Drug treatment of movement disorders

Question 1

What are the 3 defining characteristics of neurodegenerative disorders?

Answer 1

1) Loss of neurons
2) Progressive
3) Irreversible

Question 2

Does Parkinson’s disease present subtly or suddenly?

Answer 2

Present subtly and gets progressively worse

Question 3

Remission in Parkinsons is very rare, in which 2 situations does temporary remission sometimes occur?

Answer 3

1) Fear - in a life threatening situation can temporary overcome symptoms
2) Excitement - May temporarily overcome symptoms when excited
This never lasts for more than a few minutes or seconds though

Question 4

How many years from the onset of symptoms to death?

Answer 4

10-15 years

Question 5

What is the usual cause of death in Parkinson’s disease?

Answer 5

Bronchopneumonia - not the actual disease that kills you but in the end stages then movement so severely reduced that patient bed bound and has poor lung ventilation so likely to become infected with opportunistic infections

Question 6

What are the 5 main groups of symptoms of Parkinsons disease?

Answer 6

1) Tremor - 4-7Hz, pill rolling, can be unilateral
2) Rigidity - due to increased muscle tone, limb stiffness
3) Speech - slurred, monotone, dribbles, dysphagia later - all due to loss of control and increased tone of facial muscles
4) Akinesia - difficulty in initiating movement, facial immobility and blinking reduced (Serpentine stare)
5) Postural changes - stoop, shuffling, poor arm swinging, balance impaired, telegraph pole falls

Question 7

What characteristic types of falls occur in Parkinson’s and why?

Answer 7

Telegraph pole falls - increased tone, cant move easily so fall rigidly

Question 8

Is the tremor in Parkinson’s always bilateral?

Answer 8

No- can be unilateral

Question 9

What are the 5 components in the pathology of Parkinson’s disease?

Answer 9

1) Loss of neurones in substantia nigra
2) Lewy bodies acculmulate
3) DA-ergic neurones affected
4) Loss of nigro-striatal inhibitory/ excitatory pathway
5) Affects midbrain nuclei

Question 10

In Parkinson’s you get loss of neurones in what area?

Answer 10

Substantia nigra

Question 11

What kind of neurones are lost in Parkinsons?

Answer 11

dopaminergic (DA-ergic)

Question 12

What are Lewy bodies?

Answer 12

Inclusion bodies found in Parkinsons - found inside the neurones leading to their death. Made up of intracellular proteins - mainly alpha-synuclein - which aggregate and build up in neurons

Question 13

The cause of Parkinson’s disease is unknown, but what 3 conditions are Parkinson’s like disorders?

Answer 13

1) Drug-induced (iatrogenic) - eg those that alter DA activity - Reserpine, Phenothiazines, Butyrophenones
2) MPTP induced - recreational amphetamines contaminated with MPTP
3) Post encephalitic Parkinson’s-like syndrome

Question 14

What pathway is involved in Parkinson’s disease?

Answer 14

Via D2 receptors the DA-ergic neurons of the substantia nigra send output to the thalamus via the Striatum. Thalamus sends signals to the motor cortex which then innervate skeletal muscle. There are also inhibitory DA-ergic neurons from the substantia nigra which act on the striatum. Net result is output from thalamus to motor cortex

Question 15

What are the 2 general approached to treatment of Parkinson’s disease?

Answer 15

1) Increase DA activity

2) Decrease ACh activity - has an inhibitory effect on DA pathways

Question 16

In what 4 ways can you increase DA activity in Parkinson’s therapy?

Answer 16

1) Replace DA (L-DOPA)
2) Decrease DA breakdown (MAO inhibitors, COMT inhibitors)
3) Increase DA release (amantidine)
4) DA agonists (bromocriptine, pergolide)

Question 17

How can you decrease ACh activity in Parkinson’s therapy?

Answer 17

Antimuscarinics (Benzhexol, Orphenadrine)

Question 18

Which drug is used to replace DA lost in Parkinsons?

Answer 18

L-DOPA

Question 19

What are the 2 precursors in the formation of DA and which enzymes convert them?

Answer 19

Tyrosine - converted by tyrosine hydroxylase to:

L DOPA - converted by DOPA decarboxylase to Dopamine

Question 20

How does L DOPA work to increase DA activity?

Answer 20

It is the DA precursor and is able to cross the BBB , it enters neurones via carrier mechanism and is converted in neurones and glia, it is retained mainly by neurones and increases DA release from neurones

Question 21

What is the main problem with L DOPA?

Answer 21

High metabolism in periphery

• 90% metabolised in intestinal wall by DOPA decarboxylase or monoamine oxidases
• Of the remaining 10%, 9% is metabolised at other peripheral sights
• Only 1% reaches the brain - need a massive dose

Question 22

How is the problem of low bioavailability with L DOPA overcome?

Answer 22

Given as combination therapy with Carbidopa which is a DOPA decarboxylase inhibitor which doesn’t cross the BBB and thus increases the bioavailability of L DOPA

Question 23

What are the 6 main adverse effects of L DOPA?

Answer 23

1) On - off effect - worsening of the Parkinson’s symptoms as the conc of DA drops (worse than before) - mechanism unknown
2) Nausea, vomiting and anorexia (DA receptors in emetic centre in brain)
3) Dyskinesis (increased involuntary movements)
4) Tachycardia, extrasystoles (peripheral, block with domperidone)
5) Hypotension
6) Insomnia , confusion, schizophrenic effects

Question 24

How can the insomnia, confusion and schizophrenic effects of L DOPA be prevented?

Answer 24

Block with Clozapine - neuroepileptic effect with no D2 action

Question 25

How do the side effects of L DOPA change with time and why?

Answer 25

Increases with time as greater doses of L DOPA have to be used as neurones die

Question 26

Can L DOPA be used in the end stages of Parkinsons?

Answer 26

Less useful as the effect wears off as neurons die so there is nothing to convert the L DOPA to DA thus it has no effect of DA activity

Question 27

What is the mechanism of action of MAO inhibitors in Parkinson's therapy?

Answer 27

Reduce the breakdown of existing DA in the synaptic cleft by inhibiting monoamine oxidases which normally breakdown DA

Question 28

Give the names of 2 drugs which are MAO inhibitors?

Answer 28

1) Selegine | 2) Deprenyl

Question 29

Selegiline is an inhibitor of what kind of MAOs?

Answer 29

MAO B selective inhibitor

Question 30

Is Selegline effective alone?

Answer 30

Can be effective alone in the early stages, but is ineffective alone in the later stages and is given with L DOPA

Question 31

What are the 2 advantages of Selegline therapy?

Answer 31

1) May have neuroprotective effects | 2) Few side effects - no cheese reaction

Question 32

What is the advantage of giving Selegline with L DOPA?

Answer 32

Reduces the dose of L DOPA necessary

Question 33

What is the one disadvantage of giving Selegline with L DOPA?

Answer 33

Potentiates the central side effects of L DOPA

Question 34

Why is Selegline thought to have neuroprotective effects?

Answer 34

Anti oxidant and many neurons thought to be killed by oxidative stress

Question 35

What is the mechanism of action of COMT inhibitors?

Answer 35

Inhibit the enzyme catacol-o-methyl transferase which breaks down L DOPA and DA thus leading to increased levels of L DOPA and DA

Question 36

Name a drug which is a COMT inhibitor?

Answer 36

Entacapone

Question 37

What are the main advantages if COMT inhibitors, when are they useful?

Answer 37

Used as an adjunct to L DOPA/Carbidopa therapy | Used in patients with on-off problems

Question 38

What are the 5 main adverse effects of COMT inhibitors?

Answer 38

1) Aggravate L DOPA dyskinesias 2) Nausea 3) Diarrhoea 4) Abdo pain 5) Dry mouth

Question 39

What is the mechanism of actions of Amantidine?

Answer 39

Increases DA release

Question 40

In which stage of Parkison's is Amantidine most useful?

Answer 40

Early stages

Question 41

What are the side effects of Amantidine, is it recommended?

Answer 41

Causes Confusion and hallucinations in the elderly - no longer recommended by NICE in the UK

Question 42

What is the mechanism of action of Bromocriptine and Pergolide?

Answer 42

Dopamine agonsits Bromocriptine - D1/D2 Pergolide - D2 selective

Question 43

Can Bromocriptine and Pergolide be used alone?

Answer 43

Can be given alone but often used with L DOPA

Question 44

Why do dopamine agonists need to be taken regularly?

Answer 44

Half life of about 6-8 hours Peak in 1-3 hours To maintain effect have to take regularly

Question 45

What are the 4 main adverse effects of Bromocriptine and Pergolide?

Answer 45

Similar to L DOPA: 1) Dyskinesias 2) Nausea, vomiting 3) Severe hypotensive effects 4) Hallucinations

Question 46

Name 2 anti-muscarinics, used in the treatment of Parkinson's disease?

Answer 46

1) Benzhexol | 2) Orphenadrine

Question 47

Anti muscarinics are most effective on which 2 symptoms of Parkinsons?

Answer 47

Tremor and drooling

Question 48

Because of the severe central adverse effects of antimuscarinics, in which group of patients are they only used?

Answer 48

Young patients with severe tremor

Question 49

What are the 5 severe central adverse effects of anti muscarinics (they don't really have any peripheral side effects)?

Answer 49

1) Confusion 2) Delusions 3) Hallucinations 4) Drowsiness 5) Mood changes

Question 50

What are the possible surgical techniques which could be used to treat Parkinsons, but aren't used routinely or at all in some cases?

Answer 50

1) Lesion removal 2) Implantable stimulators 3) Grafts

Question 51

What are the possible lesions in Parkinsons which may be removed by surgery?

Answer 51

1) Motor thalamus - thalamotomy 2) Globus pallidus - Pallidotomy 3) Subthalamus - subthalamotomy

Question 52

How do implantable stimulators work in the treatment of Parkinsons?

Answer 52

Stimulator placed into the sub thalamic nucleus to provide direct stimulation of the thalamus

Question 53

What 5 type of grafts may one day be used to treat Parkinsons?

Answer 53

1) Adrenal medulla (autologous) 2) Foetal nigral tissue 3) GM fibroblasts (genetically modified to produce DA) 4) Stem cells 5) Xenografts- from pigs

Question 54

What are the 2 main symptoms of Huntington's?

Answer 54

1) Chorea (jerky, involuntary movements) | 2) Dementia

Question 55

What age does Huntington's typically starts?

Answer 55

30-50 - juvenile onset most severe

Question 56

How many years between onset of symptoms and death in Huntingtons?

Answer 56

10-20

Question 57

How do the 2 sets of symptoms of Huntington's disease progress?

Answer 57

1) Irritability, moodiness and anti social behaviour progresses to full blow dementia 2) Fidgeting and restlessness progresses to gross choreiform movements

Question 58

What are the 2 investigations used to diagnose Hutingtons?

Answer 58

1) Genetic testing (polyglutamine repeats) | 2) CT/MRI shows cerebellar atrophy

Question 59

What does the CT/MRI of a HD patient show?

Answer 59

Cerebellar atrophy

Question 60

What is the pathology of Huntington's disease?

Answer 60

Selective cell loss in cerebral cortex and striatum | First affected are the medium-sized spiny neurones which contain GABA and encephalin

Question 61

What is the inheritance pattern of HD?

Answer 61

Autosomal dominant

Question 62

What is the genetic defect in HD?

Answer 62

Gene defect on short arm of Chr 4 Locus 4p16.3 codes for Huntingtin Gives rise to an expanded and repeated CAG repeat

Question 63

How do the levels of neurotransmitters, GABA, Ach, GAD, choline acetyltransferase and DA change?

Answer 63

``` GABA - decrease GAD - decrease ACh - decrease Choline acetyl transferase - decrease DA - increase or stay the same ```

Question 64

Is there a cure for HD?

Answer 64

No

Question 65

Can drugs to increase GABA or ACh activity be used in HD?

Answer 65

No, they don't work

Question 66

What 2 drug treatments can be used in HD?

Answer 66

1) D2 antagonists - haloperidol and chlorpromazine | 2) DA depletion - reserpine and tetrabenzine

Question 67

What are the 2 adverse affects of D2 antagonists used in HD?

Answer 67

1) Parkinsonism | 2) Restlessness

Question 68

What are the 4 adverse effects of DA depletion used in HD?

Answer 68

1) Hypotension 2) Depression 3) Sedation 4) GI disturbances

Question 69

What is a dystonia?

Answer 69

A neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures

Question 70

What are the 5 treatments for dystonias?

Answer 70

1) DOPA replacement 2) Anticholinergics 3) Benzodiazepines 4) Baclofen 5) Botulinum toxin