21. Drugs used in Neurological Disorders

Question 1

What are the clinical features of Parkinsonism?

Answer 1

Tremor, rigidity, bradykinesia, postural instability.

Question 2

What are the non motor manifestations of Parkinson’s disease?

Answer 2

Mood changes, pain, cognitive changes, urinary symptoms, sleep disorder, sweating.

Question 3

What is the prognosis in Parkinson’s disease after 15 years concerning dyskinesia, falls, cognitive decline, somnolence, swallowing difficulty, severe speech?

Answer 3

Dyskinesia in 94%, falls in 81%, cognitive decline in 84%, somnolence in 80%, swallowing difficulty in 50%, severe speech problems in 27%.

Question 4

How is idiopathic Parkinson’s disease diagnosed?

Answer 4

Clinical features, exclude other causes, response to treatment, structural neuro imaging is normal, functional neuro imaging.

Question 5

What are the pathological features of IPD?

Answer 5

Neurodegeneration of pigmented cells in substantia nigra, Lewy bodies, loss of pigment, reduced dopamine.

Question 6

How does loss of dopaminergic neurons in the substantia nigra affect the basal ganglia circuit?

Answer 6

Reduces inhibition in neostriatum, loss of this inhibition allow increased production of ACh, this abnormal signalling leads to impaired mobility.

Question 7

How is dopamine formed from L-tyrosine?

Answer 7

L-tyrosie -> L-DOPA (tyrosine hydroxylase) -> dopamine (DOPA decarboxylase).

Question 8

How is epinephrine formed from L-tyrosine?

Answer 8

L-tyrosine -> L-DOPA (tyrosine hydroxylase) -> dopamine (DOPA decarboxylase) -> noradrenaline (dopamine B-hydroxylase) -> epinephrine (phenylethanolamine n-methyltransferase).

Question 9

How is dopamine degradated?

Answer 9

To 3-methoxytyramine (catechol-O-methyl transferase) -> homovanillic acid (monoamine oxidase, aldehyde drydrogenase). Or to 3,4-dihydrophenyl-acetic acid (MAO or ADH) -> homovanillic acid (COMT).

Question 10

What is a DAT scan?

Answer 10

Dopamine transporter - labelled tracer to measure presynaptic uptake of dopamine.

Question 11

Why is L-DOPA used as treatment for IPD and not dopamine?

Answer 11

L-DOPA can cross the BBB, whereas dopamine can’t.

Question 12

What is the mechanism of L-DOPA?

Answer 12

Taken up by dopaminergic cells in the substantia nigra to be converted to dopamine.

Question 13

What are the pharmacokinetics of L-DOPA? (How much gets to cross BBB, half life).

Answer 13

<1% gets to CNS as 90% is inactivated in the intestinal wall and 9% is converted to dopamine in the peripheral tissues, half life is 2 hours.

Question 14

What is the associated problem with the short half life of L-DOPA?

Answer 14

Fluctuations in blood levels and symptoms so control is variable.

Question 15

What can be used alongside L-DOPA to reduce peripheral conversion to dopamine? What are the effects?

Answer 15

DOPA decarboxylast inhibitor - reduces the dose required, reduces side effects, increases L-DOPA reaching the brain.

Question 16

What are the advantages of L-DOPA use in treatment of IPD?

Answer 16

Highly efficacious, low side effects.

Question 17

What are the ADRs of L-DOPA?

Answer 17

Nausea/anorexia, hypotension, psychosis, tachycardia.

Question 18

What are the disadvantages of using L-DOPA in IPD therapy?

Answer 18

Long term loss of efficacy as only effective in presence of dopaminergic neurones. Motor complications as it’s on/off in terms of frequently wearing off.

Question 19

What are the DDIs of L-DOPA?

Answer 19

Pyridoxine increases peripheral breakdown of L-DOPA, MAOIs risk hypertensive crisis, antipsychotic drugs block dopamine receptors.

Question 20

What are the types of dopamine receptor agonists? Give an example of each.

Answer 20

Ergot derived - bromocryptine, pergolide, cabergoline. Non ergot - ropinirole, pramipexole. Patch - rotigotine. Subcutaneous - apomorphine.

Question 21

What are the advantages of dopamine receptor agonists in IPD therapy?

Answer 21

Direct acting, less dyskinesias/motor complications, possible neuroprotection.

Question 22

What are the disadvantages of dopamine receptor agonists in IPD therapy?

Answer 22

Less efficacious than L-DOPA, impulse control disorders, more psychiatric side effect, expensive.

Question 23

What are some examples of impulse control disorders?

Answer 23

Pathological gambling, hypersexuality, compulsive shopping, desire to increase dosage, punding (collecting).

Question 24

What are the ADRs of dopamine receptor agonists?

Answer 24

Sedation, hallucinations, confusion, nausea, hypotension.

Question 25

What is the mechanism of action of monoamine oxidase B inhibitors?

Answer 25

MAO metabolises dopamine so inhibitors of this enzyme enhance dopamine.

Question 26

Name an example of an MAOBi.

Answer 26

Selegiline, rasagaline.

Question 27

When can MAOBi be used?

Answer 27

Alone or to prolong action of L-DOPA, smooths out motor response and may be neuroprotective.

Question 28

What is the mechanism of action of catechol-O-methyl transferase inhibitors?

Answer 28

The reduce peripheral breakdown of L-DOPA to 3-O-methyldopa, L-DOPA sparing effect to prolong motor response to L-DOPA.

Question 29

Name an example of a COMT inhibitor?

Answer 29

Entacapone, tolcapone.

Question 30

Why are COMT inhibitors not used as monotherapy for IPD treatment?

Answer 30

No therapeutic effect alone, their only action is to prolong L-DOPA life so must be used with L-DOPA.

Question 31

What is the use of anticholinergic in IPD therapy?

Answer 31

They have antagonistic effects to dopamine so may help with reducing tremor.

Question 32

Give an example of an anticholinergic used in IPD therapy.

Answer 32

Trihexyphenidydyl, orphenadrine, procyclidine.

Question 33

What are the advantages to anticholinergic use in IPD therapy?

Answer 33

Treat tremor, don’t act via dopamine systems so have different ADRs.

Question 34

What are the disadvantages of anticholinergic use in IPD therapy?

Answer 34

No effect on bradykinesia, ADRs - confusion, drowsiness, other ACh side effects.

Question 35

What are the possible mechanisms of action of amantadine used in IPD therapy?

Answer 35

Enhanced dopamine release, ACH NMDA inhibition.

Question 36

Which cases of IPD may be susceptible to successful surgery?

Answer 36

Dopamine responsive, significant side effects with L-DOPA, no psychiatric illness.

Question 37

What are the distinguishing features of myasthenia gravis?

Answer 37

Fluctuating, fatiguable, weakness of skeletal muscle, seen most commonly in extraocular muscles.

Question 38

What are the complications of mysasthenia gravis?

Answer 38

Acute exacerbation (Myasthenic crisis) or overtreatment (cholinergic crisis).

Question 39

What is the mechanism of action of acetylcholinesterase inhibitors in myasthenia gravis therapy?

Answer 39

Enhance neuromuscular transmission so more control and power for skeletal and smooth muscle.

Question 40

Give an example of an acetylcholinesterase inhibitor and its route of administration.

Answer 40

Pyridostigine - oral. Neostigmine - oral or IV.

Question 41

What is the mechanism of action of pyridostigmine in the treatment of myasthenia gravis?

Answer 41

Prevents breakdown of ACh in NMJ so ACh is more likely to engage with the remaining receptors.

Question 42

When should pyridostigmine be administered in Myasthenia gravis therapy?

Answer 42

30 mins before a meal as its onset is from 30 mins.

Question 43

What are the ADRs of pyridostigmine?

Answer 43

Cholinergic side effects ‘SSLUDGE’ - salivation, sweating, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis.