L22 Neurological Dosorder Drugs

Question 1

Clinical motor features of Parkinsonism

Answer 1

Pill rolling intention tremor
Lead pipe rigidity 
Bradykinesia 
Postural instability 
Fenestrating gait

Question 2

Non motor features of Parkinsonism

Answer 2

Mood changes 
Pain 
Cognitive change 
Urinary symptoms
Sleep disorder
Sweating

Question 3

Diagnosis of idiopathic Parkinson’s disease

Answer 3

Exclude other causes e.g.

• drug induced
• vascular (affecting the basal ganglia)
• progressive supranuclear (affects substantia nigra)
• multiple system atrophy
• corticobasal atrophy

Response to treatment - Levodopa
Normal structural neuroimaging
Functional neuro imaging e.g. PET

Question 4

Pathology of IPD

Answer 4

Neurodegeneration
Lewy bodies
Loss of pigments in substantia nigra
Reduced dopamine

Question 5

Pathology in basal ganglia of IPD

Answer 5

1. Loss of dopaminergic neurones in substantia nigra
2. Therefore less inhibition in neostriatum
3. Therefore increased production of Ach (excitatory)
4. Chain of abnormal signalling leads to impaired mobility

Question 6

Catecholamine synthesis

Answer 6

1. L - tyrosine
2. L - DOPA
3. Dopamine via DOPA decarboxylase
4. Noradrenaline
5. Adrenaline

Question 7

Dopamine degradation

Answer 7

Via:
monoamine oxidases
aldehyde dehydrogenase
Catechol-o-methyl transferase COMT

To:
Homovanillic acid

Question 8

Neurotransmitter synthesis

Answer 8

Synthesis of neurotransmitters and formation of vesicles in the cell body

Question 9

DAT scan

Answer 9

Monitors the presynaptic reuptake of dopamine using a labelled tracer
Abnormal in PD but not diagnostic as abnormal in many conditions such as stroke

Question 10

Cog wheel rigidity

Answer 10

Intention tremor and lead pipe rigidity

Question 11

Levodopa

Answer 11

Can cross the blood brain barrier via active transport
Must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine therefore if less cells, decreased efficacy

Question 12

Pharmacokinetics of L-DOPA: administration, bioavailability and half life

Answer 12

Administration- oral
Bioavailability
- 90% inactivated in intestinal wall
- 9% converted to dopamine in peripheral tissues (given DOPA decarboxylase inhibitor)
- 1% enters CNS
Half life - 2 hours with short dose interval

Question 13

DOPA decarboxylase inhibitor benefits

Answer 13

9% of LDOPA converted to dopamine in peripheral tissues and 90% metabolised in gut therefore an inhibitor is given to prevent Huntington’s disease and less side effects

• reduced dose required
• increased LDOPA reaches brain

Question 14

DOPA decarboxylase inhibitor examples

Answer 14

Co-careldopa (sinemet)

Co- beneldopa (madopar)

Question 15

Advantages of LDOPA

Answer 15

Highly efficacious 
Low side effects such as :
- nausea and vomiting 
- hypotension 
- Psychosis 
- tachycardia

Question 16

Disadvantages of LDOPA

Answer 16

Needs enzyme for conversion to active form 
Long term - loss of efficacy 
Involuntary movements 
Motor complications 
- dystonia 
- dyskinesia 
- freezing 
- on/ off

Question 17

Interactions of LDOPA

Answer 17

Pyridoxine (vit B6) increases peripheral breakdown of LDOPA
Monoamine oxidases risk hypertensive crisis
Antipsychotic block dopamine receptors

Question 18

Why are ergot derived dopamine receptors agonists not used

Answer 18

Cause retroperitoneal and pericardial fibrosis

Question 19

Dopamine therapy delivery

Answer 19

Patch or subcutaneous

Question 20

When are dopamine receptors agonists used

Answer 20

De novo therapy
Add on therapy
Severe motor fluctuations- apomorphine

Question 21

Dopamine advantages

Answer 21

Direct acting
Less dyskinesia/ motor complications
Possible neuroprotection

Question 22

Disadvantages of dopamine receptors agonists

Answer 22

Less efficacious
Impulse control disorder
More psychiatric side effects
Expensive

Question 23

Impulse control disorder

Answer 23

Pathological gambling
Hypersexuality 
Compulsive shopping 
Desire to increase dosage 
Punding - collecting and rearranging random things

Question 24

Dopamine receptor agonist side effects

Answer 24

Sedation 
Hallucinations 
Confusion 
Nausea 
Hypotension

Question 25

Monoamine oxidases B inhibitors mechanism

Answer 25

Inhibits the metabolisation of dopamine Stand alone therapy or prolongs the action of LDOPA - add on therapy Smooths our motor response

Question 26

Examples of MAO inhibitors

Answer 26

Selegiline | Rasagaline

Question 27

COMT inhibitors mechanism

Answer 27

Add on therapy given with LDOPA or MAOB as no therapeutic effect alone Reduces the peripheral breakdown of LDOPA - LDOPA sparring Reduces wear off symptoms of LDOPA

Question 28

Anticholinergic mechanisms

Answer 28

Ach May antagonise dopamine therefore reduces antagonism | Minor role in relieving tremor

Question 29

Advantages of acetylcholine

Answer 29

Treats tremor | Not acting via dopamine pathway

Question 30

Disadvantages of anticholinergics

Answer 30

``` No effect on bradykinesia Side effects: - confusion - drowsiness - anticholinergic side effects like urinary retention ```

Question 31

Amantadine mechanism

Answer 31

``` Enhances dopamine release Inhibits anticholinergic NMDA Low efficacy Few side effects Little effect on tremor ```

Question 32

Surgery

Answer 32

Done when there is: - significant side effects to LDOPA or unresponsive - no psychiatric illness - last line

Question 33

Myasthenia gravis

Answer 33

Antibody mediated blockade of Ach at postsynaptic Ach receptors Type II hypersensitivity reaction

Question 34

Symptoms of myasthenia gravis

Answer 34

``` Fluctuating Fatigue when eating Weakness of skeletal muscles - complete ptosis - bulbar involvement - dysphagia, dysphonia, dysarthria - limb weakness - respiratory muscle involvement ```

Question 35

Drugs that exacerbate myasthenia gravis

Answer 35

``` Aminoglycosides Beta blockers, CCBs Chloroquine Magnesium ACE inhibitors ```

Question 36

Myasthenia crisis

Answer 36

Acute exacerbation

Question 37

Over treatment

Answer 37

Cholinergic crisis - SSLUDGE - respiratory distress - dysphagia and drooling

Question 38

Management of myasthenia gravis

Answer 38

Acetylcholinesterase inhibitors

Question 39

Acetylcholinesterase inhibitor examples

Answer 39

``` Pyridostigmine - oral Neostigmine - oral and IV - quicker - more side effects ```

Question 40

SSLUDGE

Answer 40

``` Sweating Salivation Lacrimation Urinary incontinence Diarrhoea GI upset Emesis ```