parkinsons

Question 1

what are signs and symptoms of parkinson

Answer 1

bradykinesia/akinesia
tremor at rest
soft monotonic speech
swallowing problems
dementia

Question 2

what causes parkinsons

Answer 2

loss of dopaminergic neurones from substantia nigra, dopamine is depleated from nigrostriatal projection zones in striatum

characterised by formation of lewy bodies

70-80% of nigrostrital dopamine neurones have to die before symptoms appear

Question 3

what may speed up parkinsons

Answer 3

life events such as infection, head trauma and drugs such as MPTP speed up process but only to a small degree

Question 4

describe the basal ganglia connections

Answer 4

involved in supraspinal motor control:

direct pathway:
striatum receives input from cerebral cortex such are premotor cortex and primary motor cortex

striatum connects to GPi (interior globus pallidus) and pars reticularis of substantia nigra, these inputs are inhibitory via GABA

GPi/pars reticularis then input into the thalamus, this input is also inhibitory via GABA

thalamus then inputs into the cerebral cortex, excitatory input via glutamate
stimulation of direct pathway causes movement (since the striatum inhibits the inhibitory actions of GPi/pars reticularis)

indirect pathway:

striatum inputs into GPe, via negative GABA input

GPe inputs into subthalamic nucleus, again via GABA

subthalamic nucleus inputs into GPi/ pars reticularis via excitatory glutamate

GPi/pars reticularis input into thalamus via inhibitory GABA

thalamus has excitatory input into cerebral cortex via glutamate

(stimulation of indirect pathway via cortex causes less inhibition of subthalamic nucleus, which then causes more excitation of GPi/pars reticularis, inhibiting movement)

Question 5

how does dopamine relate to indirect/direct pathways of basal ganglia

Answer 5

dopamine is released is via pars compacta of substantia nigra
overall effect is increased movement

impacts both pathways;

excitatory inputs into direct pathway via excitatory D1 receptors in striatum in cells that project to GPi/pars reticularis

inhibitory inputs via D2 receptors in indirect pathway in cells that project to GPe

dopamine input is regulated by GABA input from striatum to pars compacta

dopamine also regulates cholinergic activity in striatum

Question 6

what is aim of parkinsons treatment

Answer 6

replenishment of dopamine transmitter or mimicking the effects

Question 7

what is used to control tremor in parkinsons

Answer 7

loss of dopaminergic control on acetylcholine neurones in striatum means muscarinic antagonists can be used to control tremor

they do not however help with the bradykinesia/akinesia

Question 8

what are dopaminergic pathways in CNS

Answer 8

nigrostriatal pathway: fails in PD and is target of treatment

mesolimbic pathway (A10 to nucleus accumbens), involved in reward pathways, overactivity may lead to psychosis

mesocortical pathway (A10 to frontal cortex) overactivity causes psychosis

median eminence to anterior pituitary: stimulation of anterior pituitary via dopamine causes inhibition of prolactin secretion

chemoreceptor trigger zone/ vomiting centre: dopamine stimulation here induces emesis (vomiting)

Question 9

describe dopamine synthesis and metabolism

Answer 9

tyrosine is converted to L-DOPA via tyrosin hydroxylase

L-DOPA is converted to dopamine via DOPA decarboxylase

dopamine metabolism:

DA is converted to DOPAC via MAO-B

or to noradrenaline via dopamine-beta hydroxylase

or to 3-methoxytyramine via COMT

Question 10

is dopamine given to treat parkinsons

Answer 10

dopamine not given since it does not cross blood brain barrier

L-DOPA given instead since it is a precursor and crosses blood brain barrier

Question 11

describe L-DOPA treatment in parkinsons

Answer 11

since most dopaminergic neurones are dead in PD it is thought that some L-DOPA may be converted to dopamine in other monoamine neurones or in remaining dopaminergic neurones which have some increased compensatory capacity

akinesia and rigidity improve more than tremor with L-DOPA treatment

works best in elderly patients

produces improvement over first 18 months of treatment, this is maintained for 2-3 years before gradual decline, probably due to further degeneration of dopaminergic neurones

large dose of L-DOPA needed (100-500mg/day orally) but due to metabolism only 2% enters brain

Question 12

what are central side effects of L-DOPA treatment

Answer 12

dyskinesia (uncontrolled movements)

psychotic effects via mesolimbic and mesocortical over stimulation (schizo drugs are dopamine antagonists)

reduction in prolactin release

“on-off” effects; uncontrolled swings from akinesia to dyskinesia, usually occurs after several months of therapy, happens as L-DOPA dosage wears off

Question 13

what are peripheral side effects of L-DOPA treatment

Answer 13

hypotension due to displacement of noradrenaline; reduction in sympathetic tone

nausea since dopamine stimulates chemoreceptor trigger zone, although it is in medulla it lacks blood brain barrier

Question 14

what is used alongside L-DOPA treatment to maximise benefits

Answer 14

adjuncts are used to maximise benefits and minimise peripheral formation of dopamine

adjuncts to L-DOPA:

DOPA decarboxylase inhibitors
 monoamine oxidase inhibitors
 dopamine receptor agonists
muscarinic antagonists
COMT antagonists
amatadine

Question 15

how are DOPA decarboxylase inhibitors used in parkinsons

Answer 15

carbidopa and benserazide are DOPA decarboxylase inhibitors

prevent L-DOPA being converted into dopamine

these drugs do not cross blood brain barrier and so reduce dopamine concentrations in periphery

allows reduced L-DOPA dosage since less metabolism in periphery

used in combination with L-DOPA treatment; improvement is faster and smoother

Question 16

how are monoamine oxidase inhibitors used in parkinsons treatment

Answer 16

selegiline; selective monoamine oxidase B inhibitor

reduces breakdown of dopamine in CNS; allows more effective therapy

is thought to reduce neuronal degeneration to some extent

Question 17

how are dopamine receptor agonists used in PD treatment

Answer 17

bromocriptine is a D2 receptor agonist

apomorphine is D1 and D2 agonist, can also be used

has no advantage over L-DOPA but can be useful in older patietns where L-DOPA is no longer effective

domperidone is a D2 antagonist, does not cross blood brain barrier and is given in conjunction with dopamine receptor agonists to prevent peripheral side effects

not an adjunct; used separately

ropinirole; D2 agonists, can be used as monotherapy in younger patients

Question 18

how does direct agonist activity compare to L-DOPA treatment

Answer 18

effectiveness same, direct agonists used in older patients where L-DOPA no longer works

dopamine agonist treatment should be highly effective since it does not rely on intact dopamine neurones and post synaptic receptors should have upregulated due to loss of inputs

however effectiveness same as L-DOPA possibly explained by low efficacy or agents may require D3-5 actions, also L-DOPA may lead to a more physiological phasic receptor activation compared to direct agonists

Question 19

how are muscarinic antagonists used in L-DOPA treatment

Answer 19

atropine and benztropine are muscarinic antagonists;

correct the relative cholinergic excess that occurs as result of dopamine deficiency

reduces tremor, useful supplements to L-DOPA therapy

Question 20

how is amatidine used in PD

Answer 20

amatidine is an anti-viral drug

weakly effective and may increase dopamine release, poorly understood mechanisms which may involve NMDA receptors

only small % of patients respond, however low side effects

Question 21

how does huntingtons disease relate to PD

Answer 21

inherited disorder

has symptoms of uncontrolled movements, may result from loss of striatal neurones which project to substantia nigra and regulate dopamine release via GABA input

loss of these neurones causes excess dopamine release in basal ganglia, thus modulating pathways

can be partly controlled by D2 antagonists

reducing dyskinesia without causing akinesia is very difficult

Question 22

describe another health issue that responds to dopamine antagonists other than huntingtons and schizo

Answer 22

tics; unknown origins but respond to dopamine antagonists

tourettes syndrome involves vocal tics

Question 23

how is surgery used in treatment of PD

Answer 23

transplantation;

about 1500 patients have received transplants of adrenal medulla or foetal mesencephallic dopamine neurones into striatum

foetal tissue into putamen can be useful and increases dopamine levels in striatum

however none of the grafts restore lost endogenous neurones which continue to die alongside healthy graft

Question 24

how are COMT antagonists used in PD treatment

Answer 24

COMT antagonists such as entacapone

dopamine is metabolised to 3-methoxytyramine via COMT, prevents dopamine breakdown