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MBChB - Y2 - Systems - Nervous System > Applied Neuro-Pharmacology > Flashcards

Applied Neuro-Pharmacology Flashcards

1
Q

What are the stages of events of synaptic transmission?

A
  1. Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
  2. Na+ action potential invades terminal
  3. Activates voltage gated Ca2+-channels
  4. Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
  5. Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
  6. Presynaptic autoreceptors inhibit further transmitter release
  7. Transmitter is (usually) inactivated by uptake into glia or neurones
  8. Or transmitter is (unusually) inactivated by extracellular breakdown
  9. Transmitter is metabolised within cells
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2
Q

How can we reduce synaptic transmission?

A

Block the voltage gated Na+ channels – eg local anaesthetics, would block all action potentials, not too useful.

Block the voltage gated Ca2+ channels – eg those clever spider toxins, would block all transmitter release, not too useful.

Block the release machinery, eg botox, would block all transmitter release, not too useful.

Block the postsynaptic receptors, eg receptor antagonists, competitive or non-competitive. Selectivity helps. Lots of examples of that.

Activate those presynaptic inhibitory receptors.

Increase breakdown of transmitter (though I can’t think of an example of that).

Increase uptake of transmitter (though I can’t think of an example of that).

Inhibit synthesis and packaging of transmitter.

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3
Q

What are the ways we can increase synaptic transmission?

A

You could:

Increase synthesis by flooding the cells with the appropriate precursors.

Use an agonist to activate the postsynaptic receptors - though that is not so useful because they get activated all the time – most of which is inappropriate.

Better to use an allosteric drug that does activate the receptor on its own, but potentiates the effects of the endogenous transmitter, eg benzodiazepines and barbiturates on GABA receptors.

Block break down of transmitter – eg anticholinesterases on Ach.

Or block the uptake of transmitter.

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4
Q

Give examples of neurotransmitters

A
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5
Q

Why are drugs described as being dirty?

A

Single neurotransmitter has multiple functions in different regions

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6
Q

What are the features of neurotransmitters?

A

They each have their own:

Anatomical distribution

Range of receptors is acts on

Range of functions in different regions (some separated by the blood brain barrier)

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7
Q

Where is the anatomical distribution in the brain of dopamine?

A

Brainstem

Basal ganglia

Limbic system and frontal cortex

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8
Q

What physiological functions are affected by dopamine?

A

Vomitting

Voluntary movement

Emotions/reward

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9
Q

What is the root cause of parkinsons disease?

A

Degeneration of dopamine cells in the substantia nigra and dopamine deficiency in the basal ganglia

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10
Q

What are the stages of dopamine synthesis?

A
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11
Q

What stage of dopamine synthesis is pharmacologically blocked and what stage of dopamine synthesis os blocked through degeneration?

A

Pharmacologically - DOPA - dopamine

Degeneration - Tyrosine - DOPA

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12
Q

Can dopamine evoke a fast EPSP or IPSP?

A

N because there are no ionotropic receptors for dopamine

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13
Q

Describe dopamine receptors

A

5 subtypes of metabotropic receptors

(G - protein coupled)

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14
Q

Why does dopamine have multiple effects on the brain?

A

Dopamine can produce many effects and different effects on different parts of the brain depending on which receptors are expressed

(•So, in theory at least, a selective agonist or antagonist could produce a specific therapeutically useful effect)

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15
Q

What are the key enzymes of dopamine metabollic breakdown?

A

MAO-B and COMT

The end breakdown product of dopamine is homovanillic acid

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16
Q

What are the features of parkinsons disease

A

Stiffness

Slow movements

Change in posture

Tremor

17
Q

Which drugs improve the symptoms of PD?

A

DA precursors

DA agonists

18
Q

Guve examples of DA precursor

A

Levadopa

19
Q

Give examples of DA agonists

A

–Ergots:

  • Bromocriptine, pergolide, cabergoline
  • No longer used: 5-HT(2B) stimulation → fibrosis

–Non-ergots

•ropinirole, pramipexole, rotigotine

–Apomorphine

20
Q

What are the relevant enzyme inhibitors to improve the symptoms of PD?

A

Peripheral AAAD inhibitors

MAOB inhibitors

COMT inhibitors

21
Q

Give examples of AAAD inhibitors

A

Carbidopa

Benserazide

22
Q

Give examples of MAOB inhibitors

A

Selegiline

Rasagiline

Safinamide

23
Q

What are examples of COMT inhibitors?

A

Entacapone

Tolcapone

24
Q

What are the effects of peripheral AAAD inhibitors?

A

↓ peripheral side-effects of levodopa and allows a greater

proportion of the oral dose to reach the CNS

25
Q

What is the effect of MAOB inhibitors and COMT inhibitors?

A

↓ metabolism of dopamine and so ­increases effectiveness of levodopa.

26
Q

Do enzyme inhibitors have any effect on synthetic dopamine agonists?

A

NO

27
Q

What do dopaminergic drugs improve?

A

Motor features of parkinsons (e.g limb rigidity and bradykinesia, tremor)

28
Q

What do dopaminergic drugs worsen or cause?

A
  • Nausea
  • Vomiting
  • Psychosis
  • Impulsivity / abnormal behaviours
29
Q

What do dopaminergic drugs fail to help?

A

Midline features

eg, dysarthia, balance and cognition

30
Q

What dopamine atagonists improve?

A

Nausea

Vomiting

Psychosis

31
Q

What do dopamine antagonists worsen?

A

Parkinsons

32
Q

Give an example of a DA antagnoist that could be used on a patient with vomiting, nausea, without worsening or causing PD

A

Area postrema (vomitting centre) in the medulla is functionally outside the BBB, so if there was a DA antagonist that didn’t cross the BBB that would be fine

DOPERIDONE

33
Q

Give features of doperidone

A
  • DA antagonist
  • Anti-emetic
  • Does not cross the BBB
  • No antipsychotic properties
  • Relatively safe to use in PD
34
Q

What is the effect of apomorphine with domperidone?

A

Domperidone has permitted the therapeutic use of apomorphine which is a poweerful emitic

35
Q

What are dyskinesias

A

Abnormality or impairment of involuntary movements

36
Q

What dyskinesia is associated with dopaminergic drugs?

A

–May cause dyskinesias (eg chorea)

“too much movement”

37
Q

What type of movement is associated with DA antagonists?

A

•DA antagonists

–May cause parkinsonism

“not enough movement”

38
Q

What is the result of long - term dopamine agonist use?

A

•Often cause parkinsonism

–e.g. receptor blockade in basal ganglia

•Sometimes cause dyskinesias

–Tardive dyskinesias (orofaciolingual) (a neurological disorder characterized by involuntary movements of the face and jaw.)

•Hard to explain: upregulation or increased sensitivity of certain DA receptors

39
Q

Examples of other neurotransmitters

A

MBChB - Y2 - Systems - Nervous System (48 decks)

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