Neurology Clinical Pharmacology

Question 1

What is idiopathic parkinson’s disease?

Answer 1

neudegenerative disorder

Progressive clinical course

Motor symptoms improve with levodopa

Non-motor symtoms

Question 2

What are the clinical features of Parkinsonism?

Answer 2

Tremor - low frequency, pill rolling tremor

Rigidity - lead pipe rigidity

Bradykinesia

Postural instability

Question 3

What are the non motor manifestations of parkinson’s?

Answer 3

Mood changes
Pain - starts asymmetrical
Cognitive change
Urinary change
Urinary symptoms 
Sleep disorder - REM sleep behaviour disorder
Sweating

Question 4

What is the prognosis of PD after 15 years?

Answer 4

94% dyskinesia
81% falls
84% cognitive decline - 50% hallucinations
80% somnolence
50% swallowing difficulty 
27% severe speech problems.

Question 5

How do you diagnose ID?

Answer 5

Clinical features
Exclude other causes of Parkinsonism
Response to Treatment
Structural neuroimaging is normal

Question 6

Describe the pathology of IPD?

Answer 6

Neurodegeneration

Lewy bodies - synucleinopathy

Loss of pigment - 50% loss before symptoms, increased turnover, upregulate receptors

Reduced dopamine

Question 7

What is a DAT scan?

Answer 7

Labelled tracer
Presynaptic uptake
Abnormal in PD
Not diagnostic
Tremor
Neuroleptic
Vascular

Question 8

Describe the synthesis of catecholamines

Answer 8

L-Tyrosine  (tyrosine hydroxylase)
L-DOPA (DOPA decarboxylase)
Dopamine (Dopamine B-Hydroxylase)
Noradrenaline (Phenylethanolamine n-methyltransferse)
Adrenaline

Question 9

Why do we use L-DOPA and not dopamine?

Answer 9

As Dopamine cannot cross BBB

Question 10

Describe the pharmacokinetics of levodopa

Answer 10

Oral administration

absorbed by AT - in competition with amino acids

90% inactivated in intestinal wall (monoamine oxidase and DOPA decarboxylase)

T1/2 = 2 hours so:
-Short dose internal (4x day)
fluctuations in blood levels and symptoms

9% converted to dopamine in peripheral tissues - DOPA decarboxylase

<1% enters CNS - competes with AA for AT across BBB.

Question 11

What are the formulations of L-DOPA?

Answer 11

Dopamine is used in combination with a peripheral DOPA decarboxylase inhibitor:

• Co-careldopa = Sinemet
• Co-beneldopa = Madopar

This reduces the dosing required
Reduces side effects
Increases L-DOPA reaching the brain

Tablets only - standard dosage of variable strengths.

Question 12

What are the advantages of L-DOPA?

Answer 12

Highly efficacious

Low side effects:
Nausea / anorexia - vomiting centres

Hypotension - central and peripheral

Psychosis - schizophrenia like effects - hallucinations / delusions / paranoia

Tachycardia

Question 13

What are the disadvantages of L-DOPA?

Answer 13

Precursor - needs enzyme conversion

Long term - loss of efficacy
Involuntary movements 
Motor complications:
On/Off
Wearing off - need before next dose
Dyskinesias
Dystonia
Freezing

Question 14

What are the interactions with L-DOPA?

Answer 14

B6 increases peripheral breakdown of L-DOPA

MAOIs risk hypertensive crisis

Many antipsychoticdrigs block dopamine receptors and parkinsonism is a side effect

Question 15

What are dopamine receptor agonists?

Answer 15

A do novo, add on therapy.

e.g. Ropinirole, pramipexole (tablet), apomorphine (subcut, only for patients with severe motor fluctuations)

Question 16

What are the advantages of DRAs?

Answer 16

Direct acting

Less dyskinesias / motor complications

Possible neuroprotection

Question 17

What are the disadvantages of DRAs?

Answer 17

Less efficacy than L-DOPA
Impulse control disorders
More psychiatric s/e dose limiting
Expensive

Question 18

What are impulse control disorders?

Answer 18

Pathological gambling
Hypersexuality
Compulsive shopping
Desire to increase dosage
Punding

Question 19

What are the side effects of dopamine receptor agonists?

Answer 19

Sedation
Hallocinations
Confusion
Nausea
Hypotension

Question 20

How does monoamine oxidase B work?

Answer 20

Metabolises dopamine
Predominates in dopamine containing regions in brain
MAOBi enhance dopamine.

Question 21

What are some examples of Monoamine oxidase B inhibitors?

Answer 21

Selegiline

Rasagaline

Question 22

Monoamine oxidase B inhibitors work?

Answer 22

Can be used alone or to prolong the action of L-DOPA.

Smooths out motor response
May be neuroprotective

Question 23

How do COMT inhibitors work?

Answer 23

It reduces the peripheral brakdown of L-DOPA to 2-O-Mythyldopa.

Only work with L-DOPA

Have an L-DOPA ‘sparing’ effect - it prolongs the motor response to L-DOPA and reduces the symptoms of ‘weaning off’

e.g. Entacapone - called ‘Stalevo’ when combined.

Question 24

Give examples of anticholinergics

Answer 24

Trihexyphenidydyl
Orphenadrine
Procyclidine

Question 25

What are the advantages of anticholinergics?

Answer 25

Treat tremor | Not acting via dopamine system

Question 26

What are the disadvantages of anticholinergics?

Answer 26

No effect on bradykinesia Side effects: - Confusion - Drowsiness - Usual anticholinergics/e

Question 27

What is amantadine?

Answer 27

Mechanism of action uncertain maybe enhanced dopamine release or anticholinergic NMDA inhibition. Poorly effective Few side effects Little effect on tremor

Question 28

What surgery can be used in Parkinsons?

Answer 28

Of value in highly selected cases - people who are dopamine responsive but have significant side effects with L-DOPA and o psychiatric illness. Controlled trials Lesion -thalamus for tremor and Globus Pallidus for dyskinesias Deep Brain Stimulation - Subthalamic Nucleus

Question 29

What is Myasthenia Gravis?

Answer 29

Myasthenia gravis is a chronic autoimmune disease that affects neuromuscular signalling. ACh is prevented from binding due to IgG at the receptor and so ACh is broken down by cholinesterase’s Fluctuating fatiguability, weakness skeletal muscle Extraocular muscles - commonest presentation Bulbar involvement - dysphagia, dysphonia, dysarthria Limb weakness - proximal symmetric Respiratory muscle involvement

Question 30

What drugs exacerbate Myasthenia Gravis?

Answer 30

Drugs affecting neuromuscular transmission exacerbate Myasthenia Gravis. ``` Aminoglycosides Beta-blockers, CCBs, quinidine, procainamide Chloroquinine, penicillamine Succinylcholine Magnesium ACE inhibitors ... lots more too! ```

Question 31

What can cause a crisis?

Answer 31

Acute exacerbation - Myasthenia crisis Over-treatment - cholinergic crisis Look exactly the same. Treat by supporting respiration and swelling immediately.

Question 32

What drugs can be used to manage MG?

Answer 32

Acetylcholinesterase inhibitors Corticosteroids - decrease immune response Steroidsparing - Aathioprine IV immunoglobulin Plasmapheresis - removed AChR antibodies and short-term improvement.

Question 33

What do acetylcholinesterase inhibitors do?

Answer 33

Enhance neuromuscular trasnmission Skeletal and smooth muscle Excess dose can cause depolarising block - cholinergic crisis Muscarinic side effects

Question 34

What is Pyridostigmine?

Answer 34

An anticholinergic. It is taken orally. Prevents breakdown of ACh in NMJ which makes ACh more likely to engage with remaining receptors. Onset: 30mins, Peak: 60-120mins, Duration: 3-6hours. Dose interval and timing is crucial.

Question 35

What are the side effects of pyridostigmine?

Answer 35

``` Miosis and the SSLUDGE syndrome: Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset Emesis ```

Question 36

What is neostigmine?

Answer 36

An anticholinergic Oral and IV preparations. Quicker action, duration up to 4 hours. BUT, significant antimuscarinic side effects.