Neuro disorders

Question 1

idiopathic Parkinson’s disease - clinical and non motor features

Answer 1

tremor, lead pipe rigidity, bradykinesia, postural instability
mood changes, pain, cognitive change, urinary symptoms, sleep disorder, sweating

Question 2

what is the pathology of Parkinson’s?

Answer 2

neurodegeneration, Lewy bodies, loss of pigment, decreased dopamine

Question 3

what occurs in the basal ganglia circuit in Parkinson’s?

Answer 3

1) loss of dopaminergic neurones in SN results in decreased inhibition of neostriatum
2) loss of inhibition in NS allows increased ACh (excitatory)
3) chain of abnormal signalling causes impaired mobility

Question 4

describe the catecholamine synthesis pathway

Answer 4

L tyrosine —> LDOPA (via tyrosine hydroxylase) —> dopamine (via DOPA decarboxylase) —> norepinephrine —> epinephrine

Question 5

what are 2 enzymes involved in the degradation of dopamine?

Answer 5

monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)

Question 6

what does a DAT scan show?

Answer 6

looking at recycling of dopamine - labelled tracer

not diagnostic but can rule out other problems as normal in drug-induced issues and for tremor symptoms

Question 7

why is dopamine not used to treat parkinsons?

Answer 7

dopamine cannot cross BBB, LDOPA crosses blood brain barrier via active transport

Question 8

describe how LDOPA is taken up, the pharmacokinetics and dynamics

Answer 8

must be taken up by dopaminergic neurones in substantial migration to be converted to dopamine

• oral administration, absorbed by active transport in competition with amino acid, wary of high protein meals
• 90% inactivated in intestinal wall by MAO and DOPA decarboxylase
• T1/2 = 2 hours
• 9% converted to dopamine in peripheral tissues via DOPA decarboxylase
• <1% enters CNS as competes with amino acids for active transport across BBB

Question 9

describe the formulations of LDOPA

Answer 9

used in combination with a peripheral DOPA decarboxylase inhibitor: co-careldopa, co-beneldopa

Question 10

what are the advantages and disadvantaged of LDOPA?

Answer 10

adv - highly efficacious, low side effects of nausea/anorexia, hypotension, psychosis, tachycardia

disadv - precursor so needs enzyme conversion, long term = loss of efficacy, involuntary movements, motor complications

Question 11

what are some interactions of LDOPA

Answer 11

• pyridine (vit b6) increases peripheral breakdown of LDOPA
• MAOIs risk hypertensive crisis
• many antipsychotic drugs block dopamine receptors and Parkinsonism is a side effect

Question 12

dopamine receptor agonists - ergot derived and non ergo, patch and subcutaneous names

Answer 12

ergot - bromocryptin, pergolide, cabergoline
non ergot - ropinrole, pramipexole
patch - rotigotine
subcutaneous - apomorphine

Question 13

what are the advantages and disadvantages of dopamine receptor agonists?

Answer 13

adv - direct acting, less dyskinesia/motor complications, possible neuroprotection
disadv - less efficacy than LDOPA, impulse control disorders , more psychiatric side effects which are dose limiting and it is expensive

Question 14

describe impulse control disorders

Answer 14

dopamine dysregulation syndrome

- pathological gambling, hyper sexuality, compulsive shopping, desire to increase dosage, punding

Question 15

what are the side effects of dopamine receptor agonists?

Answer 15

sedation, hallucinations, confusion, nausea, hypotension

Question 16

monoamine oxidase B inhibitors - what does monoamine oxidase B do, names

Answer 16

metabolises dopamine, predominates in dopamine-containing regions of the brain so these drugs enhance dopamine

selegiline, rasagaline

Question 17

COMT inhibitors - names, actions, can it be used alone?

Answer 17

entapacone - doesn’t cross BBB
tolcapone - crosses BBB but mainly effects peripheral

reduces peripheral breakdown of LDOPA to 3-O-methyldopa (3-O-methyldopa competes with LDOPA for active transport into CNS)

no therapeutic effect bone, can use in combination with LDOPA and peripheral decarboxylase inhibitor (stalevo)

have LDOPA sparing effect
prolongs motor response to LDOPA

Question 18

anticholinergics - names, advantages and disadvantages

Answer 18

trihexyphenidydyl, orphenadrine, procyclidine
adv - treats tremor, not acting via dopamine systems
disadv - no effect on bradykinesia, side effects include confusion, drowsiness, usually anticholinergic s/e

Question 19

amantadine - possible mechanism, is it useful in PD?

Answer 19

uncertain, possibly enhanced dopamine release, or anticholinergic NMDA inhibition

it is poorly effective, has few side effects, little effect on tremor

Question 20

in myasthenia gravis, what is the pathophysiology at the synapse?

Answer 20

ACh has difficulty binding due to IgG blockage of the binding site so ACh cholinesterase begins to break it down

Question 21

what are the clinical signs of myasthenia gravis?

Answer 21

fluctuating, fatiguable, weakness in skeletal muscle

• extraocular muscles commonest presentation
• bulbar involvement cause dysphagia, dysphonia, dysarthria
• limb weakness is proximal symmetric
• respiratory muscle involvement

Question 22

what are 5 therapeutic interventions used to treat MG?

Answer 22

acetylcholinesterase inhibitors, corticosteroids, steroid sparing (azothioprine), IV immunoglobulin, plasmapharesis

Question 23

acetylcholinesterase inhibitors - names, mechanism, side effects

Answer 23

pyridostigmine, neostigmine (quicker action, significant cholinergic side effects)

• prevents breakdown of ACh in NMJ so ACh more likely to engage with remaining receptors, side effects = SSLUDGE: salivation, sweating, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis (and miosis)