGRESSIVELY SMALLER. |
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Term
| What is the exact cause of the unwanted effects of L-dopa treatment? |
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Definition
It is not known why these effects develop. It has been suggested that they are related to the reduced ability
of the striatal neurones to store dopamine derived from L-dopa as more cells die. Recent clinical evidence
suggests that the pulsatile nature of L-dopa application may exacerbate the development of these side
effects. Current strategies are attempting to minimize fluctuations in plasma L-dopa with an aim to reduce
the development of these motor complications. |
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Term
| Central unwanted effects associated with L-dopa treatment? |
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Definition
Other Central side effects.
Behavioural changes. Over activity of the dopaminergic system has been implicated in the aetiology
of schizophrenia. Thus, some patients can develop a schizophrenia-like syndrome. |
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Term
| Peripheral unwanted effects associated with L-dopa therapy? |
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Definition
Peripheral acute side effects.
Peripheral side effects are due to conversion to dopamine in the periphery. Co-application of D2
antagonists (e.g. domperidone, that do not cross the blood-brain barrier) can alleviate some of these side
effects. They include:-
Nausea / vomiting – through activation of receptors in the area postrema.
Hypotension and cardiac arrhythmias. |
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Term
| Selegiline in the treatment of PD... |
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Definition
| used as an adjunct to L-dopa to increase affectiveness. Is a MOA, which is selective for MOA-B which predominates in dopaminergic brain areas but not in the periphery. It therefore prevents the degradation of dopamine and as MOA-B is not present in the periphery, its does not interact with tyramine to provoke the cheese reaction. |
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Term
| Entaccapone & Tolcapone mechanism in PD treatment? |
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Definition
| Dopamine is also degraded by COMT (catechol-O-methly transferase, that is probably located both in the periphery and on the outside of post-synaptic cells in the brain. These drugs inhibit COMT, increasing the effectiveness of L-dopa therapy. |
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Term
| Why could direct acting dopaminergic agonists be useful for patients who have already extensive neurodegeneration? |
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Definition
| L-dopa continous treatment depends on the presence of dopa decarboxylase. It does not target neurodegeration, therefore as the dopaminergic neurons die, the enzyme is also lost, therefore L-dopa effectiveness decreases 3-5years after treatment. Receptor agonists work on post-synaptic cells that do not degenerate, therefore they could be beneficial in patients where extensive neurodegeneration has already occured. |
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Term
| Direct acting dopaminergic agonists - bromocriptine & pergolide, mechnism of action? |
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Definition
| Both bind to D1 and D2, but are more potent at D1. This differential effect could explain why they are less effective than L-dopa. |
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Term
| Direct acting dopaminergic agonists - bromocriptine & pergolide, mechnism of action? |
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Definition
| Both bind to D1 and D2, but are more potent at D1. This differential effect could explain why they are less effective than L-dopa. |
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Term
| Rotigotine, ropinirole, pramipexole mechanism of action? |
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Definition
| Direct acting agonists are newer drugs more selective for D2/3 receptors and therefore have better toxicity profiles that older receptor agonists. |
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Term
| Direct acting dopaminergic agonists - bromocriptine, pergolide, rotigotine, ropinirole, pramipexole, treatment plan? |
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Definition
All of the above can be used in conjunction with L-dopa in later stages of PD or alone in the earlier stages
to supplement the actions of endogenous dopamine. The rationale is to delay the time at which L-dopa
treatment is started because of its finite effectiveness. |
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Term
| why is Amantidine (an antiviral) effective in the treatment of PD? |
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Definition
appears to be effective in Parkinson’s disease possibly by promoting dopamine
release from nerve terminals. |
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Term
Anticholinergic agents.
Trihexphenidyl, benztropine. why are they effective in PD treatment? |
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Definition
Within the striatum, acetylcholine-containing interneurones are normally strongly inhibited by dopamine
(D2). Loss of dopamine results in increased activity of these neurones, which is thought to contribute to
some of the effects of Parkinson’s disease. Thus muscarinic receptor antagonists are useful antiparkinson’s
drugs. They tend to reduce tremor more than rigidity and bradykinesia.muscarinic ACh receptors exert excitatory effects on
striatal neurones and inhibit dopamine release from nerve
terminals – blocking these effects alleviates some symptoms
of PD. |
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